Chapter 1
The Road from Nanomedicine to Precision MedicineEdited by Shaker A. Mousa, Raj Bawa, and Gerald F. AudetteCopyright © 2020 Raj BawaISBN 978-981-4800-59-4 (Hardcover), 978-0-429-29501-0 (eBook) www.jennystanford.com
Drug Delivery at the Nanoscale: A Guide for Scientists, Physicians and Lawyers
Copyright © 2020 Raj Bawa. All rights reserved. As a service to authors and researchers, the copyright holder permits unrestricted use, distribution, online posting and reproduction of this article or unaltered excerpts therefrom, in any medium, provided the author and original source are clearly identified and properly credited. The figures and tables in this chapter that are copyrighted to the author may similarly be used, distributed, or reproduced in any medium, provided the author and the original source are clearly identified and properly credited. A copy of the publication or posting must be provided via email to the copyright holder for archival.
Raj Bawa, MS, PhD
Patent Law Department, Bawa Biotech LLC, Ashburn, Virginia, USAThe Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, New York, USAGuanine Inc., Rensselaer, New York, USA
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Keywords: nanotechnology, nanoscience, nanomedicine, nanotech, nanopharmaceutical, nanodrug, nanomaterial, modern nanotechnology, commercialization, technology transfer, research and development (R&D), over-the-counter (OTC), US Food and Drug Administration (FDA), European Medicines Agency (EMA), National Science Foundation (NSF), nomenclature, regulatory definition, drug delivery, engineered nanotherapeutics, site-specific delivery, theranostics, theranostic drug delivery, nanopotential, nanoscale, nanometer (nm), nanocharacter, nanodimensions, specific surface area (SSA), controlled manipulation, nanoparticles (NPs), Theranos, nanoscale titanium dioxide, silver nanoparticles, Doxil®, Abbreviated New Drug Application (ANDA), scanning tunneling microscope (STM), transmission electron microscope (TEM), atomic force microscope (AFM), molecular nanotechnology (MNT), International Organization for Standardization (ISO), personalized medicine, precision medicine, genomic medicine, National Nanotechnology Initiative (NNI), efficacy, bioavailability, toxicity, combination products, new molecular entities (NMEs), New Drug Applications (NDAs), new biological entities (NBEs), Biologics License Applications (BLAs), Federal Food, Drug, and Cosmetic Act (FD&C Act), Public Health Service (PHS) Act, drug, biologic, device, Bayh–Dole Act of 1980, Hatch–Waxman Act of 1984, biosimilars, Biologics Price Competition and Innovation Act of 2009 (BPCI Act or Biosimilar’s Act), Humulin®, monoclonal antibody (mAb), multivalence, NanoCrystal® technology, nanoscale drug delivery systems (NDDS), drug delivery system (DDS), bioperformance, polyethylene glycol (PEG), Generally Recognized As Safe (GRAS), therapeutic monoclonal antibodies (TMAbs), active pharmaceutical ingredient (API), antibody–drug conjugates (ADCs), the “Magic Bullet” Concept, targeting ligands, liposomes, enhanced permeability and retention (EPR), AmBisome®, Abraxane®, Copaxone®, nonbiologic complex drug (NBCD), nanosimilars, US Government Accountability Office (GAO), Lipodox®, clinical studies, institutional corruption, “draft” guidance documents, adverse drug reactions (ADRs), nano-combination products (NCPs), Intellectual property (IP), US Patent and Trademark Office (PTO), patents, patent proliferation, product-line-extension, patent agent, patent attorney, patent examiner, Freedom-to-Operate (FTO), nanopatent land grabs, patent thickets, carbon nanotube (CNT), translational medicine (TM), bench-to-bedside, C activation-related pseudoallergy (CARPA), adsorption, distribution, metabolism, and excretion (ADME), Biopharmaceutical Classification Scheme (BCS), Technology Transfer Offices (TTOs), licensing, irreproducibility of preclinical research, Good Clinical Practice (GCP), Good Manufacturing Practice (GMP), Good Laboratory Practice (GLP), physiologically based pharmacokinetic (PBPK) modeling, pharmacokinetics (PK), physicochemical characterization (PCC), institutional review board (IRB), pharmacodynamic (PD) modeling, artificial intelligence (AI), nano-characterization
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1.1 Nano Frontiers: An Introduction
Small is beautiful.—Leopold Kohr (1909–1994), Austrian economist
It has long been an axiom of mine that the little things are infinitely the most important.
—Arthur Coyle Doyle (1859–1930), English author and physician
Great things are done by a series of small things brought together. —Vincent Van Gogh (1853–1890), Dutch painter
The air is thick with news of nano-breakthroughs. Although “nano” (or nanotech or nanotechnology) is a hot topic for discussion in industry, pharma, patent offices, and regulatory agencies, the average citizen knows very little about what constitutes a nanoproduct, a nanomaterial or a nanodrug. Still, there is no shortage of excitement and hype when it comes to anything nano.1 Optimists tout nano as an enabling technology, a sort of next industrial revolution that could enhance the wealth and health of nations. They promise that in many areas within nanomedicine2 (nanoscale drug delivery systems, theranostics, etc.) will soon be a healthcare game-changer by offering patients access to precision medicine. Pessimists, on the other hand, take a more cautionary position, preaching instead a go-slow approach and warning about the lack of enough scientific information on health risks, general failure on the part of regulatory agencies to formulate clearer guidelines and continuous issuance of patents of dubious scope. They highlight that nano is burdened with inflated expectations with few marketed products. The reality may be somewhere between such extremes. Like any emerging technology, the whole picture is yet to emerge...and we are just
1Popular culture has referenced nano with mentions in movies (The Hulk), books (Michael Crichton’s Prey), video games (Metal Gear Solid series), and on TV (most notably in various incarnations of Star Trek). Even Prince Charles of England has weighed in on the topic.2There is no standard definition for nanomedicine. I define it as the science and technology of diagnosing, treating and preventing disease and improving human health via nanoscale tools, devices, interventions, and procedures.
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getting started! Whatever your stance, nano has already permeated virtually every sector of the global economy, with potential applications consistently inching their way into the marketplace. But, is nano the driving force behind a new industrial revolution in the making or simply a repacking of old scientific ideas and terms? Dissecting hope from fact is often difficult.
Nano is the natural continuation of the miniaturization of materials and medical products that have been steadily arriving in the marketplace. It continues to evolve and play a pivotal role in various industry segments, spurring new directions in research, patents, commercialization, translation, and technology transfer. Although not a distinct field or disciple, it is an interdisciplinary area that draws from the interplay among numerous fields, including materials science, medicine, engineering, colloid science, supramolecular and physical chemistry, drug science, biophysics, and many more.
Nano’s potential benefits are frequently overstated or inferred to be very close to application when clear bottlenecks to commercial translation exist. In this regard, start-ups, academia, and industry exaggerate basic research and developments (R&D) as potentially revolutionary advances and claim these early-stage discoveries as confirmation of downstream novel products and applications to come. Such “fake medical news” does great disservice to all stakeholders. It not only pollutes the medical literature but also quashes public support for translational activities. This issue is quite serious and often emanates from eminent academic labs from distinguished universities or from established industry players (Box 1.1).
All of this is happening while hundreds of over-the-counter (OTC) products containing silver and other metallic nanoparticles, nanoscale titanium dioxide, carbon nanotubes, and carbon nanoparticles continue to stream into the marketplace without adequate safety testing, labeling or regulatory review. In fact, a large number of nanomaterials and nanoparticles have been synthesized over the last two decades that could be toxic, yet the Environmental Protection Agency (EPA) and the US Food and Drug Administration (FDA) do not seem to know how to regulate most of them [3]. Obviously, consumers should be cautious about potential exposure but industry workers should even be more concerned.
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Box 1.1 Nano: Dreams, Hype, Misinformation, and Reality
We live in a society exquisitely dependent on science and technology, in which hardly anyone knows anything about science and technology.
—Carl Sagan (1934–1996), American cosmologist
The rush to celebrate “eureka” moments in science is overshadowing the research enterprise. Some blame the current pervasive culture that focuses on rewarding eye-catching and positive findings. Others point to an increased emphasis on making provocative statements rather than presenting technical details or reporting basic elements of experimental design. “Fantastical claiming” is nothing new to academia and start-ups where exaggerated basic research developments are often touted as revolutionary and translatable advances. Claims of early-stage discoveries are highlighted as confirmation of downstream novel products and applications to come. Even distinguished professors at reputable universities are guilty of such spin or interpretive bias. In this context, nano’s potential benefits are also often overstated or inferred to be very close to application when clear bottlenecks to commercial translation persist.Misrepresentation and distortion of research in the biomedical literature is a serious and prevalent issue [1]: “Publication in peer-reviewed journals is an essential step in the scientific process. However, publication is not simply the reporting of facts arising from a straightforward analysis thereof. Authors have broad latitude when writing their reports and may be tempted to consciously or unconsciously ‘spin’ their study findings. Spin has been defined as a specific intentional or unintentional reporting that fails to faithfully reflect the nature and range of findings and that could affect the impression the results produce in readers. [There are] various practices of spin from misreporting by ‘beautification’ of methods to misreporting by misinterpreting the results.”Health misinformation is another negative trend [2]: “There is growing recognition that numerous social, economic, and
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academic pressures can have a negative impact on representations of biomedical research. Empirical evidence indicates spin or interpretive bias is injected throughout the knowledge production process, including at the stage of grant writing, in the execution of the research, and in the production of the relevant manuscripts and institutional press releases. The popular press, marketing forces, and online media also play significant roles in misrepresenting biomedical research.”Sadly, many have fallen prey to exaggerated scientific expectations and hype, often throwing venture funds at start-ups without conducting proper due-diligence. An extreme example of this is the recent case of the blood-testing company, Theranos, that concocted fraudulent claims of doing hundreds of tests from a single drop of human blood and raised billions in the process (market valuation of $9 billion). The now-discredited company is dissolving and returning its remaining cash to its creditors. Among the company’s most well-known investors were Rupert Murdoch, Walmart’s Walton family, and the family of Betsy DeVos. See: Carreyrou, J. (2018). Bad Blood: Secrets and Lies in a Silicon Valley Startup. Alfred A. Knopf, New York. There are also a few cautionary tales from the world of nanomedicine. Consider, for example, the recent demise and bankruptcy of BIND Therapeutics Inc. See: WTF happened to BIND Therapeutics? Available at: https://www.nanalyze.com/2017/08/wtf-happened-bind-therapeutics/ (accessed on August 25, 2019).
For example, silver nanoparticles are effective antimicrobial agents, but their potential toxicity remains a major concern due to the wide range of consumer products incorporating them. Similarly, nanoscale titanium dioxide, previously present in powdered Dunkin’ Donuts® and Hostess Donettes®, was classified as a potential carcinogen by the National Institute for Occupational Safety and Health (NIOSH) while the World Health Organization (WHO) linked it in powder form to cancers.
Even so, governments across the globe continue to stake their claims by doling out billions for R&D. In fact, this trend in research funding has stayed relatively consistent, at least in
Box 1.1 (Continued)
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the industrialized world. Stakeholders, especially investors and consumer-patients, get nervous about the “known unknown” novel applications, uncertain health risks, unclear industry motives, and general lack of government transparency. Although venture has mostly shied away in recent years, industry-university alliances have continued to gel, driven primarily by what many refer to as “nanopotential” (Box 1.2). Wall Street’s early interest in nano has been somewhat muted over the years, from cautionary involvement to generally shying away. Despite anemic nanoproduct development, there is no end in sight to publications, press releases, and patent filings.
Box 1.� Debunking Nanopotentials and Market Forecasts
Nano-developments are often driven by what some of us refer to as “nanopotential.” This is obviously true more for certain sectors of nanotech than others. In this regard, one of the most widely cited predictions was in 2001 when a National Science Foundation (NSF) report was released that forecasted the creation of a trillion-dollar industry for nanotech by 2015. This report, now proven false, was often quoted in articles, business plans, conference presentations, and grant applications. See: National Science Foundation (2001). Societal implications of nanoscience and nanotechnology. Available at: http://www.wtec.org/loyola/nano/NSET.Societal.Implications/nanosi.pdf (accessed on August 25, 2019). Given such flawed projections, Michael Berger of Nanowerk accurately pointed out: “These trillion dollar forecasts for an artificially constructed ‘market’ are an irritating, sensationalist and unfortunate way of saying that sooner or later nanotechnologies will have a deeply transformative impact on more or less all aspects of our lives.” See: Nanowerk Spotlight. (2007). Debunking the trillion dollar nanotechnology market size hype. Available at: http://www.nanowerk.com/spotlight/spotid=1792.php (accessed on August 25, 2019). There are also various technical reports highlighting the potential market for nanotech. Again, one must take all such predictions with caution and not draw too many conclusions therefrom as they may be flawed (“A good decision is based on knowledge and not on numbers.”—Plato, Laches or Courage, 380 B.C.).
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Revolutionary nanotech breakthroughs are just promises at this stage. Still, based on my definition of nano (Section 1.3(d)), there are thousands of nano-related products in the marketplace. While the widespread use of nanomaterials and nanoparticles in consumer products over the years has become pervasive and exposure inescapable, the last 25 years saw limited applications of these rather than the transformative applications envisioned by self-anointed industry experts, by politicians, and by university researchers. Instead, the current decade has witnessed relatively more advances and product development in nanomedicine. In this context, many point to the influence of nanomedicine on the pharmaceutical, device, and biotechnology industries. One can now unequivocally state that R&D is in full swing, and novel nanomedical products, especially in the drug delivery sector, are starting to arrive in the marketplace. Meanwhile, in the background, patent filings, and patent grants continue unabated. In fact, since the early 1980s, “patent prospectors” have been on a global quest for “nanopatent land grabs.” Universities and small businesses have also jumped into the fray with industry with the clear intention of patenting as much nano as they can grab. Often in the rush to patent anything and everything nano, nanopatents of dubious scope and validity are issued by patent offices.
Whether nanomedicine eventually blossoms into a robust industry, or it continues to influence medicine and healthcare, one thing is certain: The die is cast, and it is here to stay. In the meantime, tempered expectations are in order, for giant technological leaps can often leave giant scientific, ethical, legal, and regulatory gaps in their midst. Moreover, extraordinary claims and paradigm shifting advances necessitate extraordinary proof and verification.
Given this backdrop, it is also important to indicate that nano is nothing new and has been around for centuries (Box 1.3). For example, various nano terms related to pharma are a repackaging of old terms, ideas, and technologies (Box 1.4).
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Box 1.� Historical Origins of Nanotechnology
Nanotechnology is nothing new; it has been around for hundreds, possibly thousands, of years. The earliest evidence of nano can be traced back to carbon nanotubes, cementite nanowires found in the microstructure of wootz steel manufactured in ancient India around 600 BC and exported globally. Damascus sword blades, encountered by Crusaders in the 5th century, have now been shown to sometimes contain nanowires and carbon nanotubes. Another early example of nanomaterials in products dates to the 4th century (Roman times) in stained glass where gold nanoparticles were incorporated therein to exhibit a range of colors. Artisans in 9th century Mesopotamia created glittering effects on the surface of pots via nanoparticles. The most prominent example of this is the Lycurgus Cup on display at the British Museum. This cup, depicting King Lycurgus being dragged into the underworld by Ambrosia, contains a decorative pigment that is a suspension of gold and silver nanoparticles of about 70 nm whereby reflected light appears green but transmitted light appears red. Later, in the 7th century, a colloidal suspension of tin oxide and gold nanoparticles (Purple of Cassius) was used to color glass. Another early example of technology far outpacing science is in the 9th century when Arab potters used nanoparticles in their glazes so that objects would change color depending on the viewing angle (the so- called “polychrome lustre”). Nanoscale carbon black particles (“high-tech soot nanoparticles”) have been in use as reinforcing additives in tires for over a century. The accidental discovery of precipitation hardening in 1906 by Wilm in Duralumin alloys is considered a landmark development for metallurgists; this is now attributed to nanometer-sized precipitates. Modern nanotechnology may be considered to start in the 1930s when chemists generated silver coatings for photographic film. In 1947, Bell Labs discovered that the semiconductor transistor had components that operated on the nanoscale.
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Box 1.� Nanodrugs: Relabeling of Earlier Terms?
“The new concept of nanomedicine arose from merging nanoscience and nanotechnology with medicine. Pharmaceutical scientists quickly adopted nanoscience terminology, thus ‘creating’ ‘nanopharmaceuticals.’ Moreover, just using the term ‘nano’ intuitively implied state-of-the-art research and became very fashionable within the pharmaceutical science community. Colloidal systems reemerged as nanosystems. Colloidal gold, a traditional alchemical preparation, was turned into a suspension of gold nanoparticles, and colloidal drug-delivery systems became nanodrug delivery systems. The exploration of colloidal systems, i.e., systems containing nanometer sized components, for biomedical research was, however, launched already more than 50 years ago and efforts to explore colloidal (nano) particles for drug delivery date back about 40 years. For example, efforts to reduce the cardiotoxicity of anthracyclines via encapsulation into nanosized phospholipid vesicles (liposomes) began at the end of the 1970s. During the 1980s, three liposome-dedicated US start-up companies (Vestar in Pasadena, CA, USA, The Liposome Company in Princeton, NJ, USA, and Liposome Technology Inc., in Menlo Park, CA, USA) were competing with each other in developing three different liposomal anthracycline formulations. Liposome technology research culminated in 1995 in the US Food and Drug Administration (FDA) approval of Doxil®, ‘the first FDA-approved nanodrug.’ Notwithstanding, it should be noted that in the liposome literature the term ‘nano’ was essentially absent until the year 2000.”Source: [4].
1.� The Arrival of Modern Nanotechnology
There’s plenty of room at the bottom.
—Richard Feynman (1918–1988), American physicist and two-time Nobel laureate
Nature does things with molecular perfection. —Richard Smalley (1943–2005), American nanotechnologist
and Nobel laureate
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Copyright © 2020 Raj Bawa. All rights reserved.
The concept of “modern” nanotechnology, before the word itself, harks back to Nobel Laureate Dr. Richard Feynman, the charismatic physics professor from Caltech. Many, but not all,3 credit him with inspiring the development of nanotechnology through his provocative and prophetic lecture on December 29, 1959, at an American Physical Society meeting held at Caltech. At this talk [5], Dr. Feynman stated:
Now the name of the talk is ‘There’s Plenty of Room at the Bottom’—not just ‘There’s Room at the Bottom’....I will not discuss how we are going to do it, but only that it is possible in principle—in other words, what is possible according to the laws of physics. I am not inventing anti-gravity, which is possible someday only if the laws are not what we think. I am telling you what could be done if the laws are what we think; we are not doing it simply because we haven’t gotten around to it....I am not afraid to consider the final question as to whether, ultimately—in the great future—we can arrange atoms the way we want; the very atoms, all the way down!
3I question the traditional assumption that the nanotechnology pedigree descended from this often-referred-to lecture, given that nano is not a modern invention, discovery or science but has been around for a millennium. Many have questioned if Feynman’s talk is retroactively read into the history of nanotechnology. See: Toumey, C. (2008). Reading Feynman into nanotechnology: A text for a new science. Techné, 12 (3), 133–168.
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In this famous talk, he offered two challenges that were later realized.4 His talk also focused on the ability to manipulate individual atoms and molecules by discussing the storage of information on a very small scale; writing and reading in atoms; about miniaturization of the computer; and building tiny machines, factories, and electronic circuits with atoms. Dr. Feynman also suggested the idea to shrink computing devices down their physical limits (miniaturization of the computer), where “wires should be 10 or 100 atoms in diameter”; this was realized in 2009 by Samsung, which produced devices built with 30 nm technology. Additionally, he proposed that focused electron beams could write nanoscale features on a substrate (writing and reading in atoms); this was realized via e-beam lithography. He also envisioned superior microscopes, ideas that are now reflected in the form of the scanning tunneling microscope (STM), transmission electron microscope (TEM), atomic force microscope (AFM), and other examples of probe microscopy.
It appears that the term “nano” was first used in a biological context in 1908 by H. Lohmann to describe a small organism [6]. The concept of precision manufacturing of materials with nanometer tolerances at will from the very basic building blocks was christened “nanotechnology” in 1974 by Dr. Norio Taniguchi of Tokyo Science University. He coined the term via his seminal paper [7] titled “On the Basic Concept of Nano-Technology,” (with a hyphen) presented in Tokyo at the International Conference on Production Engineering. He stated: “In the processing of materials, the smallest bit size of stock removal, accretion or flow of materials is probably of one atom or one molecule, namely 0.1–0.2 nm in length. Therefore, the expected limit size of fineness would be of the order of 1 nm….‘Nano-technology’ mainly consists of the processing...separation, consolidation and deformation of materials by one atom or one molecule.”4He offered a prize of $1,000 to anyone to solve two challenges. The first challenge involved the construction of a tiny motor. This was achieved in 1960 by William McLellan, who constructed the first tiny electrical motor (less than 1/64th of an inch) using conventional tools. The second challenge involving fitting the entire Encyclopedia Britannica on the head of a pin by writing the information from a book page on a surface 1/25,000 smaller in linear scale. This was accomplished in 1985 by Tom Newman, who successfully reduced the first paragraph of A Tale of Two Cities by 1/25,000. See also, Hess, K. (2012). Room at the bottom, plenty of tyranny at the top. In: Goddard, W. A., et al., eds. Handbook of Nanoscience, Engineering, and Technology, 3rd ed., CRC Press, Boca Raton, Florida. chapter 2, pp. 13–20.
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In the 1980s, major breakthroughs propelled the growth of nano further. The invention of the scanning tunneling microscope (STM) in 1981 by Drs. Gerd Binnig and Heinrich Rohrer at IBM’s Zurich Research Laboratory provided visualization of atom clusters and bonds for the first time [8]. The discovery of fullerenes (C60) in 1985 by Drs. Harry Kroto, Richard Smalley, and Robert Curl was another major advance [9]. Both groups won the Nobel Prize.
The technological significance of nanoscale phenomena and devices was explored by Dr. K. Eric Drexler in the mid-1980s. He built upon Dr. Feynman’s concept of a billion tiny factories by theorizing that these factories could be replicated via computer-control instead of human-operator control and highlighted the potential of “molecular nanotechnology” (MNT). He popularized this idea in his 1986 book titled Engines of Creation: The Coming Era of Nanotechnology [10]. Although serious work should continue on MNT, I do not believe in its near-term feasibility because fabrication of efficient devices on a molecular/atomic scale that can conduct MNT currently do not exist.
In 1991, Drs. Donald M. Eigler and Erhard K. Schweizer of the IBM Almaden Research Center in San Jose, California, demonstrated the ability to manipulate atoms via the STM by forming the acronym “IBM” on a substrate of chilled crystal of nickel using 35 individual atoms of xenon. This technology demonstrated how the STM, which until then had been used to image surfaces or atoms/molecules on surfaces with atomic precision (nanoscale topography), could now be used to manipulate matter at the nanoscale. In my opinion, this concept of “controlled manipulation” is the foundation of nanotechnology, and as discussed ahead, a key component of my definition of the term (Section 1.3(d)).
1.� Drug Delivery in the Context of Nano: Terminology Matters
“What’s the use of their having names,” the Gnat said, “if they won’t answer to them?” “No use to them,” said Alice; “but it’s useful to the people that name them, I suppose. If not, why do things have names at all?” “I can’t say,” the Gnat replied.
(Through the Looking Glass and What Alice Found There, Chapter 3)—Lewis Carroll (1832–1898), English writer and mathematician
Drug Delivery in the Context of Nano: Terminology Matters
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(a) Need for Terms and Nomenclature: In the heady days of any emerging technology, definitions tend to abound and are only gradually documented in reports, journals, handbooks, and dictionaries. Ultimately, standard-setting organizations like the International Organization for Standardization (ISO) produce technical specifications. This evolution is essential as the development of terminology is a prerequisite for creating a common, valid language needed for effective communication in any field. Clearly, an internationally agreed nomenclature, technical specifications, standards, guidelines, and best practices are required to advance nano in a safe and responsible manner. Terminology matters because it prevents misinterpretation and confusion (Box 1.5). It is also necessary for research activities, harmonized regulatory governance, accurate patent searching and application drafting, standardization of procedures, manufacturing, quality controls, assay protocols, research grant reviews, policy decisions, ethical analysis, public discourse, safety assessment, translation, and commercialization.
Box 1.� Nano-Nomenclature: Yes, It’s Critical!
“The lack of a unified standard, or the existence of different standards, can have dire consequences. A few years ago, the Mars Climate Orbiter spacecraft was destroyed because a navigation error caused the spacecraft to fly too deep into the atmosphere of Mars. This error arose because a National Aeronautics and Space Administration (NASA) subcontractor used Imperial units (pound-seconds) instead of the metric units (newton-seconds) as specified by NASA. But even in the United States, economic and scientific needs assure the continued creeping adoption of the metric standard in various areas. Nanotechnology is such a case, were the metric system is the undisputed only standard—used even by US researchers—and sparing us conversion tables for nanometer to nanoinch and nanofoot, and nanoliter to nanogallon….Standards have a much larger role in our society than just agreeing measurements. As the British Standards Institution (BSI) explains it, put at its simplest, a standard is an agreed, repeatable way of doing something. It is a published document that contains a technical specification or other precise criteria designed to be used consistently as a rule, guideline, or
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definition. Standards help to make life simpler and to increase the reliability and the effectiveness of many goods and services we use….The need for standardization also exists in various fields of nanotechnology in order to support commercialization and market development, provide a basis for procurement, and support appropriate legislation/regulation. The lack of nanotechnology standards poses several major challenges because right now there are no internationally agreed terminology/definitions for nanotechnology, no internationally agreed protocols for toxicity testing of nanoparticles, no standardized protocols for evaluating environmental impact of nanoparticles, no standardized measurement techniques and instruments, no standardized calibration procedures and certified references materials....Standards create comparability and any standard is a collective work. Committees of manufacturers, users, research organizations, government departments and consumers work together to draw up standards that evolve to meet the demands of society and technology.”Source: [11].
“The definition of nanomedicine has implications for many aspects of translational research including fund allocation, patents, drug regulatory review processes and approvals, ethical review, clinical trials and public acceptance. Given the interdisciplinary nature of the field and common interest in developing effective clinical applications, it is important to have honest and transparent communication about nanomedicine, its benefits and potential harm. A clear and consistent definition of nanomedicine would significantly facilitate trust among various stakeholders while minimizing the risk of miscommunication and undue fears.”Source: [12].
(b) Why a Nano Nomenclature? Although various “nano” terms, including “nanotechnology,” “nanoscience,” “nanopharmaceutical,” “nanodrug,” “nanotherapeutic,” “nanomaterial,” “nanopharmacy,” and “nanomedicine” are widely used, there is ambiguity regarding their definitions. In fact, there is no precise definition of nano terms as applied to pharmaceuticals or in reference to drug delivery. This definitional issue, or lack thereof, continues to be one of the most vexing challenges for regulators, policymakers, researchers,
Drug Delivery in the Context of Nano: Terminology Matters
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and legal professionals to grapple with [13–19]. In particular, regulatory agencies and entities such as the FDA, the European Medicines Agency (EMA), EPA, the Centers for Disease Control and Prevention (CDC), NIOSH, World Intellectual Property Organization (WIPO), the US Patent and Trademark Office (PTO), ISO Technical Committee on Nanotechnology (ISO/TC229), American Society for Testing and Materials (ASTM) International, and the Organization for Economic Co-operation and Development (OECD) Working Party on Manufactured Nanomaterials continue to grapple with this critical issue.5
Clearly, the need for an internationally agreed definition for these key terms has gained urgency. Disagreements over terminology and nomenclature are nothing new and are also seen in other fields. For example, the term “super resolution microscopy,” the subject of the 2014 Nobel Prize, is considered an inaccurate description of the technique. Personalized medicine, precision medicine, genomic medicine, individualized medicine or monogrammed medicine are all phrases that strive to express a similar vision—a reality where physicians treat based on each patient’s unique biology [20]. For a long time, personalized medicine was the preferred terminology but about eight years ago the National Institutes of Health (NIH) recommended replacing it with precision medicine as it “is less likely to be misinterpreted as meaning that each patient will be treated differently from every other patient” [20].
In this chapter, the following terms are used interchangeably as they all pertain to a “drug or therapeutic”: nanomedicines, nanodrugs, nanotherapeutics, and nanopharmaceuticals. Similarly, these technology terms are used interchangeably: nano, nanotech, and nanotechnology.
So, what does the prefix “nano” refer to (Box 1.6)? Any term with this prefix is broad in scope. Consider the widely used terms, nanotechnology, nanomedicine, and nanopharmaceutical, all of which are a bit misleading since they do not refer to a single technology or entity. The terms nanotechnology and nanomedicine 5For example, see: Kica, E., Bowman, D. M. (2012). Regulation by means of standardization: Key legitimacy issues of health and safety nanotechnology standards. Jurimetrics Journal, 53, 11–56: “Despite the often-provocative nature of many of the nanotechnology-related initiatives and activities, the undertakings of the ISO/TC229 and the OECD WPMN have remained a quiet and uncontroversial affair….The work of TC229 and the WPMN to date is still embryonic in nature, with only limited outputs and impacts.”
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refer to interdisciplinary areas that draw from the interplay among numerous materials, products, and applications from several technical and scientific fields [13–19, 21–23]. In other words, nanotech is an umbrella term encompassing several technical/scientific fields, processes, and properties at the nano/micro scale. In a sense, it has brought various players with divergent scientific, medical and engineering backgrounds together to create a novel common language.
Box 1.� The Prefix “Nano”
The prefix “nano” in the SI measurement system denotes 10−9
or one-billionth. There is not even a consensus over whether the prefix “nano” is Greek or Latin. The term “nano” is often linked to the Greek word for “dwarf” but the ancient Greek word for “dwarf” is spelled “nanno” (with a double “n”), while the Latin word for dwarf is “nanus” (with a single “n”). A nanometer (nm) refers to one-billionth of a meter in size (10−9 m = 1 nm), a nanosecond refers to one billionth of a second (10−9 s = 1 ns), a nanoliter refers to one billionth of a liter (10−9 l = 1 nl) and a nanogram refers to one billionth of a gram (10−9 g = 1 ng).The diameter of an atom ranges from about 0.1 to 0.5 nm. Some other interesting comparisons: Fingernails grow around a nanometer/second; in the time it takes to pick a razor up and bring it to your face, the beard will have grown a nanometer; a single nanometer is how much the Himalayas rise in every 6.3 seconds; a sheet of newspaper is about 100,000 nanometers thick; it takes 20,000,000 nanoseconds (50 times per second) for a hummingbird to flap its wings once; a single drop of water is ~50,000 nanoliters; a grain of table salt weighs ~50,000 nanograms.
(c) Flawed National Nanotechnology Initiative (NNI) Definition: Due to the confusion over the definition of nano and a lack of any standard nomenclature, various inconsistent definitions have sprung up over the years [24]. For instance, nanotech has been inaccurately defined by the National Nanotechnology Initiative (NNI)6 since the 1990s as “the understanding and control of 6The NNI is the US government’s inter-agency program for coordinating, planning, and managing R&D in nanoscale science, engineering, technology, and related efforts across 25+ agencies and programs.
Drug Delivery in the Context of Nano: Terminology Matters
1� Drug Delivery at the Nanoscale
matter at the nanoscale, at dimensions between approximately 1 and 100 nanometers, where unique phenomena enable novel applications…” (this often-cited definition is flawed for various reasons as discussed ahead). Others label it as the manipulation, precision placement, measurement, modeling, or manufacture of matter in the sub-100 nm range. Some definitions increase the upper limit to 200 nm or 300 nm, or even 1,000 nm. Some definitions omit a lower range, others refer to sizes in one, two or three dimensions while others require a size plus special/unique property or vice versa [24]. None of these definitions is scientifically or legally plausible from a pharma perspective; they also exclude many applications with significant consequence to medicine. The NNI definition fails to appreciate the unique physiological or pharmacological behavior that can occur at the nanoscale. For instance, consider the case of gold and silver nanoparticles that naturally exhibit fundamentally different properties than at the macroscale. A definition like the one from the NNI based purely on size (or dimension) does not distinguish between (i) naturally occurring versus engineered nanoscale properties; or (ii) spherical nanoparticles versus the newer generation of nanoparticles having high aspect ratios. In fact, the ambiguousness of this definitional issue is apparent whenever the “nano” prefix is used [25]:
Nanofiltration is frequently associated with nanotechnology—obviously because of its name. However, the term “nano” in nanofiltration refers—according to the definition of the International Union of Pure and Applied Chemistry (IUPAC)—to the size of the particles rejected and not to a nanostructure as defined by the International Organisation of Standardisation (ISO) in the membrane. Evidently, the approach to standardisation of materials differs significantly between membrane technology and nanotechnology which leads to considerable confusion and inconsistent use of the terminology. There are membranes that can be unambiguously attributed to both membrane technology and nanotechnology such as those that are functionalized with nanoparticles, while the classification of hitherto considered to be conventional membranes as nanostructured material is questionable.
1�
Therefore, all definitions of nano based on size or dimensions should be dismissed. Specifically, those limiting nano to sub-100 nm has no scientific or legal basis, especially in the context of medicine, pharma or drug delivery. The arbitrary NNI definition of nano, although foolishly appearing in the 2019 literature and persisting on the NNI and other websites, has been correctly criticized over the years [26]:
The 100 nm size boundary used in these definitions, however, only loosely refers to the nano-scale around which the properties of materials are likely to change significantly from conventional equivalents. In reality, there is no clear size cut-off for this phenomenon, and the 100 nm boundary appears to have no solid scientific basis. A change in properties of particulate materials in relation to particle size is essentially a continuum, which although more likely to happen below 100 nm size range, does not preclude this happening for some materials at sizes above 100 nm….
(d) Defining Nano in the context of Drug Delivery: It is best not to blindly use any specific size range or dimension while discussing anything nano. I proposed a definition of nano in 2007 that is unconstrained by an arbitrary size limitation or dimensionality [27]:
The design, characterization, production, and application of structures, devices, and systems by controlled manipulation of size and shape at the nanometer scale (atomic, molecular, and macromolecular scale) that produces structures, devices, and systems with at least one novel/superior characteristic or property.
This flexible definition has four key features: (i) It recognizes that the “novel/superior” properties and performance of the synthetic, engineered “structures, devices, and systems” are inherently rooted in their nanoscale dimensions. The definition focuses on the unique physiological behavior of these “structures, devices, and systems” occurring at the nanoscale; it does not emphasize a specific shape, aspect ratio, size or dimension; (ii) it focuses on “technology” that has commercial potential, not “nanoscience” or
Drug Delivery in the Context of Nano: Terminology Matters
�0 Drug Delivery at the Nanoscale
“basic R&D” conducted in a laboratory; (iii) the “structures, devices, and systems” that result from or incorporate nano must be “novel/superior” compared to their bulk/conventional counterparts; and (iv) the concept of “controlled manipulation” is crucial.
If a size-limitation must be associated with or tagged onto the definition of nano while discussing nanotherapeutics or nanodrug delivery, the term may be loosely considered ranging in size from 1–1,000 nm (up to a micron, µ). Such labeling would make nanoparticle drug delivery systems consistent with wet science where colloidal solutions (in contrast to solutions or suspensions) contain particles that have at least one dimension ranging from 1–1,000 nm.7 In this regard, it is worth mentioning an important report from the UK House of Lords Science and Technology Committee that recommended that the term “nanoscale” should have an upper boundary of 1,000 nm (at least for the purpose of food regulations), contrary to the ISO and ASTM International determinations that mandate scientific usage be restricted to no greater than 100 nm [28, 29]:
We recommend...that any regulatory definition of nanomaterials...not include a size limit of 100 nm but instead refer to ‘the nanoscale’ to ensure that all materials with a dimension under 1000 nm are considered….
In fact, many experts propose definitions along these similar lines, especially in the context of nanodrugs or pharmaceutical applications:
7A colloid (or colloidal dispersion) is a chemical system composed of a continuous medium (continuous phase) throughout which are distributed small particles (dispersed phase), typically ranging from 1–1,000 nm in size, that do not settle out under the influence of gravity. The types of colloids include sol, emulsion, foam, and aerosol. Sol is a colloidal suspension with solid particles in a liquid. Emulsion is between two liquids. Foam is formed when many gas particles are trapped in a liquid or solid. Aerosol contains small particles of liquid or solid dispersed in a gas. In general, colloidal particles are aggregates of numerous atoms or molecules, but are too small to be seen with an ordinary optical microscope. They pass through most filter papers but can be detected via light scattering and sedimentation. See: Atkins, P., de Paula, J., Keeler, J. (2018). Atkins’ Physical Chemistry, 11th ed., Oxford University Press; Also see: Colloids. Available at: http://chemwiki.ucdavis.edu/Physical_Chemistry/Physical_Properties_of_Matter/Solutions_and_Mixtures/Colloid (accessed on August 20, 2019).
�1
Nanoparticles are defined as being submicronic (<1 μm) colloidal systems generally made of polymers (biodegradable or not). They were first developed in the mid-1970s by Birrenbach and Speiser (1976). Nanoparticles generally vary in size from 10 to 1000 nm. The drug is dissolved, entrapped, encapsulated, or attached to a nanoparticle matrix. [30]In drug delivery and clinical applications the technology to nanonize (i.e., to reduce in size to below 1000 nm) is one of the key factors for modern drug therapy, now and in the years to come....There are discussions about the definition of a nanoparticle, which means the size of a particle to be classified as a nanoparticle, depending on the discipline, e.g., in colloid chemistry particles are only considered as nanoparticles when they are in size below 100 nm or even below 20 nm. Based on the size unit, in the pharmaceutical area nanoparticles should be defined as having a size between a few nanometers and 1000 nm (=1 μm); microparticles therefore possess a size of 1–1000 μm. [31][f]or most pharmaceutical applications, nanoparticles are defined as having a size up to 1,000 nm… [32]The limitation of sizes to the 1–100 nm range, however, is not meaningful as new and highly valuable interactions of materials with complex biological systems have been observed at sizes considerably above the 100-nm upper limit....Within industry, a general agreement has been voiced at many conferences that the size range is not the focus but rather the improvement and optimization of material properties to deliver patient benefits is the key. As such, a broader range of dimensions, from 1 to 1000 nm is typically considered the nanomedicine range… [33]Nanotherapeutics apply the physical and chemical properties of nanomaterials (1–1000 nm in size) for the prevention and treatment of diseases. [34]In its application form for investigational medicinal products (IMPs), Swissmedic, the authority regulating medical products in Switzerland, requires investigators to elaborate and specify whether the IMP contains nanoparticles with at least one dimension in the nanoscale (1–1000 nm) and whether the IMP has a function and/or mode of action based on nanotechnology characteristics either in the active substance or adjuvant. [12]
Drug Delivery in the Context of Nano: Terminology Matters
�� Drug Delivery at the Nanoscale
It involves the three nanotechnology areas of diagnosis, imaging agents and drug delivery with nanoparticles in the 1–1000 nm range, bioships (from both “top-down” and “bottom-up” sources) and polymer therapeutics. [35]
Notably, in 2014, the FDA revised its nano definition and correctly increased the upper limit from 100 nm to 1,000 nm (Section 1.7). The agency, which still has not adopted any “official” regulatory definition, now uses a loose definition for products that involve or employ nanotechnology [79] that either (i) have at least one dimension in the 1–100 nm range; or (ii) are up to 1,000 nm, provided the novel/unique properties or phenomenon exhibited are attributable to these dimensions outside of 100 nm.
1.� Views of the Nanoworld: Physical Scientists versus Drug Developers
It has been my experience that I am always true from my point of view, but am often wrong from the point of view of my honest critics. I know that we are both right from our respective points of view.
—Mahatma Gandhi (1869–1948), Indian philosopher and apostle of nonviolence
The test of a first-rate intelligence is the ability to hold two opposed ideas in the mind at the same time, and still retain the ability to function.
—F. Scott Fitzgerald (1896–1940), American writer
Interdisciplinarity is the hallmark of nano and nanomedicine. Nevertheless, physical scientists and drug scientists view the nanoworld quite differently. Clearly, there is tension between the two camps [36, 37]. Let me illustrate this with the example of nanoparticles. The physical scientist, may for example, look at the intrinsic novel properties like the specific wavelength of light emitted from a quantum dot due to variations in the quantum dot’s size. Other examples of properties of significance to a physical scientist, but of little interest to a pharmaceutical scientist, include the increased wear resistance of a nanograined ceramic due to the Hall–Petch effect [38] or quantum confinement where
��
one photon can excite two or more excitons (electron-hole pairs) in semiconductor nanoparticles [39]. The arbitrary upper size limit of 100 nm proposed by the NNI (Section 1.3) may be relevant to a physical scientist since this is sometimes the size range at which there is a transition between bulk and nonbulk properties of metals and metal compounds. However, the drug scientist is more interested in the extrinsic novel properties of nanoparticles that arise because of their interaction with biological systems and/or of the nanodrug efficacy relating to improved bioavailability, reduced toxicity, lowered required dose, or enhanced solubility.
Materials can be scaled down (miniaturized, micronized, nanonized, etc.) many orders of magnitude from macroscopic to microscopic via conventional techniques, with specific change(s) or no change in properties. As materials are scaled down further to nanodimensions (say, from around 100 nm down to the size of atoms (~0.2 nm)), changes in optical,8 electrical, mechanical, and conductive properties, often profound, may be observed. In other words, this size variation of materials may result in unexpected properties not found in their larger bulk counterparts that make for novel application opportunities. It is important to note, however, that there is no certainty that there will be a change in characteristics at this size range: A nanomaterial in the size range of 1–100 nm does not automatically possess unique “nanocharacteristics” distinct from its bulk counterpart. In this context, when there is a change in properties or behavior of materials, the reasons are twofold: (i) an increase in relative surface area, i.e., a large surface-to-volume ratio (producing increased chemical reactivity, which can make nanomaterials more useful for biomedical applications but can also increase the risk of potential health/environmental hazards); and (ii) an enhanced dominance of quantum effects (which impact the material’s optical, physical, surface, magnetic, or electrical properties).
However, the quantum mechanical nature of materials at the nanoscale, where classical macroscopic laws of physics do not operate, are irrelevant when it comes to pharmaceutical science, 8A century after artisans used metallic particles as colorants, Michael Faraday in 1857 studied the interaction of light (photons) with gold particles and established that both the type of material and particle size were important factors in determining the specific color of emitted light. Thus, the area of research we now refer to as photonics was born. Nanometer-scale particles from the same block of gold (yellow) can have a range of colors (emitted light) like orange, red or purple.
Views of the Nanoworld
�� Drug Delivery at the Nanoscale
especially drug delivery, drug formulation, and most nano-assays. The sub-100 nm size range may be significant to a nanophotonic company where the quantum dot’s size dictates the color of light emitted therefrom. But this arbitrary size limitation is not critical to a pharmaceutical scientist from a formulation, delivery or efficacy perspective because the desired property (such as Vmax, pharmacokinetics or PK, area under the curve or AUC, z-potential, etc.) may be achieved with a particle size range greater than 100 nm. Moreover, as stated previously, pharmaceutical scientists prefer a labeling consistent with colloidal solutions while discussing nanoformulations where particles have at least one dimension ranging from 1–1,000 nm.
There is also a need for true interdisciplinarity in nano because of the different approaches of physical scientists versus drug scientists with respect to not only generation of data but also during the examination, analysis, and discussion of these data [40]:
Nanomedicine by nature is interdisciplinary, with benefits being realized at the interface of science and engineering, physical science and engineering, chemical science and engineering, cellular and molecular biology, pharmacology and pharmaceutics, medical sciences and technology and combinations thereof. The difference in perspective between disciplines may be partly responsible for the lack of nomenclature or universally accepted definition for various “nano” terminologies, which causes issues with publication consistency, regulatory agencies, patent offices, industry and the business community….Ultimately, for a clinical scientist or physician the true value of a particular material lies in its clinical utility balanced against any potential adverse effects. Therefore, effective translation of nanomedicine candidates requires a “technological push” coupled to a “clinical pull”, which is bridged by logical intermediary data that mechanistically demonstrate the efficacy and safety in biological systems…. Given this backdrop, there is a clear need for “true” interdisciplinarity during the generation of robust nanomedicine data but also during examining, discussing or analyzing these data because interpretation by physical scientists is often different than by biological scientists.
��
1.� US Food and Drug Administration
The way the FDA now behaves, and the adverse consequences, are not an accident…but a consequence of its constitution in precisely the same way that a meow is related to the constitution of a cat.
—Milton Friedman (1912–2006), American economist and Nobel laureate
[D]octors & druggists wash each other’s hands. (Canterbury Tales)
—Geoffrey Chaucer (1343–1400), English poet and diplomat
At FDA, our mission is to promote and protect the health of the public.
—Margaret Hamburg (1955-), former FDA commissioner
Courtesy of the Government Accountability Office.
According to the FDA, the products it regulates represent around 20% of all products sold in the US, representing more than $2.4 trillion. The FDA regulates products according to specific categories: food, dietary supplements, cosmetics, drugs, biologics, medical devices, veterinary products, and tobacco. The Center for Biologics Evaluation and Research (CBER) regulates what are often referred to as traditional biologics, such as vaccines, blood and blood products, allergenic extracts, and certain devices and test kits (Section 1.6). CBER also regulates gene therapy products, cellular therapy products, human tissue used in transplantation, and the tissue used in xenotransplantation—the transplantation
US Food and Drug Administration
�� Drug Delivery at the Nanoscale
of nonhuman cells, tissues, or organs into a human. On the other hand, the Center for Drug Evaluation and Research (CDER) regulates branded and generic drugs, over-the-counter (OTC) drugs, and most therapeutic biologics (Fig. 1.1, Table 1.3). Food, dietary supplements, and cosmetics fall under the authority of the Center for Food Safety and Nutrition (CFSAN). Since dietary supplements are intended to supplement the diet, they are classified under the “umbrella” of foods and do not require premarket authorization from the FDA. Cosmetics containing sunscreen components are regulated as drugs. In these cases, the products must be labeled as OTC drugs and meet OTC drug requirements. Tobacco products are subject to a unique regulatory framework as they only pose risks without providing any health benefits. They are regulated by the Center for Tobacco Products (CTP). Medical devices are regulated by the Center for Devices and Radiological Health (CDRH), and veterinary products by the Center for Veterinary Medicine (CVM). Drugs that have high potential for abuse with no accepted medical use are illegal and cannot be imported, manufactured, distributed, possessed, or used. The Drug Enforcement Administration (DEA) is the US agency tasked with overseeing these dangerous products and enforcing the controlled substances laws. The Office of Combination Products (OCP) has authority over the regulatory life cycle of combination products and assesses emerging technologies at the interface of the 3 product domains. Combination products are therapeutic and diagnostic products that combine drugs, devices, and/or biological products. As technological advances continue to merge product types and blur the historical lines of separation between various FDA centers, I expect that more products, especially nanodrugs like theranostics, soon will fall into the category of combination products. Naturally, this will present unique regulatory, policy, and review management challenges (Section 1.10).
The FDA regulates products under two primary statutes: (a) the Federal Food, Drug, and Cosmetic Act (FD&C Act), which addresses man-made drugs as well as devices; and (b) the Public Health Service (PHS) Act, which addresses biologically derived therapeutics [41]. The FDA must characterize products under definitions provided by Congress in both the FD&C Act and the PHSA. Fundamentally, these definitions and supplemental
��
FDA policies distinguish among three therapeutic product areas based on whether the product has a chemical mode of action (drug), a mechanical mode of action (device), or a biological source (biologic).9 Table 1.1 provides the FDA’s statutory definitions for each of these three product categories. Table 1.2 shows the FDA’s regulatory routes for the therapeutic products.
Table 1.1 Food and Drug Administration Product Definition Overview
Product Domain Definition
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.
Biologic A biological product is a product that is “a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein...or analogous product...applicable to the prevention, treatment, or cure of a disease or condition of human beings.”c
Device A medical device is a product that is not a drug, meaning that it does not act through chemical action and is not dependent upon metabolism to achieve its primary intended purpose. Medical devices are “intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease...or...intended to affect the structure or any function of the body.”d
aQuotation from United States Code, 21 USC § 321(g)(1).bQuotation from United States Code, 21 USC § 321(p)(1).cQuotation from United States Code, 42 USC § 262(i).dQuotation from United States Code, 21 USC § 321(h).
9Nanomedical products can span all three FDA regulatory categories, and often many of the nanomedical product mechanisms of action spans two or more of these domains. As a result, the FDA’s old classification scheme to distinguish drug products into these three categories becomes a problem for many nanomedical products primarily due to their unique characteristics, risk profiles, and cross-category features.
US Food and Drug Administration
�� Drug Delivery at the Nanoscale
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28
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15
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3238
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3534
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3641
3543
5759
0102030405060
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
Filings/Approvals
NDA
Appr
oval
sBL
AAp
prov
als
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+ B
LA F
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s
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No. ofnew drugs per billion US$ R&D spending
(inaon adjusted)
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1960
1970
1980
1990
2000
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29
Figu
re 1
.1 D
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Fili
ngs
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d A
pp
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ls b
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e FD
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e pe
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ppro
ves
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l dru
gs, e
ither
as
new
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ecul
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ntiti
es (
NM
Es)
unde
r N
ew D
rug
Appl
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(N
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s). I
n re
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own
mor
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r the
ir b
reat
htak
ing
pric
e tag
s and
rapi
dity
of a
ppro
val r
athe
r tha
n in
nova
tion.
The
FDA
def
ines
“nov
el d
rugs
” as i
nnov
ativ
e pro
duct
s tha
t ser
ve p
revi
ousl
y un
met
med
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ts a
nd th
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tive
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nt o
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redi
ents
in a
nov
el
drug
hav
e ne
ver b
een
appr
oved
in th
e US
. In
rare
inst
ance
s, it
may
be
nece
ssar
y fo
r the
FDA
to c
hang
e a
drug
’s N
ME
desi
gnat
ion
or
the
stat
us o
f its
app
licat
ion
as a
new
BLA
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inst
ance
, new
info
rmat
ion
may
bec
ome
avai
labl
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hich
coul
d le
ad to
a re
cons
ider
atio
n of
the
ori
gina
l des
igna
tion
or s
tatu
s. N
ote
that
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ls b
y th
e CB
ER a
re e
xclu
ded
from
thi
s fig
ure
(CBE
R ap
prov
ed o
nly
a fe
w
nota
ble
new
pro
duct
s in
2018
). Si
nce
appl
icat
ions
are
rece
ived
and
file
d th
roug
hout
a ca
lend
ar y
ear,
the
filed
app
licat
ions
in a
giv
en
cale
ndar
yea
r do
not
nec
essa
rily
cor
resp
ond
to a
ppro
vals
in th
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me
cale
ndar
yea
r. Ce
rtai
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plic
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re w
ithin
thei
r 60
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revi
ew p
erio
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d m
ay n
ot b
e fil
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pon
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plet
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of t
he r
evie
w.
Mul
tiple
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licat
ions
per
tain
ing
to a
sin
gle
new
m
olec
ular
/bio
logi
c en
tity
are
only
cou
nted
onc
e. O
rigi
nal B
LAs
that
do
not c
onta
in a
new
act
ive
ingr
edie
nt a
re e
xclu
ded.
The
inse
t sh
ows n
umbe
r of n
ew d
rugs
per
bill
ion
US sp
endi
ng o
n R&
D.Fo
r m
ore
info
rmat
ion
abou
t the
app
rove
d dr
ugs
in 2
018
and
for
thei
r co
mpl
ete
risk
info
rmat
ion,
refe
r to
the
drug
app
rova
l let
ters
an
d FD
A-ap
prov
ed la
belin
g at
Dru
gs@
FDA.
Als
o se
e CD
ER’s
Nov
el D
rug
Appr
oval
s fo
r 20
18 o
n th
e FD
A w
ebsi
te fo
r th
e ap
prov
al
date
s, no
npro
prie
tary
nam
es a
nd w
hat e
ach
drug
is u
sed
for.
Sour
ces:
Baw
a B
iote
ch L
LC, E
valu
ateP
harm
a, F
DA
, Bos
ton
Cons
ulti
ng G
roup
, and
var
ious
dru
g co
mpa
nies
. Cop
yrig
ht ©
202
0 Ra
j Baw
a. A
ll ri
ghts
res
erve
d.
US Food and Drug Administration
�0 Drug Delivery at the Nanoscale
Table 1.� Food and Drug Administration’s Regulatory Routes for Ther-apeutic Products
Medical Device Drug Biologic
FDA Center Jurisdiction
CDRH CDER CBER/CDER
Regulatory Route(s)
510(k) waived510(k) notificationPMA
OTCANDANDA
BLA
Clinical Trial Initiation
IDE IND IND
Abbreviations: CBER, Center for Biologics Evaluation and Research; CDER, Center for Drug Evaluation and Research; CDRH, Center for Devices and Radiological Health; NDA, New Drug Application; BLA, Biologic License Application; OTC, over-the-counter; ANDA, Abbreviated New Drug Application; PMA, Premarket Approval Application; IND, Investigational New Drug; IDE, Investigational Device Exemption.
Copyright © 2020 Raj Bawa. All rights reserved.
The FD&C Act was established in 1938 and has been amended numerous times since. The laws are passed as Acts of Congress and organized/codified into United States Code (USC). Of the 53 titles in the USC, title 21 corresponds to the FD&C Act. To operationalize the law for enforcement, federal agencies, including the FDA, are authorized to create regulations. The Code of Federal Regulations (CFR) details how the law will be enforced. The CFR is divided into 50 titles according to subject matter. Therefore, there are three types of references for regulatory compliance: FD&C Act, 21 USC, and 21 CFR. The FD&C Act provides definitions for the different product categories along with allowable claims. For example, drugs, biologics, and medical devices (Table 1.1) can make therapeutic claims like “treatment of a particular disease” or “reduction of symptoms associated with a particular disease.” Therapeutic claims also include implied statements like “relieves nausea” or “relieves congestion.” It is illegal for nonmedical products like pharma-cosmetics, dietary supplements, and cosmetics to make therapeutic claims. Even if a product lacks any therapeutic ingredient, its intended use may cause it to be categorized as a drug.
�1
Many biologics (Section 1.6) are of nanoscale and hence can also be considered nanodrugs. Conversely, many nanodrugs are biologics according to standard definitions. For example, Copaxone® is a biologic but also falls within the definition of a nanodrug.10 Many terms used in this chapter are definitions that come from specific regulations or compendia. The terms “product,” “drug formulation,” “therapeutic product,” or “medicinal product” will be used in the manner the FDA defines a “drug,” encompassing pharmaceutical drugs, biologics, and nanomedicines in the context of describing the final “drug product.”11 Some of the terms will be used synonymously. For example, biotherapeutics, protein drugs, biologicals, biological products, and biologics are equivalent terms. Similarly, nanomedicines, nanodrugs, nanopharmaceuticals, nanoparticulate drug formulations, and nanotherapeutics are the same. Branded drugs are referred to as “pioneer,” “originator,” “branded,” or “reference” drugs. Small-molecule drugs approved by the FDA are known as new chemical entities (NCEs) while approved biologics are referred to as new biological entities (NBEs) (Fig. 1.1, Table 1.3). As a result, a new drug application for an NCE is known as a New Drug Application (NDA) while a new drug application for an NBE is known as a Biologic License Application (BLA). Note that prior to the 1980s, there were very few marketed biologics, so the very term “pharmaceutical” or “drug” implied a small-molecule drug. Although biologics are subject to federal regulation under the PHS Act, they also meet the definition of “drugs” and are considered a subset of drugs. Hence, biologics are regulated under the provisions of both PHS Act and FD&C Act.
10Refer to [58] for additional details.11According to the FD&C Act (as amended through P.L. 116–22, enacted June 24, 2019), “the term ‘‘drug’’ means (A) articles recognized in the official United States Pharmacopeia, official Homeopathic Pharmacopeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any articles specified in clause (A), (B), or (C).” https://legcounsel.house.gov/Comps/Federal%20Food,%20Drug,%20And%20Cosmetic%20Act.pdf
US Food and Drug Administration
�� Drug Delivery at the Nanoscale
Tabl
e 1.
� P
rop
erti
es o
f Bio
logi
cs v
ersu
s Sm
all-
Mol
ecu
le D
rugs
Pro
per
tyB
iolo
gics
Smal
l-M
olec
ule
Dru
gs
Size
an
d M
Wge
nera
lly la
rge
and
high
MW
; MW
>70
0 Da
; co
mpl
ex st
ruct
ure
gene
rally
smal
l and
low
; MW
<70
0 Da
; sim
ple
and
defin
ed
stru
ctur
eM
anu
fact
uri
ng
num
erou
s cri
tical
pro
cess
step
s; h
ighl
y
susc
eptib
le to
slig
ht a
ltera
tions
in p
rodu
ctio
n pr
oces
s; le
ngth
y an
d co
mpl
ex p
urifi
catio
n;
grea
t pos
sibi
lity
of co
ntam
inat
ion
and
de
tect
ion/
rem
oval
ofte
n im
poss
ible
few
er cr
itica
l pro
cess
step
s; n
ot a
ffect
ed b
y sl
ight
al
tera
tions
in p
rodu
ctio
n pr
oces
s; e
asy
to p
urify
; co
ntam
inat
ion
can
gene
rally
be
avoi
ded
and
de
tect
ion/
rem
oval
eas
y
Com
pos
itio
npr
otei
n-ba
sed;
am
ino
acid
s; h
eter
ogen
ous
mix
ture
that
may
incl
ude
vari
ants
; may
in
volv
e po
st-t
rans
latio
nal m
odifi
catio
ns
chem
ical
-bas
ed; s
ynth
etic
org
anic
com
poun
d(s)
; ho
mog
enou
s dru
g su
bsta
nce
(sin
gle
entit
y)
Ori
gin
isol
ated
from
livi
ng ce
lls o
r rec
ombi
nant
ly
prod
uced
chem
ical
synt
hesi
s
Toxicity
mor
e co
nsis
tent
with
exa
gger
ated
pha
rmac
olog
y th
an o
ff-ta
rget
toxi
city
; muc
h gr
eate
r con
tact
su
rfac
e ar
ea fo
r bin
ding
allo
ws a
cces
s to
a m
uch
wid
er ra
nge
of p
rote
in ta
rget
s as w
ell a
s a m
ore
spec
ific b
indi
ng in
tera
ctio
n, d
ecre
asin
g th
e po
tent
ial f
or o
ff-ta
rget
effe
cts
drug
pro
duct
or m
etab
olite
s tha
t are
gen
erat
ed ca
n be
to
xic;
targ
et b
indi
ng re
sults
in th
e sm
all-m
olec
ule
drug
be
ing
near
ly co
mpl
etel
y bu
ried
with
in a
hyd
roph
obic
po
cket
of t
he p
rote
in ta
rget
to m
axim
ize
hydr
opho
bic
cont
act p
lus c
reat
e a
mor
e st
able
com
plex
, the
reby
eff
ectiv
ely
limiti
ng ta
rget
s to
thos
e th
at p
osse
ss
solv
ent a
cces
sibl
e po
cket
s
��
Pro
per
tyB
iolo
gics
Smal
l-M
olec
ule
Dru
gs
Dos
ing
Fr
equ
ency
in
crea
sed
bloo
d ci
rcul
atio
n tim
e ca
n al
low
far l
ess
freq
uent
dos
ing
grea
ter d
osin
g fr
eque
ncy
Hal
f-Li
feva
riab
le; l
onge
r hal
f-life
(hou
rs, d
ays,
wee
ks)
vari
able
; mos
tly sh
orte
r hal
f-life
(hou
rs to
day
s)Cl
eara
nce
sl
owra
pid
Ph
arm
acok
inet
ic
(PK
) an
d
Dis
trib
uti
on
targ
et ca
n aff
ect P
K be
havi
or (T
MDD
); la
rger
m
olec
ule(
s) a
nd h
ence
reac
h bl
ood
via
lym
phat
ics;
su
bjec
t to
prot
eoly
sis d
urin
g in
ters
titia
l and
ly
mph
atic
tran
sit;
dist
ribu
tion
gene
rally
lim
ited
to
plas
ma
and/
or e
xtra
cellu
lar f
luid
mos
tly li
near
PK;
non
linea
rity
from
satu
ratio
n of
m
etab
olic
pat
hway
s; ra
pid
entr
y in
to sy
stem
ic ci
rcul
atio
n vi
a ca
pilla
ries
; dis
trib
uted
to a
ny co
mbi
natio
n of
org
an/
tissu
e
Cost
high
, ofte
n ex
trem
ely
high
gene
rally
low
Dru
g–D
rug
Inte
ract
ion
(D
DI)
rare
or f
ew e
xam
ples
, mos
tly p
harm
acod
ynam
ic
(PD)
-rel
ated
poss
ible
and
man
y ex
ampl
es; m
etab
olic
and
/or P
D re
late
d
Off
-tar
get
Act
ion
ra
re; m
ostly
“on-
targ
et” e
ffect
sof
ten
“off-
targ
et” e
ffect
sM
ode
of A
ctio
nre
gula
tory
or e
nzym
e ac
tivity
to re
plac
e/au
gmen
t ce
ll ac
tion;
may
targ
et ce
ll su
rfac
e to
indu
ce a
ctio
n;
bind
ing
to ce
ll-su
rfac
e re
cept
ors a
nd o
ther
mar
kers
sp
ecifi
cally
ass
ocia
ted
with
or o
vere
xpre
ssed
; lim
ited
to e
xtra
cellu
lar a
nd ce
ll su
rfac
e in
tera
ctio
ns
anta
goni
stic
/ago
nist
ic a
ctiv
ity o
n in
trac
ellu
lar a
nd
extr
acel
lula
r tar
gets
Stor
age
and
H
and
lin
g R
isk
vari
able
; sen
sitiv
e to
env
iron
men
tal c
ondi
tions
(h
eat a
nd sh
ear)
rela
tivel
y st
able
(Con
tinu
ed)
US Food and Drug Administration
�� Drug Delivery at the Nanoscale
Pro
per
tyB
iolo
gics
Smal
l-M
olec
ule
Dru
gs
Con
tam
inat
ion
R
isk
high
low
Stru
ctu
rem
ay o
r may
not
be
prec
isel
y el
ucid
ated
or k
now
n;
inhe
rent
var
iabi
lity
due
to co
mpl
ex m
anuf
actu
ring
pr
ecis
ely
defin
ed st
ruct
ure
(or s
truc
ture
s, e.
g., r
acem
ic
mix
ture
s)
Del
iver
yge
nera
lly p
aren
tera
l (e.
g., I
V an
d SC
)va
riou
s rou
tes;
gen
eral
ly o
ral
Dis
pen
sed
By
phys
icia
ns (o
ften
spec
ialis
ts) o
r hos
pita
lsge
nera
l pra
ctiti
oner
or r
etai
l pha
rmac
ies
Du
rati
on o
f A
ctio
n
long
; day
s to
wee
kssh
ort;
hour
s
Char
acte
riza
tion
le
ss e
asily
char
acte
rize
d; ca
nnot
alw
ays b
e fu
lly
char
acte
rize
dca
n be
fully
char
acte
rize
d
Imm
un
ogen
icit
ylo
w to
hig
h; u
sual
ly a
ntig
enic
and
hen
ce p
oten
tial
exis
tsof
ten
non-
antig
enic
and
hen
ce lo
w to
non
e
Toxicity
rece
ptor
-med
iate
d to
xici
tysp
ecifi
c tox
icity
FDA
Ap
pro
val
licen
sed
unde
r the
pro
visi
ons o
f bot
h th
e FD
&C
Act
and
the
PHS
Act b
iolo
gics
app
rove
d by
the
FDA
are
refe
rred
to a
s new
bio
logi
cal e
ntiti
es (N
BEs)
; a
new
dru
g ap
plic
atio
n fo
r an
NBE
is ca
lled
a Bi
olog
ic L
icen
se A
pplic
atio
n (B
LA) (
see
Fig.
1.1
)
licen
sed
unde
r the
FD&
C Ac
t; sm
all-m
olec
ule
drug
s ap
prov
ed b
y th
e FD
A ar
e kn
own
as n
ew m
olec
ular
en
titie
s (N
MEs
); a
new
dru
g ap
plic
atio
n fo
r an
NCE
is
know
n as
a N
ew D
rug
Appl
icat
ion
(NDA
) (se
e Fi
g. 1
.1)
Tabl
e 1.
� (C
onti
nued
)
��
Pro
per
tyB
iolo
gics
Smal
l-M
olec
ule
Dru
gs
Com
pil
atio
n
Purp
le B
ook
publ
ishe
d by
the
FDA
lists
bio
logi
cs,
thei
r bio
sim
ilars
and
inte
rcha
ngea
ble
biol
ogic
al
prod
uct (
an a
lrea
dy-li
cens
ed F
DA b
iolo
gica
l pr
oduc
t)
Ora
nge
Boo
k pu
blis
hed
by th
e FD
A lis
ts d
rugs
and
thei
r ge
neri
c equ
ival
ents
Foll
ow-o
n
Ver
sion
sbi
osim
ilars
; hig
h ba
rrie
rs to
ent
ry; f
ollo
w-o
ns w
ill
not b
e id
entic
al to
the
refe
renc
e in
nova
tor p
rodu
ct;
prec
linic
al a
nd cl
inic
al (i
.e., s
afet
y/ef
ficac
y) st
udie
s ar
e ne
eded
to d
emon
stra
te co
mpa
rabi
lity
gene
rics
; pre
clin
ical
ana
lytic
al m
etho
ds ca
n be
use
d to
va
lidat
e an
d de
mon
stra
te co
mpa
rabi
lity;
full
clin
ical
st
udie
s not
nee
ded;
follo
w-o
ns h
ave
iden
tical
API
(s),
stre
ngth
, dos
age
form
, rou
te, a
nd p
urity
Pat
ent
Issu
espa
tent
pro
secu
tion
and
litig
atio
n ar
e of
ten
mor
e co
mpl
ex; p
aten
ts a
nd le
gal e
xclu
sivi
ties m
ay d
elay
th
e FD
A ap
prov
al o
f app
licat
ions
for b
iosi
mila
rs
pate
nt p
rose
cutio
n an
d lit
igat
ion
gene
rally
less
com
plex
; pa
tent
s and
lega
l exc
lusi
vitie
s may
del
ay th
e FD
A ap
prov
al
of a
pplic
atio
ns fo
r gen
eric
s
Sele
ctiv
ity
high
spec
ies s
elec
tivity
(affi
nity
/pot
ency
)ge
nera
lly lo
w sp
ecie
s sel
ectiv
ity
Tar
gets
mul
tiple
targ
et b
indi
ngm
ostly
a si
ngle
or f
ew ta
rget
s
Abbr
evia
tion
s: BL
A, B
iolo
gic L
icen
se A
pplic
atio
n; D
a, D
alto
ns; D
DI, d
rug–
drug
inte
ract
ion;
FD&
C Ac
t, Fe
dera
l Foo
d, D
rug,
and
Cos
met
ic
Act;
IV, in
trav
enou
s; M
W, m
olec
ular
wei
ght;
NBE
, New
Bio
logi
cal E
ntity
; NM
E, N
ew M
olec
ular
Ent
ity; N
DA, N
ew D
rug A
pplic
atio
n; T
MDD
, ta
rget
med
iate
d dr
ug d
ispo
sitio
n; P
D, p
harm
acod
ynam
ic; P
HS
Act,
Publ
ic H
ealth
Ser
vice
Act
; PK,
pha
rmac
okin
etic
; SC,
subc
utan
eous
; AP
I, ac
tive
phar
mac
eutic
al in
gred
ient
.
Copy
righ
t © 2
020
Raj B
awa.
All
righ
ts r
eser
ved.
US Food and Drug Administration
�� Drug Delivery at the Nanoscale
As the boundaries between big pharma and biotech companies have further blurred (Box 1.7), big pharma has adapted its operational strategy, employing outside collaborations with respect to research, technology, workforce, and marketing. Obviously, big pharma’s evolving role has resulted partly from the “biotech boom” and the “genomics boom,” where enormous advances resulted from molecular biology and DNA technology, but also from advances in information and computer technology. In addition, two important pieces of legislation in the 1980s have had a major impact on the drug industry in the US. The first was the Bayh–Dole (or Patent and Trademark Law Amendments) Act of 1980, which allowed universities, hospitals, nonprofit organizations, and small businesses to patent and retain ownership arising from federally funded research [42].
Box 1.� Pharma versus Biotech Companies
The demarcations between pharmaceutical and biotechnology (and between branded and generic) companies are no longer that clear. For example, Genentech (owned by the Roche group) and Medimmune (owned by AstraZeneca), although operate independently, are technically part of big pharma. Many biotechnology companies are developing therapeutics that are traditional small-molecule drugs rather than biotech products. Conversely, big pharma is developing biotech products along with traditional small molecules. Often, branded companies are developing generics and vice versa. Currently, there is a symbiotic relationship between all these diverse players. For example, big pharma (which is well versed in clinical trials and commercialization) often turns to biotech companies (that are generally low on funds, lack a robust sales force or lack regulatory expertise) to license compounds or to develop platform technologies with the promise to yield multiple molecules.
��
The second was the Hatch–Waxman (or Drug Price Competition and Patent Term Restoration) Act of 1984, which established abbreviated pathways for the approval of small-molecule drug products [43]. It set up the modern system of generic drug regulations in the US by amending the FD&C Act. Section 505(j) of the Hatch–Waxman Act, codified as 21 USC § 355(j), outlines the process for pharmaceutical manufacturers to file an Abbreviated New Drug Application (ANDA) for approval of a generic drug by the FDA.
In addition to the Bayh–Dole Act and Hatch–Waxman Act, the more recent Biologics Price Competition and Innovation Act of 2009 (BPCI Act or Biosimilar’s Act), which is included in the Patient Protection and Affordable Care Act signed into law by President Obama in 2010, pertains specifically to biologics. This Act created an abbreviated approval pathway for biologics proven to be “highly similar” (biosimilar) to or “interchangeable” with an FDA-licensed reference biologic product [44]. In concept, the goal of the BPCI Act is similar to the Hatch–Waxman Act.
The prohibitive costs of most biologics and some small- molecule drugs have led to increased scrutiny on the US government’s role in the development of costly novel drug products. For example, for almost all the 23 biosimilars approved in the US as of September 2019, the associated brand-name biologic was originally formulated by scientists at public-sector research institutions. Hence, like most US taxpayers, I question the logic behind allowing sky-rocketing drug prices, especially for branded biologics. Should there be more robust governmental controls on this front? Should the US taxpayer have significant leverage to affect the process? Based on two recent US Court of Appeals for the Federal Circuit (CAFC) decisions and imperfections in the BPCI Act itself, some argue that the law impairs the potential for a flourishing generic market for biologics [45]. Moreover, since around 90% of the global biosimilar sales come from the European
US Food and Drug Administration
�� Drug Delivery at the Nanoscale
Union (EU), compared to just 2% from the US, some have questioned whether the US biosimilar industry is falling behind [46]. The global biosimilars market in 2017 was $4.49 billion and is expected to grow with a compound annual growth rate (CAGR) of 31.7% to $23.63 billion by 2023 [47].
An overview of the therapeutic product development pathway is shown in Fig 1.2. Figures 1.3–1.6 represent the various phases of the FDA drug approval process. Box 1.8 highlights the importance of drug discovery in the overall drug development process.
Box 1.� Drug Discovery Technologies
“[D]rug discovery remains perhaps the most challenging applied science largely due to the complexity of human biology, the vastness of chemical space, the discontinuous impact of functional group changes on molecular properties, and the inability to optimize a single variable (potency, selectivity, permeability, metabolic stability, solubility) without having simultaneous and sometimes detrimental effects on other critical parameters. For these reasons, a successful drug discovery campaign often emerges after investigating dozens of pharmacological targets, with each one requiring thousands of chemical hits to be triaged and hundreds of close-in synthetic analogues to be evaluated. A recent 2016 publication based on 106 new drugs from 10 pharmaceuticals firms estimated that the overall investment in discovery and clinical development approaches $2.6 billion for each successful launch....Technologies that enable more effective selection of productive biomolecular targets provide novel ways to engage targets, or appropriately guide design to the most effective regions of chemical space will lead to transformative improvements in drug discovery efficiency.”Source: [48].
��
Safe
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re 1
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or, o
rigi
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ourt
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A.
<TYPESETTER: FIGURE 1.2 HERE. PLEASE INSERT FIGURE 58.3A FROM HANDBOOK OF CLINICAL NANOMEDICINE VOLUME 2.>
US Food and Drug Administration
�0 Drug Delivery at the Nanoscale40 Drug Delivery at the Nanoscale
IND REVIEW FDA reviews the IND toassure that the proposed studies, generally referred to as clinical trials, do not place human subjects atunreasonable risk. FDA also verifiesinformed consent and human subject protection.
CENTE
RFO
RD
RUG EVALUATIONAND
RESEARCH
.
Discovery and Screening Phase Figure 1.� Drug Sponsor’s (Preclinical).
theFDA.
Figure 1.� Drug Sponsor’s Discovery and Screening Phase (Preclinical).Modified by the author, original courtesy of the FDA.
�141
The typical number of healthy volunteers used in Phase 1; thisphase emphasizes safety. The goal here in this phase is todetermine what the drug's most frequent side effects are and,often, how the drug is metabolized and excreted.
The typical number of patients used in Phase 2; this phase emphasizeseffectiveness. This goal is to obtain preliminary data on whether the drug worksin people who have a certain disease or condition. For controlled trials, patientsreceiving the drug are compared with similar patients receiving a differenttreatment--usually a placebo, or a different drug. Safety continues to beevaluated, and short-term side effects are studied.
At the end of Phase 2, FDA and sponsors discuss how large-scalestudies in Phase 3 will be done.
The typical number of patients used in Phase 3. These studies gather moreinformation about safety and effectiveness, study different populations anddifferent dosages, and uses the drug in combination with other drugs.
PHASE
PHASE
PHASE
Figure 1.4 Drug Sponsor’s Clinical Studies/Trials.Courtesy of the FDA.
US Food and Drug Administration
Figure 1.� Drug Sponsor’s Clinical Studies/Trials.Modified by the author, original courtesy of the FDA.
US Food and Drug Administration
�� Drug Delivery at the Nanoscale42 Drug Delivery at the Nanoscale
The drug sponsor formally asks FDA to approve a drug for marketing in the U .A NDA includes all animal human data analyses of the data, and how it is manufactured.
FDA reviews the drug’sprofessional labeling and assures appropriateinformation is communicatedto health care professionalsand consumers.
FDA meets with drugsponsor prior to submissionof a
.
60DAY
FDA reviewers will approve the or issue a response letter.
FDA inspects the facilities where the drug will be manufactured.
Figure 1.5 FDA’s New Drug Application (NDA) Review.Courtesy of the FDA.
After an NDA is received, FDA has 60
Figure 1.� FDA’s New Drug Application (NDA) Review. Modified by the author, original courtesy of the FDA.
��
PHASE
4
Because it's not possible to predict all of a drug's e�ects during clinical trials, monitoringsafety issues after drugs get on the market is critical. The role of FDA’s post-marketing safety system is to detect serious unexpected adverse events andneeded and
raised
Once FDA approves a drug, the post-marketing monitoring stage begins. The sponsor (typically the manufacturer) is required tosubmit periodic safety updates to FDA. FDA’s MedWatchvoluntary system makes it easier for physicians and consumers toreport adverse events. Usually, when important new risks are uncovered, the risks are added to the drug's labeling and the public is informed of the new information through letters, public health advisories, and other education. In some cases, the use of the drug must be substantially limited. And in rare cases, thedrug is withdrawn from the market.
www.fda.gov/medwatch(800) FDA-1088 (322-1088) phone(800) FDA-0178 (322-0178) fax
fees toand
of consideras a con�ict-of-interest
FASTERAPPROVALS
The Accelerated Approval
The approval is faster because FDA can base thedrug’s e�ectiveness on a“surrogate endpoint,” such as a blood test or X-ray result, ratherthan waiting for results from a clinical trial. ponsors can submitportions of an application as the information becomes available(“rolling submission”) instead ofhaving to wait until allinformation is available.
Figure 1.� FDA’s Post-Approval Risk Assessment Systems.Modified by the author, original courtesy of the FDA.
US Food and Drug Administration
�� Drug Delivery at the Nanoscale
1.� What Is a Biologic?
Biologics12 have already entered an era of rapid growth due to their wider applications, and in the near future they will replace many existing organic based small-molecule drugs. According to one drug analysis firm, biologics have grown from 11% of the total global drug market in 2002 to around 20% in 2017.13 On the other hand, nanodrugs have sputtered along a somewhat different trajectory with greater challenges to their translation [21, 49–53]. I estimate that since the FDA approval in October 1982 of the first recombinant biologic (recombinant human insulin), there are over 225+ marketed biologics and at least 75 nanodrugs for various clinical applications approved by various regulatory agencies.14 According to the Pharmaceutical Research and Manufacturers of America (PhRMA) website, as of 2013, there are over 900 biologic medicines and vaccines in development. The growth of biologics can be traced back to the FDA approval of genetically engineered human insulin in 1982 (Box 1.9). I estimate that hundreds of companies globally are engaged in nanomedicine R&D, the clear majority of these have continued to be startups or small- to medium-sized enterprises rather than big pharma. Despite immature regulatory mechanisms, follow-on versions of these two drug classes, namely biosimilars and nanosimilars, respectively, have also started to trickle into the marketplace.
Biologics are a distinct regulatory category of drugs that differ from conventional small-molecule drugs by their manufacturing processes (i.e., biological sources vs. chemical/synthetic anufacturing). They are biologically derived from microorganisms (generally engineered) or cells (often mammalian, including human). In other words, biologics are drugs produced via modern molecular biological methods, and they are distinguished from traditional biological products that are directly extracted
12Biosimilars are not discussed in this chapter. Details on biosimilars can be found in [67]. For the differences between biosimilars, biologics and generics, see: Biosimilars: What to know considerations for healthcare professionals (2019). Genentech, Available at: https://www.examinebiosimilars.com/content/dam/gene/examinebiosimilars/pdfs/Biosimilars_What_to_Know_Brochure.pdf (accessed on September 20, 2019).13Data from the IMS Institute for Healthcare Informatics.14My estimate for nanodrugs is based on my definition of a nanodrug (Section 1.8).
��
from natural biological sources (such as proteins derived from plasma or plants). Biologics include a diverse range of therapeutics, including blockbuster therapeutic monoclonal antibodies (TMAbs) (e.g., Avastin® (bevacizumab) and Humira® (adalimumab)), Fc fusion proteins, anticoagulants, blood factors, hormones, cytokines, growth factors, engineered protein scaffolds, and cell-based gene therapies (e.g., chimeric antigen receptor T-cell therapy (CAR-T)) to treat various diseases—cancers, rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel disease (IBD), hemophilia, anemia, etc. Most biologics are large, complex molecules as compared to small-molecule drugs (Fig. 1.7, Table 1.3) and are often more difficult to characterize than small-molecule drugs.
Box 1.� Growth of Biologics: Technological Drivers
Advances built on two seminal technologies (recombinant DNA technology and hybridoma technology) have been the driving forces behind the expansion of biologics. Specifically, the development of recombinant DNA technology in the 1970s revolutionized the production of biologics. In 1982, human insulin (brand name Humulin® and manufactured by Eli Lilly under license from Genentech) was the first recombinant protein therapeutic approved by the FDA in merely five months. Since Humulin® was fully human and produced via genetically engineered Escherichia coli, issues with immunogenicity were minimized. In the 1980s, modified biologics joined recombinant versions of natural proteins as a major new class of biologics. In 1975, Köhler and Milstein’s hybridoma technology established a continuous immortal culture of cells secreting an antibody of predefined specificity (monoclonal antibody (mAb)) by fusing antibody-producing B cells with myeloma cells.
Below appears a well-accepted definition of a biologic [54]:
A biopharmaceutical is a protein or nucleic acid-based pharmaceutical substance used for therapeutic or in vivo diagnostic purposes, which is produced by means other than direct extraction from a native (non-engineered) biological source.
What Is a Biologic?
�� Drug Delivery at the Nanoscale
(a) Insulin (~5,800 Daltons)
(c) Monoclonal An y (~150,000 Daltons)Aspirin (180 Daltons)
Figure 1.� Comparing Biologics to Small-Molecule Drugs. The molecular model of two biologics (insulin and monoclonal antibody) and the molecular structure of a small-molecule drug (acetylsalicylic acid or aspirin) are shown to demonstrate the differences in size and molecular complexity associated with these two overlapping drug classes. The molecular weight (MW) of insulin is ~5,800 Daltons and that of a monoclonal antibody is ~150,000 Daltons. The MW of aspirin is 180 Daltons. Structures shown are not to scale. (a) The left side is a space-filling model of the insulin monomer, believed to be biologically active. Carbon atoms are shown in green, hydrogen in gray, oxygen in red, and nitrogen in blue. On the right side is a ribbon diagram of the insulin hexamer, believed to be the stored form. A monomer unit is highlighted with the A chain in blue and the B chain in cyan. Yellow denotes disulfide bonds, and magenta spheres are zinc ions (courtesy of Wikipedia). (b) Ball-and-stick model of the aspirin molecule. (c) X-ray crystallographic structure of a monoclonal antibody shown as a space-filling model (Courtesy of the FDA).
��
Since most biologics are very complex molecules and cannot be fully characterized by existing scientific technologies, they are often characterized via their manufacturing processes. However, due to their structural complexity, the manufacturing processes are also often complex, very sensitive, and kept proprietary. In fact, minor variations in temperature or other production factors can profoundly change the final biologic drug product. Naturally, this can affect product performance and patient safety. Hence, even minor alterations in the manufacturing process or facility may require clinical studies to demonstrate safety (including immune-related), purity, and potency of the synthesized biologic. According to the FDA [55], “[t]he nature of biological products, including the inherent variations that can result from the manufacturing process, can present challenges in characterizing and manufacturing these products that often do not exist in the development of small-molecule drugs. Slight differences between manufactured lots of the same biological product (i.e., acceptable within-product variations) are normal and expected within the manufacturing process.”
1.� Size Matters in Drug Delivery
It’s not the size of the dog in the fight, it’s the size of the fight in the dog.
—Mark Twain (1835–1910), American writer and humorist
Never confuse the size of your paycheck with the size of your talent.
—Marlon Brando (1924–2004), American actor/director
Size of drug particles is a critical aspect of drug delivery. In a clinical setting, the following three size-based features of nanodrugs could correlate to an enhanced in vivo bioperformance:
(a) Scientifically speaking, as a particle’s size decreases to nanoscale dimensions, a greater proportion of its atoms are located on the surface relative to its core, often rendering the particle more chemically reactive (Fig. 1.8). An example
Size Matters in Drug Delivery
�� Drug Delivery at the Nanoscale
of this is nanosilver (“colloidal silver”), a highly reactive and antimicrobial form of silver as compared to its docile, bulk counterpart. However, depending on the intended use, such enhanced activities could either be advantageous (antioxidation, carrier capacity for drugs, enhanced uptake, and interaction with tissues) or disadvantageous (toxicity issues, instability, and induction of oxidative stress) [56].
Figure 1.� Particle Size versus Percentage Surface Atoms. As the particle size decreases, the percentage of atoms displayed on the surface of the particle relative to the total atoms in the particle increases exponentially. In other words, the fewer the number of atoms in a particle, a greater percentage of atoms are found on the surface of the particle. In this hypothetical graph, a particle with a 10 nm diameter has ~16–18% atoms displayed on the surface whereas a 50 nm particle has about ~6–8% surface atoms.Copyright © 2020 Raj Bawa. All rights reserved.
��
(b) It is also a scientific fact that, as we granulate a particle into smaller particles, the total surface area of the smaller particles becomes much greater relative to its volume (i.e., an enormously increased surface area-to-volume ratio15) (Table 1.4; Figs. 1.9 and 1.10). As materials are scaled down from macroscopic to nanoscopic, the interfacial and surface properties dominate particle interactions instead of gravity. However, from a drug delivery perspective, smaller particles have a higher dissolution rate, water solubility, and saturation solubility compared to their larger counterparts. This change in properties may result in superior bioavailability due to a greater percentage of active agents being available at the site of action (tissue or disease site).16 This could translate into a reduced drug dosage needed by the patient, which in turn may reduce the potential side effects and offer superior drug compliance.
(c) Nanoparticle therapeutics have a greater potential for interaction with biological tissues, i.e., an increase in adhesiveness onto biosurfaces.17 This can be a tricky, double-edged issue. On one side, the multiple binding sites
15One of the most utilized properties of nanoparticles is their high specific surface area (SSA). Specific surface area is defined as the surface area per unit weight as expressed in the following equation:
where S denotes the specific surface area in m2/g, d represents the particle diameter in nm and r is the density of the material in g/cm3. As the particle size decreases, relatively more atoms become exposed on the particle surface (Fig. 1.6). In other words, as the particle size is reduced, the specific surface area increases.16A classic example of improving drug bioavailability is Élan Corporation’s (since 2013, Perrigo Company PLC) NanoCrystal® technology, where nanodrug particles are produced by a proprietary attrition-based wet-milling technique that reduces their size to less than one micron (µ). This technology has generated numerous marketed drugs. For details on NanoCrystal® technology, see [31].17For instance, nanoparticles like dendrimers work more effectively than traditional small molecule therapeutics. Small molecules can interact with only a select few cell surface receptors while certain nanodrugs can potentially interact with multiple receptors simultaneously, thereby potentiating the biological effect.
Size Matters in Drug Delivery
�0 Drug Delivery at the Nanoscale
of nanodrugs (“multivalence”18) allow for superior binding to tissue receptors, but on the other side, intrinsic toxicity of any given mass of nanoparticles is often greater than that of the same mass of larger particles. Nanodrugs, such as liposomes (Fig. 1.11), can further contribute to “signal enhancement” over that of a single drug molecule because of the enormous active agent payload encapsulated.
Figure 1.� Nanoparticle Surface Area-to-Volume Ratio. Comparison of size, number of particles formed and available surface area when taking a single cubic structure of 1 mm3 and reduce its dimensions systematically to 10 μm3 and then 200 nm3.
Courtesy of Dr. Andrew Owen and Dr. Steve P. Rannard, University of Liverpool, UK.
18In the context of drug delivery, multivalency is the chemical interaction of ligands with several identical binding sites (receptors) on a multi-presented cell. In biological systems, multivalent interactions are widely used (e.g., in cellular recognition and signal transduction) and are generally stronger than the individual bonding of a corresponding number of monovalent ligands to a multivalent receptor.
�1
Table 1.� Surface-to-Volume Atomic Ratio of Spherical Gold Particles
Particle Diameter (nm) Total Atom Count
Surface Atoms (%)
Specific Surface Area (m2/g)
1,000 ~30,000,000,000 ~0.2 0.3100 ~30,000,000 ~1.6 ~310 ~30,000 ~15 ~311 ~30 ~90 ~310
Courtesy of Dr. Takuya Tsuzuki, Australian National University.
Figure 1.10 Spheres of Decreasing Size and the Relationship between Their Diameters and Surface Areas. The surface of a spherical particle scales with its radius2 while its volume scales with radius3. Hence, the surface-to-volume is inversely proportional to the size. In other words, as the particle size decreases, the number of particles per mass unit increases by the cube of the size difference factor (i.e., a 1,000-fold increase for a 10-fold decrease in size). In addition, the surface area per mass unit, along with the percentage of atoms in the material being present on the particle surface, increases by the size difference (i.e., a 10-fold increase for a 10-fold decrease in size). Spherical particles shown here are not to scale.
Courtesy of Pan Stanford Publishing, Singapore.
Size Matters in Drug Delivery
�� Drug Delivery at the Nanoscale
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Size Matters in Drug Delivery
�� Drug Delivery at the Nanoscale
Sche
mat
ic r
epre
sent
atio
n of
sel
ecte
d en
gine
ered
nan
opar
ticle
s (N
Ps)
used
in d
rug
deliv
ery
that
are
eith
er a
ppro
ved
by g
loba
l re
gula
tory
bod
ies,
are
in p
recl
inic
al d
evel
opm
ent o
r ar
e in
var
ious
pha
ses
of c
linic
al tr
ials
. The
y ar
e co
nsid
ered
as
first
or
seco
nd
gene
ratio
n, s
ome
are
mul
tifun
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nal i
n th
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mod
e of
act
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mos
t ran
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n av
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amet
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om o
ne n
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eter
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m) t
o a
mic
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is o
ften
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eved
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con
juga
ting
ligan
ds o
r fu
nctio
nal g
roup
s (e
.g.,
antib
odie
s, pe
ptid
es, a
ptam
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fola
te, h
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e m
olec
ules
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ged
to t
he N
P su
rfac
e w
ith o
r w
ithou
t sp
acer
s/lin
kers
suc
h as
PEG
. M
any
nano
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s de
pict
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bove
(e.
g.,
met
al-b
ased
NPs
, fu
nctio
naliz
ed c
arbo
n na
notu
bes
[f-CN
Ts],
nano
scal
e m
etal
or
gani
c fr
amew
orks
[N
MOF
s]),
alth
ough
ext
ensi
vely
adv
ertis
ed f
or d
rug
deliv
ery,
will
pos
e en
orm
ous
regu
lato
ry a
ppro
val
and
com
mer
cial
izat
ion
chal
leng
es. T
hey
will
not
app
ear
in t
he c
linic
thi
s ce
ntur
y. N
on-e
ngin
eere
d an
tibod
ies,
natu
ral b
iolo
gica
l m
otor
s (e
.g.,
sper
ms)
, eng
inee
red
nano
mot
ors,
and
natu
rally
occ
urri
ng N
Ps (
e.g.
, nat
ural
pro
tein
nan
otub
es),
alth
ough
pot
entia
l dr
ug d
eliv
ery
cand
idat
es,
are
spec
ifica
lly e
xclu
ded
here
. N
ote
that
ant
ibod
y–dr
ug c
onju
gate
s (A
DCs)
are
als
o en
com
pass
ed
by t
he c
arto
on l
abel
ed “
Poly
mer
-Pol
ypep
tide
Conj
ugat
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hera
peut
ic m
onoc
lona
l an
tibod
ies
(TM
Abs)
, po
lym
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eptid
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njug
ates
, an
d ap
tam
ers
show
n ar
e cl
assi
c bi
olog
ics,
but
they
are
als
o na
nodr
ugs
as t
hey
fall
with
in t
he w
idel
y ac
cept
ed
stan
dard
def
initi
on o
f na
nodr
ugs.
The
list
of N
Ps d
epic
ted
here
is n
ot e
xhau
stiv
e, t
he il
lust
ratio
ns d
o no
t re
flect
pre
cise
thr
ee-
dim
ensi
onal
shap
e or
conf
igur
atio
n, a
nd th
e N
Ps a
re n
ot d
raw
n to
scal
e.Ab
brev
iati
ons:
NP,
nano
part
icle
; PE
G, p
olye
thyl
ene
glyc
ol;
GRAS
, Gen
eral
ly R
ecog
nize
d As
Saf
e; C
dot
, Cor
nell
dot;
API,
activ
e ph
arm
aceu
tical
ingr
edie
nt; A
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1.� What Are Nanodrugs?
Poisons and medicine are often the same substance given with different intents.
—Peter Mere Latham (1789–1875), English physician
1.�.1 The “Magic Bullet” Concept
The Holy Grail of any drug delivery system (DDS), whether it is nanoscale or not, is to deliver to a patient the correct dose of an active agent to a specific disease or tissue site while simultaneously minimizing toxic side effects and optimizing therapeutic benefit. This is mostly unachievable via conventional small-molecule formulations and drug delivery systems. However, the potential to do so may be greater now via nanodrugs. The prototype of targeted drug delivery can be traced back to the concept of a “magic bullet” (or “silver bullet”) that was postulated by Nobel laureate Paul Ehrlich in 1908 (magische Kugel, his term for an ideal therapeutic agent) wherein a drug could selectively target a pathogenic organism or diseased tissue [57].
Later, this concept of the magic bullet was realized by the development of antibody–drug conjugates (ADCs) when in 1958 methotrexate was linked to an antibody targeting leukemia cells wherein the antibody component provided specificity for a target antigen and the active agent portion conferred cytotoxicity. (Technically, ADCs are nanodrugs, see Fig. 1.1.)
1.�.� Potential Advantages
In the pharmaceutical sciences, “nano” offers several potential advantages in the context of drug delivery that pharma is interested in (Table 1.5). In general terms, it can be concluded that nanoscale therapeutics may have unique properties (“nanocharacter”) that can often be beneficial for drug delivery [21, 49, 50, 58]. Hence, novel nanodrugs and nanocarriers are being designed that address some fundamental problems of traditional drug formulations—ranging from poor water solubility, unacceptable toxicity profiles, poor bioavailability, physical/chemical instability, and a lack of target specificity. Additionally, via tagging with targeting ligands,
What Are Nanodrugs?
�� Drug Delivery at the Nanoscale
nanodrugs can serve as innovative drug delivery systems for enhanced cellular uptake of active agents into tissues of interest. As a result, nanodrugs are being developed that allow delivery of active agents more efficaciously to the patient while minimizing side effects, improving stability in vivo and increasing blood circulation time. Apart from these pharmacological benefits, nanodrugs also offer economic value to a drug company—the opportunity to reduce time-to-market, extend the economic life of proprietary drugs, and create additional revenue streams. Therefore, nanodrugs are starting to influence the drug and device commercialization landscapes and will likely continue to impact medical practice and healthcare delivery into the next century.
Table 1.� Select Potential Advantages of Nanodrugs
• Increased bioavailability due to enhanced water solubility of hydrophobic drugs due to the large specific surface area (SSA)
• Ability to protect biologically unstable drugs from the hostile bioenvironment of use/delivery/release (e.g., against potential enzymatic or hydrolytic degradation)
• Extended drug residence time at a site of action or within specific targeted tissue
• Extended systemic circulation time• Controlled (or semi-controlled) drug release at a specific desired
site of delivery• Endocytosis-mediated transport of drugs through the epithelial
membrane• Bypassing or inhibition of efflux pumps such as P glycoprotein• Targeting of specific carriers for receptor-mediated transport of
drugs• Enhanced drug accumulation at the target site to reduce
systemic toxicity• Biocompatibility and biodegradability• High drug-loading capacity• Long-term physical and chemical stability of drugs• Improved patient compliance
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1.�.� Size of Nanodrugs
Reverting back to the issue of size (Sections 1.3 and 1.7), it is important to emphasize that a size limitation below 100 nm, frequently recited in journals and talks as well as touted as the definition of anything “nano” by US federal agencies like the NNI, cannot serve as an arbitrary basis of novel properties of nanodrugs [21, 49, 50, 59]. In fact, properties other than size can also have a dramatic effect on the nanocharacter of nanodrugs: shape, geometry, zeta potential, specific nanomaterial class employed, composition, delivery route, crystallinity, aspect ratio, surface charge, etc. Clearly, numerous nanomaterials and their corresponding nanodrugs fall outside the sub-100 nm size range (Fig. 1.11). Examples include liposomes (80–200 nm), block copolymer micelles (50–200 nm), nanoparticles (20–200 nm), and nanosize drug crystals (100–1,000 nm). In addition, there are no clear scientific boundaries to distinguish the nano from the non-nano space, especially with respect to drug products. Moreover, as stated earlier (Sections 1.3 and 1.7), a sub-100 nm range is not critical to a drug company from a formulation, delivery, or efficacy perspective because the desired or novel physicochemical properties (e.g., improved bioavailability, reduced toxicities, lower dose, or enhanced solubility) may be achieved in a size outside this arbitrary range. For example, the surface plasmon-resonance (SPR)19 in gold or silver nanoshells or nanoprisms that imparts their unique property as anticancer thermal drug delivery agents also operates at sizes greater than 100 nm. Similarly, at the tissue level, the enhanced permeability and retention (EPR)20 effect 19A variety of light-triggered delivery systems are currently under development. Near infrared (NIR) light is a promising source of radiation that is absorbed by nanosilver and nanogold particles but not biological tissue. This property can be exploited if these particles (alone or with incorporated active agents) are targeted to tumors and irradiated via NIR, thereby causing thermolysis of tumors without damage to the surrounding tissue.20There are two major concepts in drug delivery in oncology: (i) active targeting that involves tumor targeting via the specific binding ability between an antibody and antigen or between the ligand and its receptor; and (ii) passive targeting achieved via the EPR effect. Although not a generalization, if the nanoparticle is too small (<10 nm?), it is generally rapidly excreted via renal filtration while particles too large (>~150 nm?) may not penetrate deep inside tumor tissue. These are general statements as there is a wide variability in nanoparticle type and size employed to achieve the desired result or therapeutic outcome. One must examine the specific nanoparticle on a case-by-case basis to see whether it is
What Are Nanodrugs?
�� Drug Delivery at the Nanoscale
that makes nanoparticle drug delivery an attractive option operates in a wide range, with nanoparticles of 100–1,000 nm diffusing selectively (extravasation and accumulation) into the tumor [60]. At the cellular level, size range for optimal nanoparticle uptake and processing depends on many factors but is often beyond 100 nm. Liposomes in a size range (diameter) of about 150–200 nm have been shown to have a greater blood residence time than those with a size below 70 nm. Furthermore, there are numerous FDA-approved and/or marketed nanodrug products where the particle size does not fit the sub-100 nanometer profile: Abraxane (~130 nm), Myocet (~190 nm), Amphotec (~130 nm), Epaxal (~150 nm), Inflexal (~150 nm), Lipodox (180 nm), Oncaspar (50–200 nm), Copaxone (1.5 to 550 nm), etc. This does not imply that any size will do for nanodrug delivery. For example, submicron sizes are generally considered essential for biological distribution of biopharmaceuticals for safety reasons [61]. Particles greater than 5 μm can often cause pulmonary embolism following intravenous injection [62]. Therefore, submicron particle size is preferred for all parenteral formulations. In ophthalmic applications, the optimal particle size is less than 1 μm because microparticles around 5 μm can cause a scratchy feeling in the eyes [63].
Since there is no formal or internationally accepted definition for anything “nano,” there is no standard definition for a nanodrug. The following is my definition for a nanodrug [59]:
A nanodrug is a formulation, often colloidal, containing therapeutic nanoparticles of size 1–1,000 nm; wherein the therapeutic is also the carrier or the therapeutic is directly coupled (functionalized, solubilized, entrapped, coated) to a carrier.
phagocytosed by RES (e.g., Kupffer cells in liver) or internalized by target cells through endocytosis. Size obviously is important while engineering nanoparticles for tumor applications, but it needs to be fine-tuned depending upon the nanomaterial used, route of delivery, application sought, toxicity issues, etc.
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1.�.� Developing Future Nanodrugs
By all estimates, nanomedicine is blossoming into a robust industry, albeit gradually. The global nanomedicine market was reported to be worth $72.8 billion in 2011, $138 billion in 2016 and is predicted to be worth $350 billion by 2025 [64]. Data obtained from industry and the FDA show that most of the approved or pending nanodrugs are oncology-related and based on protein–polymer conjugates or liposomes.
The first FDA-approved nanodrug was Doxil® (doxorubicin hydrochloride liposome injection) in 1995 while AmBisome® (amphotericin B liposome injection) was the first one approved by the EMA in 1997. The first protein-based nanodrug to receive regulatory approval was albumin-bound paclitaxel (Abraxane®), approved by the FDA in 2005. However, note that a nanoparticulate iron oxide intravenous solution that was marketed in the 1960s and certain nanoliposomal products that were approved in the 1950s should, in fact, be considered true first-generation nanodrugs. Polymer–drug conjugates (with a short peptide spacer between the two that prolonged release) were also prepared back in the 1950s, when a polyvinylpyrrolidone–mescaline conjugate was produced.
Half a century since ADCs, various classes of nanoscale drug delivery systems are in early development though first- generation nanodrugs have been commercialized (Fig. 1.11). Few are completely novel while most are redesigned or reformulated versions of earlier drug formulations (Fig. 1.11). However, the revolutionary second- and third generation nanodrugs are currently in preclinical or clinical stages. Advanced future nano-drug will be those that can (i) deliver active agents to specific tissue, cells, or even organelles (“site-specific, precision, or targeted drug delivery”); and/or (ii) offer simultaneous controlled delivery of active agents with concurrent real-time imaging (“theranostic drug delivery”). As nanodrugs move out of the laboratory and into the clinic, various global regulatory agencies and patent offices will continue to struggle to encourage their development while imposing some sort of order in light of regulatory, safety, and patent concerns.
What Are Nanodrugs?
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1.� Nanodrugs in the Era of Generics
There are enormous pressures on drug regulatory agencies such as the FDA and the EMA to approve follow-on versions (i.e., generic equivalents) of branded drug products. Frankly, judging from the rapid pace of biosimilars approved in the past 2–3 years, the Trump administration seems to be pushing for an increase in generic approvals at the FDA. Concurrently, the increase in the number of drug companies targeting generic opportunities and seeking US market exclusivity for generic versions of major branded products is on the rise. There are many factors for this, including governmental drug policy, price pressures, and statutes. But it is critical that safety issues, immune aspects, and efficacy of these follow-on versions be transparently evaluated by regulators in a science-based context and also fully reported by developers during all phases of the drug R&D process (from preclinical to post-marketing). Lower drug prices, a priority for the Trump Administration [65], should not supplant patient safety and drug efficacy (Box 1.19).
Globally, the regulatory landscape for approval of generic nanodrugs is a murky one. On the one hand, the FDA has published several draft documents pertaining to specific nanodrugs. On the other hand, some countries have already approved multiple generic nanodrugs of dubious efficacy, safety, purity and composition that are being provided to patients without rigorous physicochemical characterization (PCC), adequate clinical trials and with little to no manufacturing oversight. In this context, the recent FDA approval of multiple generic versions of Copaxone®, despite immunological concerns, is an example that merits discussion as it highlights this problematic issue [66]. Copaxone® is a nonbiologic complex drug (NBCD) (Box 1.10) but can also be defined a nanodrug. Furthermore, it shares features with biologics and given the loose definition for biologics, it can also be classified as a biologic. In this chapter, it will be considered a NBCD, a nanodrug, and a biologic. Owing to the complexity of NBCDs and nanodrugs, showing equivalence is more challenging for their follow-on versions [66–69]. Therefore, the interchangeability or substitutability of nanosimilars and their reference listed drug(s)21 21A Reference Listed Drug (RLD) is an approved drug product to which new generic versions are compared to show that they are bioequivalent and a generic
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cannot be taken for granted. In the past, nanosimilars have been approved via generic pathways but differences in clinical efficacy and safety have been reported in the scientific literature following approval [66, 69].
Box 1.10 What Is a Nonbiologic Complex Drug?
“A medicinal product, not being a biological medicine, where the active substance is not a homomolecular structure, but consists of different (closely) related and often nanoparticulate structures that cannot be isolated and fully quantitated, characterized, and/or described by physicochemical analytical means. It is also unknown which structural elements might affect the therapeutic performance. The composition, quality, and in vivo performance of NBCDs are highly dependent on the manufacturing processes of both the active ingredient and the formulation. Examples of NBCDs include liposomes, iron-carbohydrate (iron-sugar) drugs, and glatiramoids.”Source: [66].
Bioequivalence regarding biologics and nanodrugs is a complex and prickly issue. Regulatory approval of biosimilars and nanosimilars is neither straightforward nor standardized. The following discussion regarding biosimilar therapeutic monoclonal antibodies (TMAbs) highlights the fact that such follow-on biologic approval by a regulatory agency must be carefully evaluated on a case-by-case basis for clinical data based on the “totality- of-evidence” [70]:
By contrast with generic small-molecule drugs, clinical performance of a biologic pharmaceutical is a function of its structural complexity and higher-order structure (HOS). Biomanufacturing controls of such complex products cannot fully ensure chemical similarity between an innovator product and putative biosimilar because minor differences in chemical modifications and HOS can significantly alter a product’s safety and efficacy. Therefore, to substantiate claims of clinical functionality, a demonstration of bioequivalence is inadequate
drug company seeking approval to market a generic equivalent must refer to it in its ANDA filing.
Nanodrugs in the Era of Generics
�� Drug Delivery at the Nanoscale
for biosimilar pharmaceuticals. This is different from regulatory approval for generic drugs, in which bioequivalence demonstration is adequate. The overall challenge in approving biosimilar pharmaceuticals is to enable scientific inference of similarity in safety and efficacy for a new biologically derived product compared with an innovator without repeating burdensome clinical studies….So although they are helpful, biological and/or functional assays may not fill a gap in analytical assay sensitivity to detect minor conformational differences between biosimilar TMAbs and innovator products. It is important to note that no analytical test or combination for HOS has yet been sufficiently validated for analytical testing as a substitute for clinical studies in the development of a biosimilar TMAbs drug substance.
In 2010, the Biosimilars Act (Section 1.5) was enacted into law in the US. This established an approval route for generic biologics analogous to small molecule drugs, expanding patient access to some of the most expensive drugs on the market [44]. However, there is no codified generics approval pathway for nanodrugs at present. Moreover, in the absence of universal nomenclature for nanodrugs, although some overlap exists, the biosimilar definition does not fit them. The rules in place for small molecule drugs are being tailored for nanosimilars; this is an imperfect approach.
Furthermore, as indicated above, some of these complex nanodrugs can be classified as NBCDs, which could present additional issues for regulatory agencies as they review generic versions of NBCDs (Box 1.11). The FDA currently lacks an official definition of NBCDs for regulatory purposes and has categorized certain drug products as complex based on a variety of factors as outlined in the GDUFA II Commitment Letter (Table 1.6). The FDA has approved few generic versions of NBCDs. However, I strongly believe that since it is difficult to assess bioequivalence for these complex drug formulations, there will almost certainly be safety and efficacy problems later after generic NBCDs are on the market for some time. Echoing this point, the US Government Accountability Office (GAO) has recently voiced its concern via a detailed report [71] critical of the FDA (Box 1.12).
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Box 1.11 Producing Generics of Complex Drugs
“The experience gained with biosimilars has made it clear that copies of complex drugs are more challenging to produce and put on the market than generics. In the case of so-called NBCDs, the complexity can arise either from a complex active substance or by other factors, such as formulation or route of delivery. Regulatory policies in the USA and the EU for the marketing of NBCD copies are reviewed, using glatiramer acetate copies as a case study. In the USA, they are approved and marketed as generics (although needing additional data), and so they are interchangeable with the originator. In the EU, they are managed with a hybrid application, and their interchangeability and substitution are established by individual member states.
The current orientation of regulatory agencies in the USA and Europe is toward a generic approach, integrated with additional data determined on a case-by-case basis. Even though the specificity of NBCDs is recognized and further studies are required in addition to bioavailability, the outcomes might be different in the two jurisdictions. The case of GA [Glatiramer acetate] is particularly indicative of this divergence. In the USA, copies of Copaxone® were approved by the FDA based on equivalence of (i) the fundamental reaction scheme, (ii) physico-chemical properties, (iii) structural signatures for polymerization and depolymerization and (iv) biological assay results. Those copies are considered interchangeable. In the EU, regulatory authorities required an additional clinical study, based on EMA recommendations. Interchangeability and substitution schemes have been managed on a case-by-case basis by national agencies. However, an alignment of US and EU regulatory policies has started. On the one hand, based on the ‘Deemed to be a License’ provision of the BPCIA, the copies of some biologics, such as insulins, will be treated similarly. On the other hand, the divergence in regulatory policies for products, such as LMWHs [Low-molecular-weight heparins] that are considered biologics in the EU but not in the USA, are deemed to converge owing to advances in analytical methods, which
Nanodrugs in the Era of Generics
(Continued)
�� Drug Delivery at the Nanoscale
enable a reduction in required clinical data, and to the increased regulatory experience...even where NBCD copies are approved as generics, they should not be automatically considered in the same class as small molecule bioequivalent medicinal products and regulatory authorities should consider the impact of the generic classification on post-marketing issues, such as traceability and substitution practices.”Source: [72].
Box 1.1� GAO to FDA: Revised Guidance on NBCDs Needed
“To assess the equivalence of generic versions of NBCDs, drug company sponsors and FDA may need to take more steps compared with generic versions of noncomplex drugs. All but 2 of the 19 stakeholders GAO interviewed agreed that it is challenging to demonstrate equivalence. However, they disagreed about the extent of the challenges and whether those challenges could be overcome. For example, while some brand-name drug sponsors suggest it may be impossible to show that the active ingredient is equivalent between a brand-name and generic complex drug, some generic drug sponsors believe it can be done through advanced scientific methods. GAO identified several steps that have been taken that may help address the challenges associated with reviews to determine equivalence of generic NBCDs to their brand-name counterparts. However, stakeholders disagreed about whether these steps have been enough. For example, to facilitate the entry of generic drugs on the market, including NBCDs, FDA issued product-specific guidance documents to industry, providing recommendations on how to demonstrate equivalence for certain products. While some stakeholders cited product-specific guidance as helpful, representatives of four brand sponsors said the guidance does not adequately address the scientific complexities of NBCDs. Further, guidance for some NBCDs was revised numerous times without any advance notification to industry, according to representatives of generic drug sponsors. Internal control standards for the federal government on communication state that sharing quality
Box 1.11 (Continued)
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information with external parties is necessary to achieve an entity’s objectives. FDA’s good guidance practices regulation also specifies that the agency will publish a list of possible topics for guidance development or revision for the next year. Although the FDA publishes such a list annually, it does not include product-specific guidance documents. The lack of advance communication on guidance issuance and subsequent revisions can create setbacks for generic drug sponsors. For example, according to such sponsors, it may take considerable time, effort, and other resources for them to update their applications to market a generic drug in response to unexpected changes in guidance. This could delay or prevent the entry of some generics to the market.”Source: [71].
Table 1.� Categories and Descriptions of Drug Products that the FDA Categorizes as Complex
Category Examples
Complex active ingredients
Peptides, polymeric compounds, complex mixtures of active pharmaceutical ingredients, naturally sourced ingredients
Complex formulations
Liposomes and colloids
Complex routes of delivery
Locally acting drugs such as dermatological products and complex ophthalmological products and otic dosage forms that are formulated as suspensions, emulsions, or gels
Complex dosage forms
Transdermals, metered dose inhalers, and extended release injectables
Complex drug-device combinations
Auto injectors, metered dose inhalers
Other Other products where complexity or uncertainty concerning the approval pathway or possible alternative approach would benefit from early scientific engagement
Courtesy of the GAO and the FDA.
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�� Drug Delivery at the Nanoscale
In 2011, drug shortages were such a pressing issue in the US that an executive order from the President was issued directing the FDA to streamline the approval process for new therapeutics that could fill the voids. One of the major drugs whose supply was deficient was Doxil®, and to curb this shortage, the FDA on February 21, 2012, authorized the temporary importation of Lipodox® (doxorubicin hydrochloride liposome injection, Sun Pharmaceutical Industries Ltd., India), a generic version of Doxil®. Following this, the FDA evaluated and approved Lipodox® within a year on February 4, 2013, in roughly one-third of the time it takes for an average generic to receive premarket regulatory approval. Hence, Lipodox® became the first generic nanodrug (nanosimilar) approved in the US. Obviously, this helped alleviate the Doxil® shortage and reduced the cost of care (Fig. 1.12). However, a recent study [73] concluded that “the data available from this study and in the peer-reviewed literature are compelling suggesting that Lipodox for treatment of recurrent ovarian cancer does not appear to have equal efficacy compared to Doxil. It raises many concerns how to balance the challenges of drug shortages with maintaining the standards for drug approval. A prospective clinical study to compare the two products is warranted before Lipodox can be deemed equivalent substitution for Doxil.”
Figure 1.1� Cost for Treatment of AIDS-Related Kaposi Sarcoma (KS) from January 2008 to September 2014.
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It is clear from the specific examples of Copaxone® as well as Lipodox® discussed above, generic approval of nanodrugs, biologics and NBCDs is a complex problem. I believe that while the development of generics is important to facilitate patient access to vital drugs at a reasonable price, generic approvals, especially those of nanodrugs, biologics, and NBCDs should be science-based, data-driven, and reported transparently. Often, this will mean that any proposed follow-on product (nanosimilar, biosimilar or NBCD follow-on) be reviewed by regulatory agencies on a case-by-case basis vis-à-vis its long-term safety and efficacy profiles relative to its corresponding branded version. Often, this may only be possible if regulatory review is based upon data from appropriate (non-abbreviated) clinical testing.22 Despite the complexity of NBCDs, surprisingly, regulatory agencies continue to approve generic versions of NBCDs through the ANDA pathway. This is alarming to me. How can the FDA or the EMA approve a generic NBCD if its branded counterpart (i.e., RLD) has not been fully characterized? How can a generic NBCD be shown to be equivalent to its brand-name counterpart? What about some basic proof that no adverse drug reactions (ADRs) are possible for the generic NBCD in the absence of trials? What about the immune aspects, safety and efficacy problems that might not appear until after the generic drug is on the market?
1.10 FDA Regulation of Nanodrugs: Gaps and Baby Steps on a Bumpy Road
Advances in nanomedicine and the FDA system for governing nanodrugs are inevitably intertwined. Internationally, regulatory agencies continue to struggle in their efforts to develop new, meaningful, regulatory definitions and balance them with policies 22Tyler, R. S. (2013). The goals of FDA regulation and the challenges of meeting them. Health Matrix, 22(2), 423–431: “[W]ith respect to drugs, there is no substitute for a well-controlled clinical trial to establish a drug’s safety and effectiveness and conducting such a trial is beyond the competence of individual consumers. Consumers, unprotected by regulations requiring such trials, are unable to judge the safety and effectiveness of a drug.…Nevertheless, the regulatory framework is unsettled and there are now, as there have been in the past, demands in Congress and elsewhere to change the laws under which FDA operates.”
FDA Regulation of Nanodrugs
�� Drug Delivery at the Nanoscale
and laws that are already in place. However, guidance is critically needed to provide clarity and legal certainty to manufacturers, policymakers, healthcare providers and, most importantly, the consumer. Common sense warrants that some sort of oversight or regulation by the FDA is in order, at least on a case-by-case basis. But, so far, the FDA has chosen to regulate nanodrugs solely via laws that are already in the books.
Transparent and effective governmental regulatory guidance is critical for nanomedical translation. However, emerging technologies such as nanotech are particularly problematic for governmental regulatory agencies to handle, given their insular nature, slow response rate, significant inertia, and a general mistrust of industry. Major global regulatory systems, bodies, and regimes regarding nanomedicines are not fully mature, hampered in part by a lack of specific protocols for preclinical development and characterization. Additionally, despite numerous harmonization talks and meetings, there is lack of consensus on procedures, assays, and protocols to be employed during preclinical development and characterization of nanomedicines. The baby steps the FDA has undertaken over the past decade have led to regulatory uncertainty [14–16, 51, 67, 68, 74, 75]. The bumpy ride is likely to continue.
On a broader scale, there are major concerns regarding the drug R&D and regulatory processes themselves. For example, the “evidence” from clinical studies of drug effects and why such evidence might fail in the prediction of the clinical utility of drugs is an issue of much concern to many. Although the standards used by the regulatory agencies have evolved and expanded over the past two decades, serious issues persist with the current approach (Box 1.13).
Many concerned experts highlight another key issue that affects the entire pharma enterprise. It is referred to as the “institutional corruption of pharmaceuticals” (Box 1.14) and is due to an interplay of key players with often-serious conflicts of interest: physicians, Congress, and the drug industry. Naturally, this jeopardizes the safety and effectiveness of all drug products, not only nanodrugs.
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Box 1.1� Defects in the Drug Research Environment
“Problems in clinical studies are an indication of missed opportunities to successfully define the real-world effectiveness and safety of drugs. Driven largely by commercial interests, many clinical studies generate more noise than meaningful evidence to guide clinical decision making. Greater involvement of nonconflicted bodies is needed in the design and conduct of clinical studies, along with more head-to-head comparisons, representative patient populations, hard clinical outcomes, and appropriate analytical approaches. Documenting, registering, and publishing study protocols at the outset and sharing participant-level data at study completion would help ensure transparency and enhance public trust in the clinical research enterprise. Such an approach is needed to generate evidence that is better suited to the tasks of predicting the clinical utility of drugs and providing the information needed by patients and clinicians. Future efforts should focus on engaging the industry, researchers, regulators, clinicians, patients, and other decision makers in discussions to develop transformative ideas with the aim of tackling the numerous defects in the current research environment. Emerging ideas should be piloted and subjected to scientific scrutiny before they are widely implemented and touted as solutions.”Source: [76].
Box 1.1� Institutional Corruption of Pharmaceuticals
“Institutional corruption is a normative concept of growing importance that embodies the systemic dependencies and informal practices that distort an institution’s societal mission. An extensive range of studies and lawsuits already documents strategies by which pharmaceutical companies hide, ignore, or misrepresent evidence about new drugs; distort the medical literature; and misrepresent products to prescribing physicians.... First, through large-scale lobbying and political contributions, the pharmaceutical industry has influenced Congress to pass legislation that has compromised the mission of the Food
FDA Regulation of Nanodrugs
(Continued)
�0 Drug Delivery at the Nanoscale
and Drug Administration (FDA). Second, largely as a result of industry pressure, Congress has underfunded FDA enforcement capacities since 1906, and turning to industry-paid “user fees” since 1992 has biased funding to limit the FDA’s ability to protect the public from serious adverse reactions to drugs that have few offsetting advantages. Finally, industry has commercialized the role of physicians and undermined their position as independent, trusted advisers to patients.”Source: [77].
Not all nanoscale materials are created equal. Some nanomaterials or products that incorporate nanotech may be toxic, their toxicities depend upon factors that are material-specific and/or geometry-specific. But, the toxicity of many nanoscale materials is not fully apparent. Moreover, because premarket testing of nanodrugs will not detect all adverse reactions, it is crucial that long-term safety testing be conducted. Therefore, postmarket tracking or a surveillance system must be adopted to assist in recalls. Toxicity data specific to nanomaterials and nanodrugs needs to be collected and an effective risk research strategy devised. The FDA should seriously contemplate nano-ingredient labeling, where appropriate. Clearly, in many cases, explicit labeling of nanomedical products for consumers is warranted to inform the consumer that these products contain nanotechnology or nanomaterials, especially if there is some evidence of toxicity of their nano-ingredients. Consumer education and public awareness campaigns are the way to go.
The FDA is criticized for producing legally nonbinding “draft” guidance documents while the EMA has similarly issued “position papers.” The FDA’s use of “unofficial” definitions and “draft” guidance documents is legendary and the subject of concern, ridicule and criticism. Such FDA recommendations are nonbinding and come with a standard disclaimer [78]: “This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does
Box 1.1� (Continued)
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not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations....”
As briefly discussed previously (Section 1.3), if a size limit must be tagged onto nanodrugs, then an upper limit of 1,000 nm may be most appropriate. The FDA, which was involved in the formulation of the flawed sub-100 nm NNI definition, has not adopted any “official” regulatory definition for nanotechnology or nanoscale. However, since 2011, following the publication of a “draft” guidance document on nano, it uses an awkward, “unofficial” size-based definition for engineered nanoproducts or products that employ nanotechnology that either: (i) have at least one dimension in the 1–100 nm range; or (ii) are of a size range of up to 1,000 nm (i.e., 1 μm), provided the novel/unique properties or phenomenon (including physical/chemical properties or biological effects) exhibited are attributable to these dimensions greater than 100 nm [79].
Products submitted to the FDA for market approval, including some that may contain nanomaterials, nanodrugs or involve nanomedicine, are evaluated according to a category-based system in one of nine FDA centers that focus on a specific area of regulation. However, certain therapeutics are combination products, which consist of two or more regulated components (drug, biologic or device) that are physically, chemically or otherwise combined/mixed to produce a single entity. In such cases, the FDA determines the “primary mode of action (PMOA)” of the product, which is defined as “the single mode of action of a combination product that provides the most important therapeutic action.” This process is frequently imprecise because it is not always possible to elucidate a combination product’s PMOA. Especially, with the demise of pharma’s blockbuster model, in future, novel “multifunctional/multicomponent” nanodrugs (theranostics) will be designed that incorporate a drug plus in vivo diagnostic in the same engineered nanoparticle. In the future, innovative drugs may also depend upon the use of associated in vitro diagnostics. As these increasingly complex combination products23 (known 23For example, biohybrid sperm microbots, which could be used in the future to deliver anti-cancer drugs to cancerous tumors in women’s reproductive tracts, are being developed. See: Xu, H., Medina-Sánchez, M., Magdanz, V., Schwarz, L., Hebenstreit, F., and Schmidt, O. G. (2018).
FDA Regulation of Nanodrugs
�� Drug Delivery at the Nanoscale
as “borderline products” by EMA) seek regulatory approval, they are sure to present additional headaches for the FDA because the agency’s current PMOA regulatory paradigm may prove ineffective. Moreover, adverse drug reactions (ADRs), especially immunogenic effects, are likely to be especially challenging to evaluate for highly complex drugs. In fact, more than a decade ago in 2007, an FDA Nanotechnology Task Force highlighted this problem with nano-combination products (NCPs) as necessitating further exploration—specifically, whether employing the combination product approach to determine the regulatory pathway to market a NCP as a drug, medical device, or biological product was appropriate. Sadly, no guidance or report on this important issue has been issued by the FDA. The 2007 FDA Nanotechnology Task Force report states [80]: “The very nature of nanoscale materials—their dynamic quality as the size of nanoscale features change, for example, and their potential for diverse applications—could permit development of highly integrated combinations of drugs, biological products, and/or devices, having multiple types of uses, such as combined diagnostic and therapeutic intended uses. As a consequence, the adequacy of the current paradigm for selecting regulatory pathways for ‘combination products’ should be assessed to ensure predictable determinations of the most appropriate pathway for such highly integrated combination products.”
Obviously, there are potentially serious and inhibitory consequences if nanodrugs are overregulated. A balanced approach is required, at least on a case-by-case basis, that addresses the needs of commercialization against mitigation of inadvertent harm to patients or the environment. Obviously, not every nanomedical product needs to be regulated. However, more is clearly needed from regulatory agencies like the FDA and EMA than a stream of draft guidance documents and policy papers that are often short on specifics and fail to address key regulatory issues. There is a very real need for regulatory guidelines that follow a science-based approach and that are responsive to the associated shifts in knowledge and risks.
Sperm-hybrid micromotor for targeted drug delivery. ACS Nano, 12(1), 327–337. Also, see Chapters 14 and 15 in this volume.
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1.11 Protecting Inventions via US Patents
The patent system...secured to the inventor for a limited time exclusive use of his inventions, and thereby added the fuel of interest to the fire of genius in the discovery and production of new and useful things.
—Abraham Lincoln (1809–1865), 16th US President and inventor
A country without a patent office and good patent laws is just a crab, and can’t travel any way but sideways and backways.
—Mark Twain (1835–1910), American writer and humorist
Chance favors only the prepared mind.
—Louis Pasteur (1822–1895), French chemist and Father of Microbiology
Globally, industries that produce and manage “knowledge” and “creativity” have replaced capital and raw materials as the new wealth of nations. Property, which has always been the essence of capitalism, is increasingly changing from tangible to intangible. Intellectual property (IP) rights are a class of assets that accountants call intangible assets. These assets play an ever-increasing role in
Protecting Inventions via US Patents
�� Drug Delivery at the Nanoscale
the development of emerging technologies like biotechnology, drug development, and nanotechnology. Modern IP consists of patents, trademarks, copyrights, and trade secrets. Patents are the most complex, tightly regulated, and expensive form of IP. They have the attributes of personal property—they may be assigned, bought, sold, or licensed.
Patent law is a subtle and esoteric area of law that has evolved in response to technological change. It has been modified numerous times since 1790, the year the first US Patent Act was enacted. This is due to new interpretations of existing laws by the PTO and by the courts, or by creation of new laws by Congress, often in response to new technology. Patent law, arguably one of the most obscure legal disciplines, is now at the forefront of nanomedicine.24
The Founding Fathers incorporated the concept of patents into the Constitution under Article 1, Section 8, Clause 8, whereby Congress was given the authority “[t]o promote the progress of science and the useful arts, by securing for limited times to authors and inventors the exclusive right to their respective writings and discoveries.” President Washington signed the first US Patent Act on April 10, 1790. Title 35 of the United States Code codified the Patent Act of 1952, the Act currently in use. Since the granting of the first US patent in 1790, more than 10 million patents have been issued by the PTO, an agency of the US Department of Commerce. In fact, 1790 was the first year of operation for the PTO and it issued only three patents. The number of patent applications filed have been generally increasing over the years and currently there is an astounding backlog of over 500,000+ unexamined US patent applications. The PTO is unique among federal agencies because it operates solely on fees collected by its users, and not on taxpayer dollars and it operates like a business
24As the line between academia and industry becomes fuzzier, the axiom for success in science, “publish or perish,” is being replaced with “patent or perish” or “patent and prosper.” Some universities are straying away from their “education mission” by focusing on patents for potential license revenue. I believe that patents are as important, if not more so, as publications on curriculum vitae, and have a major impact in academia on hiring, tenure, and promotion.
��
in that it receives requests for services—applications for patent examination and trademark registrations—and charges fees.
Patentable inventions need not be pioneering breakthroughs; improvements of existing inventions or unique combinations or arrangements of old formulations may also be patented. In fact, majority of inventions are improvements on existing technologies. However, not every innovation is patentable. For example, abstract ideas, laws of nature, works of art, mathematical algorithms, unique symbols, and writings cannot be patented. Works of art and writings, however, may be copyrighted and symbols may be trademarked. Laws of the universe or discoveries in the natural world, even if revolutionary, cannot be patented. For instance, Einstein’s Law of Relativity cannot be considered anyone’s IP. For a US patent to be granted, an invention must meet specific criteria as set forth in US statutes.
A US patent provides protection only in the United States, its territories, and its possessions for the term of the patent. A patent is not a “hunting license”; it is merely a “no trespassing fence” that clearly marks the boundaries of an invention (Brenner v. Manson, 1966) [81]. In other words, a patent grant is a negative grant; it prevents other parties from using the invention without prior permission of the patent holder (which can be in the form of a license). This does not imply that the patent holder can automatically publicly practice (i.e., commercialize) the invention. Often, appropriate government regulatory approval is required. It is estimated that most of the of the world’s patents are issued through the US, China, South Korea, Europe, and Japan. Legally speaking, a US patent is a document granted by the federal government (at the PTO) whereby the recipient (“patentee”) is conferred the temporary right to exclude others from making, using, selling, offering for sale, or importing the patented invention into the US for up to 20 years from the filing date. Similarly, if the invention is a process, then the products made by that process cannot be imported into the US.
All patented inventions eventually move “off patent” at the end of their patent term (“patent expiration”) at which time they are dedicated to the public domain. This is the basis for low-cost generic drugs that appear in the marketplace following expiration
Protecting Inventions via US Patents
�� Drug Delivery at the Nanoscale
of the costlier versions of the patented branded drug. Current US patent laws allow granting a patent on new drug formulations that have been created from old drugs, for instance, via novel DDS. Nanotechnology could also allow reformulation of existing and orphaned compounds. These new reformulations may qualify as NCEs at the FDA and for patents at the PTO. In other words, “nanoformulations” of older drugs may be patentable if they fulfill all the criteria for patentability. Furthermore, innovative DDS or platforms may be patented on their own under current US patent statutes. Innovative DDS could enable drug companies to devise novel drug reformulations of off-patent or soon-to-be off-patent compounds. This strategy could delay or discourage generic competition during the most profitable years of an innovator drug’s life cycle, especially if the reformulated drug is superior to its off-patent or soon-to-be off-patent counterpart. This approach, in effect, stretches the product life cycle of an existing, branded, patented drug. This strategy, commonly referred to as “product-line-extension,” is broad in scope and includes any second-generation adaptation of an existing drug that offers improved safety, efficacy, or patient compliance. In fact, successful reformulation strategies should focus on how to add value through added ease and convenience for the consumer. If this approach is successful, the innovative DDS or platforms can maintain market share even after generics appear in the marketplace. Another often-employed approach is to develop and patent a novel polymorph of the innovative drug compound prior to patent expiration. Yet another strategy involves generating patent protection from a competitor’s formulation (patented or off patent), by analyzing the competitor’s existing patent claims, then tweaking them and filing patents that circumvent the competitor’s specific use or DDS.
The basic rationale underlying patent systems, both in the US and abroad, is simple enough: An inventor is encouraged to apply for a patent by a grant from the government of legal monopoly of limited duration for the invention. This limited monopoly or proprietary right justifies R&D costs by assuring inventors the ability to derive economic benefit from their work. In exchange for this grant, the inventor publicly discloses the new technology that might have otherwise remained secret (an “immediate
��
benefit” to the public) and allows the public to freely use, make, sell, or import the invention once the patent expires (a “delayed benefit” to the public). Hence, the new technology that is brought to light in the form of valuable technical information provides a continuous incentive for future innovation. In this way, society obtains a quid pro quo from inventors in exchange for the temporary grant of exclusive rights. Such an advantageous exchange stimulates commerce (a “long-term benefit” to the public). Patent protection is the engine that drives industry and the incentive for it to invest in R&D to innovate. Clearly, without such protection, most companies would avoid costly R&D, and society would be deprived of the many benefits thereof. However, it is critical that the scope or breadth of the patent issued by the PTO be just right; it should neither be unduly broad, nor should it be too limiting. In other words, the invention granted a patent should just fit within the boundaries of that patent. Unfortunately, this is not always the case.
Obtaining a patent for an invention is often a long, expensive, and tedious process that generally involves the inventor, patent counsel, or practitioner (i.e., patent agent or patent attorney) and PTO staff (especially a “patent examiner”). Patent examiners are PTO personnel who review the filed patent application to ensure that it fulfils all pertinent requirements of the law. This review process is commonly referred to as an “examination.” The exchange of documents between the PTO and the patent counsel is broadly known as “prosecution.” If the examiner believes that all requirements for a patent are met, then a “notice of allowance” is issued to the applicant. Following this, a patent is issued once the applicant pays an “issuance fee.” Upon issuance, the entire contents of the patent application (“the file wrapper” or “prosecution history”) along with a copy of the patent and all future documents pertaining to the patent, are made available to the public. The entire patent examination process, starting with the filing of the patent application to its allowance or final rejection, may take anywhere from 1 to 5 years, or longer. This depends upon variables such as the specific technology area within the PTO where the patent is being reviewed by the patent examiner and the time to process the paperwork that accompanies the patent application
Protecting Inventions via US Patents
78 Drug Delivery at the Nanoscale
by the PTO. As part of the patent prosecution, all applications filed on or after November 29, 1999, are generally published 18 months after filing.
Top: Courtesy of ReubenGBrewer, licensed under the Creative Commons Attribution-Share Alike 4.0 International license. Bottom: Courtesy of Alan Kotok, licensed under the Creative Commons Attribution-2.0 Generic (CC BY 2.0).
79
Because, for most patents, the patent term commences on the date of filing and ends 20 years thereafter, most commercially valuable nanomedicine inventions are, in reality, in the marketplace prior to the actual patent grant date (unless regulatory approval is sought). Generally, it is impossible to predict the future commercial success or commercial viability of an issued patent. In part, this is because most patents are filed at the PTO without any clear idea of whether the invention is commercially valuable. For example, in nanomedicine, patent applications are continuously being filed on many drugs, therapies, and devices even before it is known that they will be ruled safe and effective by the FDA. If litigation rates are any indicator of commercial value, then only a tiny fraction of patents are commercially significant. Although obtaining a patent does not ensure commercial success, economists view patenting as an indicator of scientific activity [82]. They argue that this is the basis for providing a nation with a competitive advantage, fueling its economy.
In recent years, however, patents have become the subject of much debate, controversy and even outright theft (Box 1.15). Some view patent laws (and most international treaties) are unfairly providing an economic advantage to some over others [83]. It has even been suggested that patent laws and IP are the products of a new form of Western colonialism designed to deny the developing world access to common goods. Issues like biopiracy and IP theft have been proffered as reasons for the unavailability of essential drugs to the poorest and neediest people in the world. Not surprisingly, those in the developing world support patent protection but prefer a regime that suits their own national interests. In this regard, they highlight the fact that although Western drug companies continue to cite the need to reward innovation as a justification for stronger patent laws or patent enforcement, in reality, they continue to spend more on reformulating preexisting drug formulations and on expensive litigation to protect their current patents than to discover novel molecules. Regarding the longstanding and contentious issue of IP theft, China has been the major culprit (Box 1.15).
Protecting Inventions via US Patents
�0 Drug Delivery at the Nanoscale
Box 1.1� China’s Illegitimate Game of Intellectual Property (IP) Theft
China’s disregard and theft of all forms of IP dates back decades. Rampant Chinese theft of corporate IP ranges from forced technology transfers, in which the Chinese government compels companies investing in China to provide IP details and licenses, to actual theft of IP—counterfeit of famous brands, pirating software, and espionage and cyberattacks of trade secrets. In fact, a new CNBC poll finds that one in five corporations say China has stolen their IP within the last year [84]. The US Trade Representative (USTR) has recently estimated the annual IP loss to China at between $225 billion and $600 billion [84]. Chinese IP theft obviously damages non-Chinese companies as not only they lose out due to direct counterfeiting, but they need to lower their prices to compete in a country that supports domestic industry. They are also forced to spend billions of dollars to address possible infringements. Trademark infringement is the most common form of IP violation in China, but copyright infringement is the most damaging. The Chinese judicial system is subservient to the ruling Communist Party, so court decisions are usually rigged. Some studies conclude that more than half of all technology owned by Chinese firms was obtained by hook-or-crook from foreign companies.
On August 14, 2017, the US President via a Memorandum (82 FR 39007) instructed the USTR to determine under Section 301 of the Trade Act of 1974 whether to investigate China’s laws,
�1
policies, practices, or actions that may be unreasonable or discriminatory and that may be harming American IP rights, innovation, or technology development. On August 18, 2017, the USTR, following a thorough Section 301 investigation, determined the following Chinese actions are unreasonable or discriminatory and burden or restrict US commerce [85a, 85b]:
First, China uses foreign ownership restrictions, such as joint venture requirements and foreign equity limitations, and various administrative review and licensing processes, to require or pressure technology transfer from US companies.
Second, China’s regime of technology regulations forces US companies seeking to license technologies to Chinese entities to do so on non-market-based terms that favor Chinese recipients
Third, China directs and unfairly facilitates the systematic investment in, and acquisition of, US companies and assets by Chinese companies to obtain cutting-edge technologies and IP, and generate the transfer of technology to Chinese companies.
Fourth, China conducts and supports unauthorized intrusions into, and theft from, the computer networks of US companies to access their sensitive commercial information and trade secrets.
The PTO does not police or monitor patent infringement and it does not enforce issued patents against potential infringers. It is solely up to the patentee to protect or enforce the patent, all at the patentee’s own cost. The patentee may enlist the US government’s help via the court system to prevent patent infringement. However, PTO decisions are subject to review by the courts, including the CAFC, and rarely, the US Supreme Court. Sometimes Congress intervenes and changes or modifies some of the laws governing patents. If a court deems a patent to be invalid, the patent holder is unable to enforce it against any party. However, suing an alleged infringer is a risky business because when a patent holder sues an alleged infringer, there is a risk that his/her own patent will be found to be invalid.
It took 75 years to issue the first million patents. The last million patents took only three years to issue. It took 155 years
Protecting Inventions via US Patents
�� Drug Delivery at the Nanoscale
(1836 to 1991) for the PTO to issue its first 5 million patents but took only 27 years to issue the next 5 million.25 Has the quality of patent examination at PTO gone down or are we in a world that is generating more patentable technologies? I agree with legal scholars who consider PTO grant rates to be high and this may indirectly reflect a less rigorous review of patent applications as compared to the other major patent offices. In other words, these high allowance rates may be partly to blame for the granting of poor-quality patents by the PTO [86]. In the US, since the grant of a patent for a genetically modified (“engineered”) microorganism in 1980 in Diamond v. Chakrabarty, it is accepted that “anything under the sun that is made by man” is eligible for a US patent. This legal interpretation encompasses genetically modified animals (Box 1.16).
In the context of IP, patents in the nanomedical space are essential. The protection of inventions via patents provides an opportunity for nanomedical companies to recoup the high cost of discovery by preventing competitors from entering the marketplace while the patent is in force. Simply put, securing valid and defensible patent protection from the patent offices is critical to any commercialization effort. Valid patents stimulate market growth and innovation, generate revenue, prevent unnecessary licensing, and reduce infringement lawsuits. Obtaining patents can add value to the bottom line of a company by increasing its intangible assets and, more importantly, enhance the company’s power in the marketplace by providing it with the right to stop others from making or using the invention without permission. Understanding the patent process, the patent landscape, and white-space opportunities are essential to translational research and the development of innovations for clinical use. White-space opportunity, a metaphor about opportunity, is defined variously: as a business space where there is little or no competition, or it refers to entirely new markets, or it indicates gaps in existing markets or product lines. So far, the process of converting basic
25The first US patent was issued in 1790 while the numbering system was established in 1836.
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research in nanomedicine into commercially viable products has been difficult. IP, obviously, is the lifeblood of any nano-enterprise, both as an enabler of translation and sometimes as a barrier to competition or litigation. Patents can have an impact at all stages in the translation pipeline: preclinical research stage, clinical trial stage, at the point of commercialization, and when the product is in the clinic.
Freedom-to-operate or FTO (also called “product clearance” or “right to use” opinions) is another important patent concept that nano-researchers should become fluent with so that they are aware of the patents in existence when developing novel technologies in the first place. This will help (i) identify technology in development that could potentially infringe valid patents and lead to enforcement action on the part of the patent holder (a time-consuming and expensive process for both parties); and (ii) assist researchers in protecting their own IP by assessing their inventions and the scope of protecting them via patents relative to other art in their field of research. In other words, FTOs are often used to determine whether a particular action, such as testing or commercializing a product, can be done without infringing valid patents belonging to others. Because patents are specific to different jurisdictions, an FTO analysis should relate to countries or regions where you want to operate or commercialize your nanoproduct. FTO analysis involves identifying and analyzing patents belonging to others that may subject your company to patent infringement liability. To limit its risk of potential litigation and avoid unnecessary expenses, an FTO should be performed before developing and launching a new product or before acquiring a new company. Preferably, in nanomedicine, it should be done during the preclinical stage so that the company is able to (i) modify the product to work around the patent and avoid future infringement before reaching a point of no return, (ii) identify additional opportunities for patenting or further R&D, or (iii) analyze its business position and have an opportunity to take out a license.
Protecting Inventions via US Patents
�� Drug Delivery at the Nanoscale
Box
1.1�
An
imal
s an
d P
aten
ts: T
he
Mou
se T
hat
Wen
t to
Har
vard
!
The
idea
of p
aten
ting
life
soun
ds li
ke s
omet
hing
str
aigh
t out
of G
eorg
e Or
wel
l’s n
ovel
198
4. H
ow ir
onic
then
that
on
June
22,
198
4, H
arva
rd U
nive
rsity
file
d a
pate
nt a
pplic
atio
n at
the
US
Pate
nt O
ffice
for
the
Har
vard
Onc
oMou
se...a
ge
netic
ally
eng
inee
red
mou
se c
onta
inin
g hu
man
onc
ogen
es (
and
henc
e its
nam
e) t
hat
pred
ispo
ses
it to
dev
elop
ing
brea
st c
ance
r. Th
e ap
plic
atio
n, t
itled
“tr
ansg
enic
non
-hum
an m
amm
als,”
was
aw
arde
d US
Pat
ent
No.
4,7
36,8
66 o
n Ap
ril
12, 1
988
(exp
ired
in
2005
). Th
is i
s th
e fir
st p
aten
t on
an
anim
al a
nd i
s a
true
mile
ston
e in
bio
tech
nolo
gy
pate
ntin
g. T
he m
ouse
, w
hich
has
bee
n lic
ense
d to
Du
Pont
, is
sol
d as
a m
odel
for
bre
ast
canc
er r
esea
rch.
Al
thou
gh, i
ts n
ame
is n
ot a
s in
spir
ing
as “
Mic
key”
or
“Mig
hty,”
the
Har
vard
Onc
oMou
se c
erta
inly
has
som
ethi
ng t
o sq
ueak
(or
roa
r) a
bout
. Was
ther
e so
me
cont
rove
rsy
over
pat
entin
g a
livin
g an
imal
? Yo
u be
t. Th
ere
still
is a
nd th
ere
prob
ably
alw
ays
will
be.
To
the
outs
ide
obse
rver
, the
not
ion
of p
aten
ting
a liv
ing
thin
g sm
acks
of
scie
ntis
ts a
nd
busi
ness
men
pla
ying
God
. So
how
did
this
pat
ent g
ain
supp
ort?
The
see
ds o
f app
rova
l wer
e pl
ante
d by
the
land
mar
k 19
80 S
upre
me
Cour
t’s 5
-4 d
ecis
ion
in D
iam
ond
v. C
hakr
abar
ty, a
rul
ing
that
for
the
first
tim
e in
the
hist
ory
of p
aten
t la
w e
stab
lishe
d th
at l
ife w
as p
aten
tabl
e. T
he S
upre
me
Cour
t st
ated
tha
t “a
pat
ent
can
be g
rant
ed o
n an
ythi
ng
unde
r th
e su
n w
hich
can
be
mad
e by
man
” an
d “t
he r
elev
ant d
istin
ctio
n [in
pat
enta
bilit
y] is
not
bet
wee
n liv
ing
and
inan
imat
e th
ings
, but
whe
ther
livi
ng p
rodu
cts
can
be s
een
as ‘h
uman
-mad
e in
vent
ions
.’” P
rior
to 1
980,
the
US P
aten
t Of
fice
did
not
gran
t pa
tent
s on
mic
roor
gani
sms
and
cells
dev
elop
ed v
ia r
ecom
bina
nt D
NA t
echn
olog
y, de
emin
g th
em t
o be
“pr
oduc
ts o
f na
ture
.” In
fac
t, it
rout
inel
y re
ject
ed p
aten
t ap
plic
atio
ns p
erta
inin
g to
life
-form
s as
non
-st
atut
ory
subj
ect
mat
ter
unde
r th
e tr
aditi
onal
lega
l doc
trin
e de
fined
by
35 U
SC §
101
. Alth
ough
no
pate
nts
wer
e gr
ante
d on
livi
ng o
rgan
ism
s pe
r se
at
this
tim
e, c
ompo
sitio
ns c
onta
inin
g liv
ing
thin
gs, s
uch
as v
acci
nes
cont
aini
ng
atte
nuat
ed b
acte
ria
wer
e pa
tent
able
. A b
oom
in t
he U
S bi
otec
hnol
ogy
indu
stry
follo
wed
the
Cha
krab
arty
dec
isio
n,
larg
ely
due
to t
he i
ntel
lect
ual p
rope
rty
prot
ectio
n no
w a
vaila
ble
to i
nven
tions
of
life.
Bas
ed o
n th
is d
ecis
ion,
the
US
Pat
ent O
ffice
in 1
987
foun
d in
Ex
Part
e Al
len
that
a r
adia
tion-
indu
ced
vari
ety
of o
yste
rs w
ere
pate
ntab
le, t
here
by
furt
her
rein
forc
ing
the
conc
ept
of g
rant
ing
pate
nts
on m
odifi
ed li
fe fo
rms.
On A
pril
7, 1
987,
bar
ely
four
day
s af
ter
the
Alle
n ru
ling,
the
US
Pate
nt O
ffice
ann
ounc
ed t
hat
it no
w c
onsi
dere
d “n
onna
tura
lly o
ccur
ring
non
-hum
an
mul
ticel
lula
r liv
ing
orga
nism
s, in
clud
ing
anim
als,
to b
e pa
tent
able
sub
ject
mat
ter
with
in th
e sc
ope
of 3
5 US
C §
101.
”
��
In o
ther
wor
ds, t
he U
S Pa
tent
Offi
ce n
ow v
iew
ed a
ltere
d or
gen
etic
ally
mod
ified
ani
mal
s to
be “n
onna
tura
lly o
ccur
ring
” an
d “a
pro
duct
of h
uman
inge
nuity
.” Fo
llow
ing
this
ann
ounc
emen
t, th
e H
arva
rd O
ncoM
ouse
pat
ent
was
gra
nted
in
1988
. A
1989
cha
lleng
e by
the
Anim
al L
egal
Def
ense
Fun
d in
fede
ral c
ourt
to th
e H
arva
rd O
ncoM
ouse
pat
ent f
ollo
wed
but
fa
iled.
Sin
ce t
hen,
pub
lic o
utra
ge a
nd c
once
rn a
bout
ani
mal
pat
ents
has
bee
n ex
pres
sed
both
in c
ourt
and
sev
eral
se
ssio
ns o
f Con
gres
s. Th
e co
urts
hav
e st
ated
tha
t th
e m
atte
r of
ani
mal
pat
ents
sho
uld
be d
irec
ted
to C
ongr
ess,
not
the
judi
ciar
y br
anch
. So
far
, va
riou
s le
gisl
ativ
e eff
orts
in
Cong
ress
at
plac
ing
a m
orat
oriu
m o
n an
imal
pat
ents
ha
ve b
een
unsu
cces
sful
. In
fac
t, as
of
2019
, ov
er a
tho
usan
d pa
tent
s ha
ve b
een
gran
ted
for
vari
ous
tran
sgen
ic
(gen
etic
ally
alte
red)
ani
mal
s in
the
US a
nd o
ther
nat
ions
, fur
ther
fuel
ing
the
biot
echn
olog
y re
volu
tion
of th
e 19
80s.
The
Har
vard
Onc
oMou
se w
as fi
nally
aw
arde
d a
pate
nt in
Eur
ope
(199
2, r
evok
ed in
200
6), J
apan
(19
94),
and
Cana
da
(200
3), f
ollo
win
g en
orm
ous o
ppos
ition
and
del
ay.
Tran
sgen
ic a
nim
als
like
the
Har
vard
Onc
oMou
se h
ave
enor
mou
s po
tent
ial t
o se
rve
as m
odel
s fo
r st
udyi
ng h
uman
di
seas
es a
nd in
var
ious
asp
ects
of t
he d
rug
or d
evic
e de
velo
pmen
t pro
cess
. In
addi
tion,
they
can
act
as
“bio
fact
orie
s”
for b
ioth
erap
eutic
pro
duct
ion;
be
used
to g
ener
ate
orga
ns a
nd ti
ssue
s fo
r hum
an tr
ansp
lant
atio
n; o
r ser
ve a
s su
peri
or
farm
ani
mal
s th
at a
re m
ore
resi
stan
t to
dis
ease
or
have
enh
ance
d gr
owth
. Cer
tain
act
ivis
t or
gani
zatio
ns, h
owev
er,
view
that
it is
an
unet
hica
l and
inap
prop
riat
e us
e of
the
pate
nt sy
stem
to is
sue
pate
nts f
or se
ntie
nt b
eing
s. In
fact
, ove
r th
e ye
ars
som
e an
imal
pat
ents
hav
e be
en r
esci
nded
by
the
US P
aten
t Offi
ce. E
xam
ples
incl
ude
a pa
tent
that
had
bee
n gr
ante
d fo
r ra
bbits
who
se e
yes
wer
e in
tent
iona
lly d
amag
ed t
o se
rve
as a
mod
el fo
r hu
man
dry
eye
syn
drom
e an
d an
othe
r to
beag
les u
sefu
l in
the
eval
uatio
n of
hum
an in
tral
umin
al v
alve
pro
sthe
ses.
Sinc
e de
velo
pmen
t of
tra
nsge
nic
anim
als
is o
ne o
f the
mos
t re
sear
ch-in
tens
ive
indu
stri
es in
exi
sten
ce, w
ithou
t th
e m
arke
t exc
lusi
vity
offe
red
by a
US p
aten
t, de
velo
pmen
t of t
rans
geni
c ani
mal
s and
thei
r int
rodu
ctio
n in
to th
e mar
ketp
lace
w
ould
be
sign
ifica
ntly
ham
pere
d. S
till,
anim
al p
aten
ting
cont
inue
s to
be
one
of th
e m
ost
cont
entio
us m
oral
, eth
ical
, ec
onom
ic a
nd le
gal i
ssue
s of o
ur ti
mes
. Thi
s iss
ue re
mai
ns fa
r fro
m se
ttle
d.
Protecting Inventions via US Patents
�� Drug Delivery at the Nanoscale
Details on nanopatents, including the legal criteria necessary to obtain a US patent (Fig. 1.13) and the prosecution process for obtaining a US patent (Fig. 1.14), can be found elsewhere [3, 5, 21, 27].
Despite scanty product development, nanopatent filings and grants have continued unabated. However, it is no secret that nanopatents of dubious scope and breath, especially on foundational nanomaterials and upstream nanotechnologies, have been routinely granted by patent offices. In fact, “patent prospectors” have been on a global quest for “nanopatent land grabs” since the early to mid-1980s [27, 86–91]. As a result, patent thickets26 in certain sectors of nanotechnology have arisen that could have a chilling impact on commercialization activities. They may also require innovators to reach licensing deals with multiple partners for multiple patents. For example, the US carbon nanotube (CNT) patent landscape is a tangled mess, mainly due to issuance of multiple US patents in error by the PTO. Also, to blame for this is the fact that there is a lack of a nano-nomenclature whereby inventors and scientists have employed distinct terms to refer to CNTs. As a result, contrary to the foundations of US patent law, various US patents on CNTs have been granted with legally identical claims [92]. The expected negative impact on commercialization and patent litigation has not arrived as of now because CNTs have failed to deliver on their commercial potential. Fabrication of affordable and high-quality CNTs has not materialized and scientists are now pursuing other exciting materials such as graphene instead. Hype and technology often evolve together and, in the case of CNTs, the “peak of inflated expectations” of the 1990s was replaced by the “trough of disillusionment” in the early 2000s [93].
Patent offices continue to be under enormous strain and scrutiny. Issues ranging from poor patent quality, questionable examination practices, inadequate search capabilities, rising attrition, poor examiner morale, and an enormous patent backlog are just a few issues that need reform. Additionally, nano’s nomenclature issue (Section 1.3) is negatively affecting patent drafting and prosecution.
26A patent thicket is a dense web of overlapping patent claims that can potentially impede a company to commercialize new technology.
��
Inven on
Patent Eligible Subject Ma er?(Not Merely an Abstract Idea,Mathema cal Formula, etc.)
Does the Inven on Have U lity?(Is It Useful?)
Is the Inven on Novel?
Is the Inven on Obvious OverCurrently Exis ng Prior Art?
Inven on Is NotPatentable
Inven on Is LikelyPatentable!
(assuming compliance withdisclosure requirements
and other formali es)
Yes
Yes
Yes
No
No
No
No
Yes
Figure 1.1� Legal Criterion to Obtain a US Patent.Courtesy of Dr. Brian E. Reese, Choate, Hall & Stewart LLP, Boston, USA.
Protecting Inventions via US Patents
�� Drug Delivery at the Nanoscale
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Figu
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Protecting Inventions via US Patents
�0 Drug Delivery at the Nanoscale
1.1� Bench-to-Bedside Translation of Nanomedicine
The good physician treats the disease; the great physician treats the patient who has the disease.
—William Osler (1849–1919), Canadian physician and co-founder of Johns Hopkins Hospital
The successful warrior is the average man, with laser-like focus.
—Bruce Lee (1940–1973), American/Hong Kong actor and martial arts master
No one can argue that the enormous infusion of public and private investments in biomedical research has yielded drastically less clinical products than expected. The relatively long time for medical products from discovery to ultimate clinical use and the relatively low proportion of discoveries that survived that journey is a problem. There is consensus that the development of (nano) medical products and interventions takes too long, is too expensive, and fraught with failures at every stage of
�1
development. There is too wide an innovation gap between basic sciences (preclinical biomedical research) and clinical sciences (development of novel therapeutic options for the patient). This continues to threaten or stall translation of advances in the laboratory to the patient’s bedside. These barriers to translational research are relatively recent. In the 1950s and 1960s, basic (or preclinical) and clinical research were tightly linked in agencies such as the NIH, and clinical research was mainly conducted by physician–scientists who also undertook patient care [94]. In the 1970s, this model changed with the explosion of genetic engineering. Clinical and basic research started to diverge, and biomedical research emerged as a unique discipline with its own training. As a result, nowadays most of biomedical research is conducted by highly specialized PhD-scientists while physician-scientists are a minority.
Creating medical products today, including nanomedical, whether they are drugs, devices, or combination products, is a complex process that requires a multiple of scientific disciplines. It is time-consuming, expensive, and enormously challenging. For example, de novo drug discovery and development is a 10–17 year process from conception to marketed drug (Figs. 1.2 and 1.3). Inherent to this complexity is low solubility and poor bioavailability of the molecules being studied. It may take up to a decade for a drug candidate to just enter clinical trials, with very few tested candidates in trials reaching the clinic. In fact, often, more drugs come off patent each year than are approved by the FDA. According to a 2014 study by the Tufts Center for the Study of Drug Development, developing a new prescription medicine that gains marketing approval is estimated to cost nearly $2.6 billion [95].
Regardless of the industry or the origin of technology, for a product to become successful it must endure and traverse a most difficult period in its lifetime, the so-called “valley of death” (Fig. 1.15). It is a graveyard for many good scientific ideas, technologies, new products, and processes, representing the transition from basic research activities to product development. By extension, the same is true for nanomedicines. All stakeholders—pharma, patients, regulators, patent offices, funders—have suffered and are to blame for the valley of death. Each needs to re-examine its role and become an active, full partner
Bench-to-Bedside Translation of Nanomedicine
�� Drug Delivery at the Nanoscale
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.1� Mapping the “Valley of Death” in the Context of Product Development and Com
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��
in the biomedical ecosystem so that translational activities are more fruitful. Similarly, although great strides have been made in nanomedicine at the R&D or science level, especially in the areas of drug delivery and nanoimaging, bottlenecks at the translational level are impeding commercialization (Table 1.7). Therefore, improving nanomedicine is a global priority that needs full stakeholder input and serous focus (Table 1.8).
The European Society for Translational Medicine defines translational medicine (TM) as an interdisciplinary branch of the biomedical field supported by three main pillars (bench side, bedside, and community) with the goal to combine disciplines, resources, expertise, and techniques within these pillars to promote enhancements in prevention, diagnosis, and therapies [96]. Given this, the aim of TM [96] is to facilitate the transition of preclinical or basic research into clinical or medical application, generally via a faster, easier, cheaper, and more efficient route. This allows realizing the social value of science, that is, the production of medical products, applications, and methods that help improve human health. The primary impetus for TM is that there are better ways to move preclinical biomedical research to medical practice more quickly without sacrificing quality or increasing costs. TM invariably involves multidisciplinarity, collaboration, and networking along with novel models, modes of communication, and regulatory systems—all features that are the hallmark of nanomedicine. The growth of TM, in general, has coincided with an ever-changing pharma landscape.
However, despite significant investments by the public and private sectors, major issues that led to the emergence of TM in the first place have continued to dog TM and persist along the research–practice continuum (Table 1.7). In the US, the NIH has made TM a central piece of its so-called NIH Roadmap for Medical Research [97] while the FDA launched a similar “Critical Path Initiative” [98] to address the growing crisis in moving basic discoveries to the market where they can be available to patients. Although both governmental initiatives [97, 98] were launched over a decade ago, they have proven unsuccessful in dramatically improving the availability of new diagnostic/therapeutic modalities to the American public. This is because both the NIH and FDA have failed to address key blocks in
Bench-to-Bedside Translation of Nanomedicine
�� Drug Delivery at the Nanoscale
Tabl
e 1.
� Se
lect
Bar
rier
s to
Nan
omed
icin
e T
ran
slat
ion
Nom
encl
atu
re a
nd
term
inol
ogy
–Im
prec
ise
and
conf
usin
g de
finiti
on fo
r nan
o-re
late
d te
rms i
n th
e lit
erat
ure,
in p
aten
ts a
nd o
n w
ebsi
tes
–Fl
awed
US
NN
I def
initi
on o
f nan
otec
hnol
ogy
is a
maj
or is
sue
–La
ck o
f tec
hnic
al sp
ecifi
catio
ns, s
tand
ards
, gui
delin
es, b
est p
ract
ices
, and
mea
sure
men
ts re
gard
ing
“nan
o”
–Di
ffere
nt te
rms r
efer
to id
entic
al n
anom
ater
ials
and
nan
opar
ticle
s
–Di
scre
panc
ies
and
inco
nsis
tent
def
initi
ons
in p
harm
a, g
over
nmen
tal a
genc
ies
and
regu
lato
ry b
odie
s w
ith r
espe
ct t
o va
riou
s te
rms r
elev
ant t
o dr
ug R
&D
spill
s int
o na
nom
edic
ine
–FD
A, E
MA,
and
WH
O ca
nnot
agr
ee o
n de
finiti
ons c
entr
al to
nan
odru
g de
velo
pmen
t
–Fa
ilure
of s
tand
ard-
sett
ing
orga
niza
tions
like
ISO
and
ASTM
to p
rodu
ce te
chni
cal s
peci
ficat
ions
that
clar
ify th
e is
sue
Com
mercial manufacturing and quality control (“the process is the product”)
–Is
sues
per
tain
ing
to s
epar
atio
n of
und
esir
able
s an
d im
puri
ties
(by-
prod
ucts
, ca
taly
sts,
star
ting
mat
eria
ls,
etc.)
dur
ing
man
ufac
turi
ng;
pres
ence
of
impu
ritie
s or
con
tam
inan
ts m
ay t
rigg
er a
n im
mun
e re
spon
se i
n pa
tient
s; p
rote
in-b
ased
na
nodr
ug p
oten
cy m
ay b
e im
pair
ed v
ia d
egra
datio
n
–La
ck o
f pre
cise
cont
rol o
ver n
anop
artic
le/n
anom
ater
ial m
anuf
actu
ring
par
amet
ers a
nd co
ntro
l ass
ays
–M
any
curr
ently
use
d co
mpo
unds
/com
pone
nts
for
synt
hesi
s po
se p
robl
ems
for
larg
e-sc
ale
curr
ent G
ood
Man
ufac
turi
ng P
ract
ice
(cGM
P)
–Te
chno
logi
cal c
halle
nges
exp
erie
nced
dur
ing
scal
e-up
; sca
labi
lity
com
plex
ities
reg
ardi
ng in
crea
sing
pro
duct
ion
rate
to e
nhan
ce
yiel
d
��
–Co
mpl
exiti
es a
nd h
igh
fabr
icat
ion
cost
s of
var
ious
nan
omat
eria
ls, n
anop
artic
les,
and
nano
ther
apeu
tics;
cos
t of
raw
mat
eria
ls;
expe
nsiv
e an
d tim
e-co
nsum
ing
sepa
ratio
n pr
oces
ses m
ay b
e re
quir
ed–
Repr
oduc
ibili
ty is
sues
such
as c
ontr
ol o
f siz
e di
stri
butio
n an
d m
ass
–St
abili
ty o
f bot
h th
e st
artin
g m
ater
ials
and
the
prod
uct (
aggr
egat
ion,
deg
rada
tion,
etc
.)–
Batc
h-to
-bat
ch v
aria
bilit
yToxicity and im
munogenicity (Box 1.17)
–Un
pred
icta
ble
toxi
city
with
resp
ect t
o th
e di
vers
e po
pula
tion
of n
anom
ater
ials
and
nan
opar
ticle
s–
Lack
of i
n vi
vo k
now
ledg
e re
gard
ing
the
inte
ract
ion
betw
een
nano
med
ical
pro
duct
s and
com
plex
bio
surf
aces
/tis
sues
–La
ck o
f rat
iona
l pre
clin
ical
char
acte
riza
tion
stra
tegi
es v
ia m
ultip
le te
chni
ques
–Li
mite
d kn
owle
dge
on b
ioco
mpa
tibili
ty a
nd b
iodi
stri
butio
n of
div
erse
nan
omat
eria
ls a
nd n
anop
artic
les
–Li
mite
d pr
ior
expe
rien
ce w
ith t
oxic
ity a
sses
smen
t of
nan
osca
le t
hera
peut
ics;
sm
all
num
ber
of a
ppro
ved
nano
med
icin
e cl
asse
s off
ers
limite
d op
port
uniti
es f
or s
tudy
; la
ck o
f st
anda
rd i
n vi
tro
scre
enin
g pl
atfo
rms
that
pro
vide
cor
rela
tion
of
pote
ntia
l in
vivo
bio
perf
orm
ance
; hig
h-th
roug
hput
met
hods
for
nano
mat
eria
l bin
ding
, cel
l int
erna
lizat
ion
and
inte
ract
ion
with
pl
asm
a pr
otei
ns a
nd im
mun
e fa
ctor
s (e
.g.,
com
plem
ent)
not
ava
ilabl
e; b
iom
arke
r m
etho
ds fo
r sm
all-m
olec
ule
anal
ysis
ofte
n no
t su
itabl
e fo
r nan
odru
gs
–M
ixed
mes
sage
s em
anat
e fr
om v
ario
us fe
dera
l age
ncie
s an
d tr
ansn
atio
nal r
egul
ator
y bo
dies
rega
rdin
g sa
fety
and
toxi
city
issu
es
on si
mila
r/id
entic
al n
anom
ater
ials
and
nan
opar
ticle
s–
Imm
unog
enic
ity o
f na
noth
erap
eutic
s, es
peci
ally
pro
tein
-bas
ed,
pres
ents
a m
ajor
cha
lleng
e to
the
ir d
evel
opm
ent;
imm
une
resp
onse
s of
ten
resu
lt in
red
uced
effi
cacy
of t
he t
hera
peut
ic o
r an
aphy
laxi
s in
pat
ient
; C a
ctiv
atio
n-re
late
d ad
vers
e eff
ects
of
cert
ain
nano
drug
s, re
ferr
ed to
as C
act
ivat
ion-
rela
ted
pseu
doal
lerg
y (C
ARPA
), is
now
wel
l acc
epte
d
(Con
tinu
ed)
Bench-to-Bedside Translation of Nanomedicine
�� Drug Delivery at the Nanoscale
–Li
mite
d or
lack
of a
dvan
ced
tool
s, te
chno
logi
es, a
nd c
hara
cter
izat
ion
assa
ys re
gard
ing
nano
med
ical
pro
duct
s pr
ovid
ing
pote
ntia
l cl
arity
; cr
itica
l an
alys
is,
and
com
pari
son
cann
ot b
e co
mpr
ehen
sive
at
this
sta
ge g
iven
the
sca
rcity
of
clin
ical
ly a
ppro
ved
nano
prod
ucts
, het
erog
enei
ty o
f nan
omat
eria
ls fa
bric
ated
, lac
k of
app
ropr
iate
in s
ilico
mod
elin
g to
ols,
and
limite
d gu
idan
ce fr
om
regu
lato
ry a
genc
ies
–Ad
sorp
tion,
dis
trib
utio
n, m
etab
olis
m, a
nd e
xcre
tion
(ADM
E) s
tudi
es re
gard
ing
nano
drug
s ei
ther
lack
ing
alto
geth
er o
r lim
ited
in
scop
e; p
hysi
oche
mic
al p
rope
rtie
s of e
ngin
eere
d na
nopa
rtic
les d
irec
tly im
pact
ADM
E an
d he
nce
are
fund
amen
tal d
eter
min
ants
of
toxi
city
and
effi
cacy
Consumer confidence
–Pu
blic
’s ge
nera
l re
luct
ance
to
embr
ace
inno
vativ
e or
em
ergi
ng m
edic
al t
echn
olog
ies
with
out
clea
r sa
fety
and
reg
ulat
ory
guid
elin
es–
Perc
eptio
n th
at m
any
nano
prod
ucts
are
inhe
rent
ly u
nsaf
e–
Publ
ic su
spic
ion
of G
over
nmen
tal a
genc
ies a
nd in
dust
ry–
Med
ia h
ype
and
mis
info
rmat
ion
not e
ffect
ivel
y co
unte
red
by a
cade
mia
, gov
ernm
ent,
and
indu
stry
–Et
hica
l cha
lleng
es a
nd so
ciet
al is
sues
not
tran
spar
ently
add
ress
ed b
y st
akeh
olde
rs
Fu
nd
ing
chal
len
ges
–Re
lativ
e sc
arci
ty o
f ven
ture
fund
s due
to th
e pe
rcep
tion
that
mos
t med
ical
nan
opro
duct
s lac
k a
good
retu
rn o
n in
vest
men
t (RO
I)–
Prol
onge
d tim
esca
le is
a d
etri
men
t to
fund
ers a
nd in
vest
ors
–Fu
nder
s an
d ve
ntur
e ca
pita
lists
ofte
n no
t ex
peri
ence
d or
ver
sed
in te
chno
logi
cal a
spec
ts a
nd c
anno
t fu
lly g
auge
pot
entia
l for
tr
ansl
atio
n–
Barr
iers
stee
per f
or n
anot
hera
peut
ics w
ith re
spec
t to
proc
urin
g fu
nds t
o in
itiat
e a
first
-in-h
uman
(FIH
) clin
ical
tria
l
Tabl
e 1.
� (C
onti
nued
)
��
–Bi
g ph
arm
a’s c
ontin
ued
relu
ctan
ce to
seri
ousl
y in
vest
in n
anom
edic
ine,
esp
ecia
lly e
arly
-sta
ge p
recl
inic
al re
sear
ch la
ckin
g “p
roof
-of
-con
cept
” in
man
–
Lack
of i
ndus
try
supp
ort l
imits
pot
entia
l to
reac
h FI
H cl
inic
al tr
ials
in a
ny re
sear
ch se
ttin
g (a
cade
mic
, sta
rt-u
p, sm
all c
ompa
ny)
–Du
e di
ligen
ce a
nd p
eer r
evie
w re
gard
ing
tran
slat
iona
l pot
entia
l of p
roje
cts o
r res
earc
h pr
opos
als o
ften
lack
ing
duri
ng th
e fu
ndin
g pr
oces
s
Cli
nic
al r
esea
rch
an
d t
rial
s
–Co
st, t
ime,
and
effo
rt re
quir
ed fo
r clin
ical
tria
ls a
re a
det
erre
nt–
Gene
ral l
ack
of k
now
ledg
e ab
out t
he F
DA/E
MA
drug
or
devi
ce r
evie
w p
roce
ss; l
imite
d un
ders
tand
ing
of th
e va
riou
s as
pect
s of
dr
ug a
nd d
evic
e la
ws i
n va
riou
s jur
isdi
ctio
ns–
Chal
leng
es in
pat
ient
rec
ruitm
ent i
s m
ore
acut
e in
nan
omed
icin
e du
e to
fact
ors
such
as
stri
ct in
clus
ion/
excl
usio
n cr
iteri
on a
nd
dela
y by
eth
ics c
omm
ittee
s–
Chal
leng
es (
cost
, tri
al d
esig
n, s
elec
tion
of p
artic
ipan
ts, d
ata
anal
ysis
) w
ith r
espe
ct t
o in
tern
atio
nal h
arm
oniz
atio
n of
bri
dgin
g st
udie
s and
the
desi
gn o
f glo
bal c
linic
al tr
ials
–La
ck o
f co
nsen
sus
on t
he d
iffer
ent
proc
edur
es, a
ssay
s, an
d pr
otoc
ols
to b
e em
ploy
ed d
urin
g pr
eclin
ical
dev
elop
men
t an
d ch
arac
teri
zatio
n of
nan
omed
icin
es; t
his c
an a
lso
impa
ct cl
inic
al tr
ial d
esig
n
Pat
ents
–Pa
tent
revi
ew d
elay
s, sp
otty
exa
min
atio
n, a
nd a
cces
s to
rele
vant
“pri
or a
rt” b
y pa
tent
exa
min
ers a
t pat
ent o
ffice
s–
Issu
ance
of i
nval
id p
aten
ts o
r pat
ents
of u
ndul
y br
oad
scop
e –
Emer
ging
pat
ent t
hick
ets d
ue to
a “p
aten
t pro
spec
tor”
men
talit
y an
d is
suan
ce o
f ove
rlap
ping
pat
ent c
laim
s
(Con
tinu
ed)
Bench-to-Bedside Translation of Nanomedicine
�� Drug Delivery at the Nanoscale
–A
gene
ral l
ack
of u
nder
stan
ding
of t
he p
aten
t pro
cess
by
stak
ehol
ders
–Li
mite
d kn
owle
dge
rega
rdin
g th
e ba
sics
of i
ntel
lect
ual p
rope
rty
law
in a
cade
mic
circ
les a
nd a
t sta
rt-u
ps
Su
pp
ort
for
smal
l bu
sin
esse
s an
d s
tart
up
s
–Ge
nera
l lac
k of
fina
ncia
l inc
entiv
es fa
vori
ng lo
ng te
rm n
anom
edic
ine
inve
stm
ents
–Li
mite
d ta
x-fr
ee b
onds
for f
inan
cing
, tax
cred
its fo
r cap
ital i
nves
tmen
ts, r
educ
ed ca
pita
l gai
ns ta
x ra
tes,
or in
vest
men
t-sp
ecifi
c loa
n gu
aran
tees
–La
ck o
f men
tors
hip
and
busi
ness
pla
nnin
g as
sist
ance
–Li
ttle
ass
ista
nce
in a
ttra
ctin
g pr
ivat
e an
d pu
blic
fund
s–
The
Smal
l Bu
sine
ss I
nnov
atio
n Re
sear
ch (
SBIR
) pr
oces
s in
the
US
is s
till
prim
arily
foc
used
on
rese
arch
and
les
s on
co
mm
erci
aliz
atio
n–
Cent
raliz
ed a
udit
syst
ems a
re co
stly
and
slow
dow
n w
ork
at sm
all b
usin
esse
s–
Mor
e na
no to
ols n
eede
d in
aca
dem
ia, s
tart
-ups
, and
smal
l bus
ines
ses
Aca
dem
ia a
nd
th
e u
niv
ersi
ty p
rofe
ssor
–Ex
agge
rate
d pr
ess r
elea
ses f
rom
em
inen
t uni
vers
ity la
bora
tori
es–
Prof
esso
rs b
ehav
e m
ore
like
“cel
ebri
ty-a
cade
mic
s” th
an se
riou
s res
earc
hers
–Re
sear
ch o
ften
focu
sed
on p
oorly
char
acte
rize
d an
d no
nbio
degr
adab
le n
anom
ater
ial-b
ased
pla
tform
s tha
t may
pos
e to
xici
ty–
Fanc
y an
imat
ions
on
labo
rato
ry w
ebsi
tes
exag
gera
te p
recl
inic
al d
ata
and
clin
ical
par
tner
ship
s w
ith p
harm
a pr
ojec
t fal
se h
ope
of
tran
slat
iona
l pot
entia
l
Tabl
e 1.
� (C
onti
nued
)
��
–Ir
repr
oduc
ibili
ty o
f bas
ic, p
recl
inic
al re
sear
ch is
a m
ajor
pro
blem
at u
nive
rsiti
es–
Rese
arch
that
gen
erat
es p
ublic
atio
ns (l
’art
pou
r l’a
rt) i
s mor
e va
lued
–Ge
nera
lly, p
aten
ts o
f lim
ited
scop
e an
d po
or tr
ansl
atio
nal p
oten
tial (
“pap
er p
aten
ts”)
are
obt
aine
d–
Focu
s is o
n jo
urna
l im
pact
fact
ors,
cita
tions
, aw
ard
plaq
ues,
pres
s rel
ease
s, co
nfer
ence
par
ticip
atio
n, a
nd sp
eech
es–
Focu
s is o
n re
sear
ch a
nd p
ublic
atio
ns ra
ther
than
com
mer
cial
izat
ion;
som
e ac
adem
ics e
ven
shun
com
mer
cial
izat
ion
–In
abili
ty o
r lac
k of
will
ingn
ess t
o co
nfor
m to
tran
slat
iona
l act
iviti
es; f
ew in
cent
ives
for t
rans
latio
nal a
ctiv
ities
–La
ck o
f coh
eren
t tec
hnol
ogy
tran
sfer
pol
icy
at u
nive
rsiti
es sp
ills i
nto
the
nano
wor
ld–
Lim
ited
com
mun
icat
ion
betw
een
clin
ical
rese
arch
ers a
nd b
asic
scie
ntis
ts–
Evid
ence
of c
linic
al v
alid
ity a
nd cl
inic
al u
tility
of t
he re
sear
ch b
eing
cond
ucte
d is
ofte
n la
ckin
g–
Lack
of i
nter
disc
iplin
ary
rese
arch
app
roac
h; la
ck o
f a co
llabo
rativ
e sp
irit
betw
een
indu
stry
and
aca
dem
ia, o
r bet
wee
n cl
inic
al a
nd
basi
c res
earc
hers
–A
defic
it in
cros
s-di
scip
linar
y or
hyb
rid
scie
ntifi
c tra
inin
g at
edu
catio
nal i
nstit
utio
ns; g
radu
ate
stud
ies t
oo fo
cuse
d
Reg
ula
tory
un
cert
ain
ty: g
aps
and
bab
y st
eps
–Co
nfus
ion
and
unce
rtai
nty
due
to “b
aby
step
s” u
nder
take
n by
regu
lato
ry b
odie
s suc
h as
the
FDA
and
EMA
–A
lack
of c
lear
regu
lato
ry o
r saf
ety
guid
elin
es–
Gove
rnm
enta
l re
gula
tory
bod
ies
lack
tec
hnic
al a
nd s
cien
tific
kno
wle
dge
to s
uppo
rt r
isk-
base
d na
no-r
egul
atio
n, c
reat
ing
a si
gnifi
cant
regu
lato
ry v
oid
–Is
suan
ce o
f too
man
y no
nbin
ding
“dra
ft” g
uida
nce
docu
men
ts b
y th
e FD
A an
d “p
ositi
on p
aper
s” b
y th
e EM
A to
mak
e su
bsta
ntiv
e po
licy
chan
ges
(Con
tinu
ed)
Bench-to-Bedside Translation of Nanomedicine
100 Drug Delivery at the Nanoscale
–Pr
oduc
t cl
assi
ficat
ion
issu
es b
lur
the
regu
lato
ry b
ound
arie
s be
twee
n va
riou
s pr
oduc
t cl
asse
s gi
ven
that
man
y na
no-m
edic
al
prod
ucts
are
mul
timod
al h
ybri
d st
ruct
ures
(“co
mbi
natio
n pr
oduc
ts”)
–Pr
ecau
tiona
ry s
tanc
e by
reg
ulat
ory
agen
cies
ref
lect
s th
eir
lack
of
expe
rtis
e an
d ex
peri
ence
with
nan
osca
le fo
rmul
atio
ns a
nd
nano
med
ical
pro
duct
s
–N
atio
nal d
iffer
ence
s in
regu
lato
ry re
quir
emen
ts p
ose
chal
leng
es fo
r clin
ical
tria
ls in
volv
ing
inte
rnat
iona
l mul
ticen
ters
–Di
ffere
nces
bet
wee
n re
gula
tory
age
ncie
s ab
out t
he d
efin
ition
of c
ompo
und
char
acte
rist
ics
need
to b
e ha
rmon
ized
to c
lari
fy th
e Bi
opha
rmac
eutic
al C
lass
ifica
tion
Sche
me
(BCS
)
–Bu
reau
crac
y an
d a
cons
erva
tive,
insu
lar a
ttitu
de a
mon
g go
vern
men
t reg
ulat
ors p
ose
a bo
ttle
neck
to tr
ansl
atio
n
–Ri
se o
f div
erse
nan
o-sp
ecifi
c re
gula
tory
arr
ange
men
ts a
nd s
yste
ms
cont
ribu
te to
a d
ense
glo
bal n
ano-
regu
lato
ry la
ndsc
ape,
full
of g
aps
and
devo
id o
f cen
tral
coo
rdin
atio
n; s
tand
ardi
zatio
n, a
nd h
arm
oniz
atio
n on
a g
loba
l sca
le is
com
plic
ated
by
tech
nica
l, po
litic
al, l
egal
, and
eco
nom
ic is
sues
Technology Transfer Offices (TTOs)
–TT
Os a
t uni
vers
ities
and
inst
itute
s lac
k in
-dep
th te
chni
cal,
pate
nt la
w a
nd b
usin
ess e
xper
tise
–M
ost d
ecis
ions
mad
e in
a v
acuu
m o
r on
impe
rfec
t ana
lysi
s/re
sear
ch
–Is
sues
suc
h as
an
isol
ated
wor
k en
viro
nmen
t, im
prop
er b
udge
tary
allo
catio
ns, a
nd a
hig
h em
ploy
ee tu
rnov
er in
dire
ctly
impe
de
the
gene
ratio
n of
val
uabl
e IP
–Fo
llow
-up
of fi
led
pate
nts a
t pat
ent o
ffice
s or c
oord
inat
ion
with
out
side
law
firm
s not
opt
imal
–IP
pro
secu
tion
stra
tegy
poo
rly p
lann
ed
–Li
mite
d IP
val
uatio
n an
d/or
impr
oper
aud
it of
“tru
e” li
cens
ing
roya
lties
add
s to
inac
cura
te co
nclu
sion
s
Tabl
e 1.
� (C
onti
nued
)
101
Oth
er fa
ctor
s
–Ke
y te
chno
logy
ben
efits
not
iden
tifie
d ea
rly o
n in
pro
duct
dev
elop
men
t
–Li
mite
d in
fras
truc
ture
that
bec
omes
out
date
d qu
ickl
y du
e to
adv
ance
s in
tech
nolo
gy
–Re
lativ
e sc
arci
ty o
f wor
kers
trai
ned
for R
&D;
nee
d fo
r for
eign
wor
kers
pos
es p
robl
ems
–Cr
isis
of r
epro
duci
bilit
y in
ant
ibod
y pe
rfor
man
ce d
ue to
sho
rtcu
ts ta
ken
by m
anuf
actu
rers
and
rese
arch
ers;
this
has
con
trib
uted
to
irre
prod
ucib
ility
of p
recl
inic
al re
sear
ch d
ata
in b
iom
edic
ine
whi
ch d
irec
tly im
pede
s nan
omed
ical
tran
slat
ion
–Ab
senc
e of
out
stan
ding
dru
g re
sear
cher
s in
aca
dem
ic s
ettin
gs w
ho a
re tr
aine
d to
sep
arat
e “h
its” i
nto
com
poun
ds g
ood,
bad
, and
ug
ly; a
cade
mia
not
as w
ell v
erse
d as
big
pha
rma
whe
n it
com
es to
dru
g R&
D
–“T
rue”
int
erdi
scip
linar
ity s
till
mis
sing
fro
m n
anom
edic
ine
tran
slat
ion;
wid
e ga
ps p
ersi
st b
etw
een
conc
eptio
n of
inn
ovat
ive
nano
med
icin
e pl
atfo
rms a
nd re
gula
tory
clin
ical
app
rova
l; tr
aver
sing
the
“val
ley
of d
eath
” esp
ecia
lly d
iffic
ult i
n na
nom
edic
ine
–M
isus
e of
P-v
alue
s are
cont
ribu
ting
to th
e ir
repr
oduc
ibili
ty o
f pre
clin
ical
bio
med
ical
rese
arch
, ind
irec
tly im
pact
ing
tran
slat
ion
–Qu
ality
ass
uran
ce (Q
A) g
uide
lines
for b
asic
rese
arch
lack
ing
or n
ot p
rope
rly im
plem
ente
d
–La
ck o
f abi
lity
for
trac
ing
data
, inc
ludi
ng w
hich
equ
ipm
ent
the
expe
rim
ent
was
con
duct
ed o
n an
d w
here
the
sou
rce
data
are
st
ored
Copy
righ
t © 2
020
Raj B
awa.
All
righ
ts r
eser
ved.
Bench-to-Bedside Translation of Nanomedicine
10� Drug Delivery at the Nanoscale
translational research. In fact, experts frequently accuse these federal bureaucracies for neglecting their mandates of translating advances at the preclinical stage in the laboratory to clinical applications in the practice of medicine (i.e., the classical “bench-to-bedside” paradigm).
Box 1.1� Are Biologics and Nanodrugs Adversely Immunogenic?
Almost all small-molecule drug-induced allergic reactions may be easily classified into one of four classic Gell and Coombs hypersensitivity categories. However, many others with an immunologic component, including biologics and nanodrugs, are difficult to classify in such a manner because of a lack of mechanistic information. Adverse clinical events (sometimes referred to as ADRs) can not only occur due to primary factors such as off-target toxicity or exaggerated pharmacologic effects, but also due to secondary drug effects such as immune reactions to the drug product. While approximately 80% of human adverse drug reactions are directly related to an effect of the drug or a metabolite, around 6–10% are immune-mediated and unpredictable. One study showed that 10–20% of the medicinal products removed from clinical practice between 1969 and 2002 were withdrawn due to immunotoxic effects. Some claim that the actual number of serious adverse events like hospitalizations and death from FDA-approved drugs, vaccines, and medical devices is grossly underreported by the FDA. Suspected ADRs can be reported to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.Immune-mediated side effects of small molecules are unpredictable. Most small molecules that have a MW <1 KDa do not elicit an immune response in their native state, becoming immunogenic only when they act as a hapten, bind covalently to high-molecular-weight proteins, and undergo antigen processing and presentation. On the other hand, “newer” larger molecule drugs can be inherently immunogenic. For example, protein-based biologics and nanodrugs can be digested and processed for presentation by antigen-presenting cells (APCs); this can sometimes cause ADRs. The very untested nature of these therapeutics that make them so revolutionary in some respects also makes them problematic and potentially dangerous. For example, major benefits touted for nanodrugs—a reduction
10�
in unwanted side effects, increased specificity, fewer off-target effects, generation of fewer harmful metabolites, slower clearance from the body, longer duration of effect, reduced intrinsic toxicity, etc.—do not guarantee the absence of adverse immune side effects: An inherent risk of introducing these drug products into the human body is the potential to provoke an unwanted immune response. Thus, managing their immunogenicity profile is critical during drug R&D and later phases. Studies have shown that these drug products can interact with various components of the immune system to various immunological endpoints, interactions that are fast, complex, and poorly understood. These interactions with the immune system play a leading role in the intensity and extent of side effects occurring simultaneously with their therapeutic efficacy. In fact, when compared to conventional small-molecule drugs, both biologics and nanodrugs have biological and synthetic entities of a size, shape, reactivity, and structure that are often recognized by the human immune system, sometimes in an adverse manner. This can obviously negatively affect their effectiveness and safety, and thereby, limit their therapeutic application. This also poses challenges for regulatory agencies and patent offices, all serving as bottlenecks to effective translation of these therapeutics.Multiple risk factors influencing the immunogenicity of biologics and nanodrugs include patient-, clinical use-, manufacturing-, and product-related factors. Some of the ADRs include complement activation, tissue inflammation, leucocyte hypersensitivity, and formation of antibodies associated with clinical conditions. However, detailed mechanisms and causal linkages between various risk factors and immunogenicity induction onset have yet to be fully elucidated. This is primarily due to the limited amount of data from mechanistic studies, a lack of multi-factorial analysis and a lack of standard immunogenicity assessment methods.Source: [67].
Figure 1.16 illustrates the translation of nanomedicine from the R&D phases to product development and eventual adoption in the clinic. In fact, when used correctly, translational research is a highly interactive and complex process, with a flow of information in multiple directions as highlighted in Fig. 1.17.
Bench-to-Bedside Translation of Nanomedicine
10� Drug Delivery at the Nanoscale
Tabl
e 1.
� Fr
om t
he
Lab
to t
he
Clin
ic: I
mp
rovi
ng
Tra
nsl
atio
nal
Nan
omed
icin
e
•Re
sear
ch sc
ient
ists
in ac
adem
ia sh
ould
und
erst
and
the e
ntir
e sup
ply
chai
n fr
om re
sear
ch to
dev
elop
men
t, in
clud
ing b
asic
conc
epts
re
leva
nt to
IP, r
egul
ator
y is
sues
, and
com
mer
cial
izat
ion.
•Gr
antin
g ag
enci
es a
nd p
eer
revi
ewer
s th
at r
evie
w g
rant
s sh
ould
hav
e ex
pert
ise
in t
rans
latio
nal m
edic
ine,
indu
stri
al p
ortfo
lio
man
agem
ent,
and
com
mer
cial
izat
ion
of re
sear
ch to
pro
perly
acce
ss fe
asib
ility
of p
ropo
sals
that
hav
e a g
reat
er p
oten
tial f
or p
atie
nt
appl
icat
ion.
It is
very
impo
rtan
t tha
t rev
iew
pan
els o
r com
mitt
ees s
houl
d re
flect
appr
opri
ate b
alan
ce o
f tec
hnic
al, b
usin
ess,
vent
ure,
an
d co
mm
erci
aliz
atio
n ex
pert
ise.
Pro
posa
ls a
nd s
ubm
issi
ons
shou
ld s
eek/
incl
ude
crite
ria
to e
valu
ate
whe
ther
the
rese
arch
is
capa
ble
of cl
inic
al a
pplic
atio
n. F
undi
ng p
roje
cts s
houl
d be
eva
luat
ed in
term
s of r
ealis
tic p
oten
tial o
f mak
ing
it to
the
clin
ic ra
ther
th
an sp
ecifi
c dis
ease
targ
ets.
In o
ther
wor
ds, t
he m
inds
et n
eeds
to b
e ch
ange
d fr
om a
“pro
duct
-” to
a “p
atie
nt”-
orie
nted
app
roac
h in
nan
omed
ical
pro
duct
dev
elop
men
t.•
Ther
e is
an
urge
nt n
eed
for c
oord
inat
ed e
duca
tion
and
trai
ning
pro
gram
s. Ed
ucat
iona
l ins
titut
ions
and
uni
vers
ities
sho
uld
offer
m
ore
inte
rdis
cipl
inar
y/hy
brid
cour
ses a
nd g
radu
ate
trai
ning
mod
ules
whe
re a
pplie
d re
sear
ch, b
usin
ess l
ands
capi
ng, i
ntel
lect
ual
prop
erty
law
, FDA
reg
ulat
ory
issu
es, a
nd t
he p
aten
t pr
oces
s ar
e em
phas
ized
. Cou
rses
for
heal
thca
re p
erso
nnel
, res
earc
hers
, ph
ysic
ians
, pha
rmac
ists
, and
nur
ses s
houl
d fo
cus o
n m
ore i
n-de
pth
inst
ruct
ion.
The
pub
lic sh
ould
be e
duca
ted
via m
ore i
nnov
ativ
e po
rtal
s of
edu
catio
n bo
th d
irec
tly a
nd th
roug
h th
e ne
ws
med
ia a
nd In
tern
et r
egar
ding
bot
h th
e po
ssib
ilitie
s an
d lim
itatio
ns o
f na
nom
edic
ine
alon
g w
ith it
s tra
nsla
tiona
l pot
entia
l. •
Acad
emic
res
earc
hers
sho
uld
be e
ncou
rage
d to
dev
elop
inno
vativ
e tr
ansl
atab
le p
rodu
cts.
Acad
emic
res
earc
h th
at is
adv
ertis
ed
as b
eing
app
lied
or t
rans
latio
nal s
houl
d ha
ve t
o de
mon
stra
te a
min
imum
thr
esho
ld r
equi
rem
ent
on r
ealis
tic c
hanc
es t
o he
lp
patie
nts
prio
r to
fund
ing.
Por
tfolio
s and
pro
ject
s sh
ould
be
deve
lope
d an
d ev
alua
ted
with
an
eye
on a
pplie
d re
sear
ch; e
ven
basi
c re
sear
ch sh
ould
be a
naly
zed
to d
eter
min
e suc
h po
tent
ial. A
cade
mia
and
indu
stry
mus
t enh
ance
colla
bora
tive e
ffort
s to
addr
ess t
he
irre
prod
ucib
ility
of p
recl
inic
al re
sear
ch th
at p
rim
arily
em
anat
es fr
om a
cade
mic
rese
arch
labo
rato
ries
. Uni
vers
ities
may
con
side
r es
tabl
ishi
ng a
“gap
fund
” to
supp
ort t
rans
latio
n st
udie
s con
side
ring
dim
inis
hed
gran
t fun
ding
.•
Regi
onal
har
mon
izat
ion
effor
ts (
rath
er t
han
glob
al)
shou
ld b
e un
dert
aken
with
res
pect
to
brid
ging
stu
dies
and
the
des
ign
of
clin
ical
tria
ls fo
r nan
omed
icin
es.
10�
•M
atri
ces
and
stri
ngen
t ev
alua
tion
crite
ria
shou
ld b
e em
ploy
ed t
hrou
ghou
t a
fund
ed a
pplie
d ac
adem
ic p
roje
ct t
o se
e ho
w
succ
essf
ul it
is w
ith re
spec
t to
tran
slat
ion
and
whe
ther
it m
erits
furt
her f
undi
ng.
•Ad
vanc
ed m
anuf
actu
ring
tec
hnol
ogie
s m
ust
be e
xplo
red
that
ena
ble
mor
e co
ntro
l ov
er s
ize
and
shap
e th
at a
llow
sur
face
m
odifi
catio
ns u
sing
cova
lent
and
non
cova
lent
app
roac
hes t
o fa
bric
ate
prec
isel
y de
fined
NDD
S. T
op-d
own
nano
collo
id fa
bric
atio
n te
chni
ques
suc
h as
pho
tolit
hogr
aphy
, mic
roflu
idic
syn
thes
is, a
nd m
oldi
ng te
chno
logy
suc
h as
par
ticle
rep
licat
ion
in n
onw
ettin
g te
mpl
ates
are
of
inte
rest
to
over
com
e th
e lim
itatio
ns o
f co
nven
tiona
l bot
tom
-up
fabr
icat
ion
met
hods
. Fle
xibl
e an
d ad
aptiv
e m
anuf
actu
ring
(“on
dem
and”
) are
impo
rtan
t in
this
cont
ext.
•On
a c
ase-
by-c
ase
basi
s an
d in
con
junc
tion
with
indu
stry
, the
FDA
(an
d an
alog
ous
regu
lato
ry a
genc
ies)
sho
uld
iden
tify
uniq
ue
safe
ty is
sues
ass
ocia
ted
with
spe
cific
nan
opar
ticle
s an
d na
nom
ater
ials
. The
age
ncy
shou
ld m
eet
its r
egul
ator
y an
d st
atut
ory
oblig
atio
ns b
y off
erin
g te
chni
cal a
dvic
e an
d gu
idan
ce to
indu
stry
bey
ond
wha
t its
trac
k re
cord
cur
rent
ly r
efle
cts.
With
indu
stry
in
put,
a co
mpr
ehen
sive
pub
lic d
atab
ank
rela
ting
to th
e bi
olog
ical
inte
ract
ions
of e
ngin
eere
d na
nom
ater
ials
(EN
Ms)
sho
uld
be
gene
rate
d. T
he F
DA s
houl
d ac
tivel
y se
ek p
rodu
ct s
afet
y da
ta fr
om in
dust
ry w
here
FDA
sta
tuto
ry a
utho
rity
exi
sts
for
prem
arke
t re
view
. Fur
ther
mor
e, it
sho
uld
ince
ntiv
ize
and
enco
urag
e vo
lunt
ary
indu
stry
sub
mis
sion
s of
saf
ety
data
on
nano
mat
eria
ls o
r pr
oduc
ts t
hat
inco
rpor
ate
nano
tech
nolo
gy p
rior
to
mar
ket
laun
ch, e
spec
ially
in
case
s (e
.g.,
cosm
etic
s) w
here
the
FDA
lack
s st
atut
ory
auth
ority
for
prem
arke
t re
view
. FDA
’s ex
cess
ive
relia
nce
on p
ublic
ly a
vaila
ble
or v
olun
tari
ly s
ubm
itted
info
rmat
ion,
ad
vers
e ev
ent r
epor
ting,
and
on
post
mar
ket s
urve
illan
ce a
ctiv
ities
may
not
be
idea
l in
the
case
of E
NM
s for
hum
an u
se.
•La
bora
tori
es th
at fo
cus o
n cl
inic
al a
pplic
atio
ns sh
ould
impl
emen
t qua
lity
assu
ranc
e sy
stem
s suc
h as
Goo
d Cl
inic
al P
ract
ice
(GCP
), Go
od M
anuf
actu
ring
Pra
ctic
e (G
MP)
and
Goo
d La
bora
tory
Pra
ctic
e (G
LP),
espe
cial
ly if
subm
ittin
g da
ta to
regu
lato
ry a
genc
ies.
•Ke
y qu
estio
ns s
houl
d be
ask
ed e
arly
on
duri
ng th
e de
velo
pmen
t pha
se o
f the
pro
ject
: Is
the
idea
pat
enta
ble,
will
it h
elp
patie
nts
in a
clin
ical
set
ting,
is th
e cl
inic
al h
ypot
hesi
s ba
cked
by
gene
rate
d pr
eclin
ical
dat
a, is
ther
e fr
eedo
m-to
-ope
rate
with
res
pect
to
the
pate
nt e
stat
e an
d co
mm
erci
al la
ndsc
ape,
is it
like
ly to
be
reim
burs
ed b
y in
sura
nce
com
pani
es, i
s th
ere
a ne
ed c
omm
erci
ally
, is
ther
e a
sign
ifica
nt m
arke
t siz
e, a
re m
ajor
saf
ety
issu
es a
ddre
ssed
, is
the
imm
unol
ogy
and
phar
mac
olog
y w
ell s
tudi
ed, a
re a
ll co
mpo
nent
s (a
ctiv
e, c
arri
er, e
xcip
ient
, etc
.) w
ell c
hara
cter
ized
, are
ther
e un
ique
saf
ety
conc
erns
due
to th
e na
nosc
ale,
are
ther
e ex
cess
ive
fabr
icat
ion
cost
s and
com
plex
ities
?
(Con
tinu
ed)
Bench-to-Bedside Translation of Nanomedicine
10� Drug Delivery at the Nanoscale
•Sc
ienc
e po
licym
aker
s sh
ould
sub
sidi
ze m
ore
risk
y re
sear
ch s
trat
egie
s, in
cent
iviz
e st
rate
gy d
iver
sity
, and
enc
oura
ge p
ublic
atio
n of
faile
d ex
peri
men
ts/n
egat
ive
data
—al
l the
se a
ctiv
ities
are
kno
wn
to in
crea
se th
e sp
eed
of d
isco
very
. Med
ical
and
bas
ic s
cien
ce
jour
nal e
dito
rs sh
ould
stre
ngth
en th
e pe
er-r
evie
w p
roce
ss, m
anda
te su
ffici
ent d
ata
and
met
hods
to re
prod
uce
repo
rted
rese
arch
, se
ek in
clus
ion
of in
form
atio
n on
dat
a pr
oven
ance
, pub
lish
softw
are
code
s use
d fo
r dat
a an
alys
is, a
nd se
ek d
ata
man
ipul
atio
n st
eps
done
by
hand
that
wer
e no
t inc
lude
d in
the
softw
are
code
.
•Un
iver
sity
TTO
s sh
ould
be
reva
mpe
d an
d re
quir
ed to
dis
clos
e th
e RO
I in
term
s of
fund
s ex
pend
ed o
n pa
tent
pro
secu
tion
vers
us
licen
sing
roya
lties
gen
erat
ed. Q
ualif
ied
IP a
nd li
cens
ing
pers
onne
l sho
uld
be h
ired
.
•QA
gui
delin
es fo
r ba
sic
rese
arch
pub
lishe
d by
the
WH
O sh
ould
be
impl
emen
ted
by la
bora
tori
es to
saf
egua
rd d
ata
and
ensu
re
scie
ntifi
c rig
or. D
igita
l man
ipul
atio
n or
erro
rs ca
n be
min
imiz
ed o
r pre
vent
ed vi
a “re
ad-o
nly f
iles”
stor
ed o
n la
bora
tory
inst
rum
ents
. St
reng
then
ing
data
sta
ndar
ds a
nd m
etho
ds tr
ansp
aren
cy in
sci
entif
ic p
ublic
atio
ns s
houl
d be
sup
port
ed to
ena
ble
repl
icat
ion
of
publ
ishe
d re
sults
. Gra
ntin
g ag
enci
es s
houl
d re
quir
e pr
oof t
hat i
nstr
umen
ts h
ave
been
cal
ibra
ted
and
that
pla
ns e
xist
for
trac
ing
data
, inc
ludi
ng w
hich
equ
ipm
ent t
he e
xper
imen
t was
cond
ucte
d on
and
whe
re th
e so
urce
dat
a ar
e st
ored
.
•Re
cogn
izin
g ge
nuin
e re
ques
ts fo
r scr
utin
y fr
om h
aras
smen
t in
a cl
imat
e of
rese
arch
tran
spar
ency
is e
ssen
tial t
o sa
fegu
ardi
ng th
e re
sear
ch co
mm
unity
and
dri
ving
tran
slat
iona
l effo
rts.
•Co
nsen
sus-
test
ing
prot
ocol
s to
prov
ide
benc
hmar
ks fo
r the
crea
tion
of cl
asse
s of n
anos
cale
mat
eria
ls, b
oth
engi
neer
ed a
nd n
ativ
e,
shou
ld b
e de
velo
ped.
In a
dditi
on, r
efer
ence
clas
ses f
or E
NM
s tha
t are
synt
hesi
zed
and
char
acte
rize
d ne
ed to
be
cata
loge
d pr
ior t
o tr
ansl
atio
n. T
his c
an b
e ac
com
plis
hed
by c
reat
ing
a m
inim
um u
nive
rsal
set o
f cha
ract
eriz
atio
n te
chni
ques
via
cur
rent
ly a
vaila
ble
tool
s an
d te
sts.
This
effo
rt c
an b
e su
pple
men
ted
by d
evel
opin
g un
ique
tool
s, im
agin
g m
odal
ities
, and
tech
niqu
es. M
athe
mat
ical
an
d co
mpu
ter m
odel
s for
risk
/ben
efit
anal
ysis
that
can
mon
itor q
ualit
y, sa
fety
, and
effec
tiven
ess v
is-à
-vis
stan
dard
EN
Ms a
re o
ther
op
tions
. Sin
ce m
inor
var
iatio
ns in
the
phys
icoc
hem
ical
char
acte
rist
ics o
f nan
othe
rape
utic
s (na
nom
ater
ial +
API
) can
affe
ct sa
fety
, im
mun
ogen
icity
and
effi
cacy
, mul
tiple
met
hods
bas
ed o
n di
ffere
nt p
rinc
iple
s sh
ould
be
empl
oyed
dur
ing
nano
mat
eria
ls a
nd A
PI
T abl
e 1.
� (C
onti
nued
)
10�
asse
ssm
ent.
Inno
vativ
e in
vit
ro/e
x vi
vo, i
n si
lico,
and
in v
ivo
(ani
mal
) scr
eeni
ng sy
stem
s, in
clud
ing
nove
l 3D
cell
syst
ems (
3D tu
mor
sp
hero
ids)
, may
be
requ
ired
. In
this
cont
ext,
it is
impo
rtan
t to
empl
oy m
etho
ds re
leva
nt to
the
spec
ific r
oute
of a
dmin
istr
atio
n th
at
are
stan
dard
ized
, val
idat
ed, a
nd w
idel
y ac
cept
ed b
y re
sear
cher
s and
regu
lato
ry a
genc
ies a
like.
How
ever
, it i
s cri
tical
to co
nduc
t all
thes
e as
says
and
test
s un
der
biol
ogic
ally
rel
evan
t con
ditio
ns s
uch
as th
e m
icro
envi
ronm
ent o
f an
imm
unoc
ompr
omis
ed c
ance
r pa
tient
or a
pat
ient
who
se p
lasm
a pr
otei
ns p
rodu
ce “p
rote
in co
rona
s.”
•Ex
istin
g m
etho
dolo
gies
shou
ld b
e ada
pted
, as w
ell a
s new
par
adig
ms s
houl
d be
dev
elop
ed fo
r eva
luat
ing
in v
ivo
anim
al an
d cl
inic
al
data
per
tain
ing
to s
afet
y an
d ef
ficac
y of
nan
omed
ical
pro
duct
s be
fore
and
dur
ing
the
prod
uct
life
cycl
e. R
egul
ator
y gu
idan
ce
shou
ld e
labo
rate
spec
ifics
as t
o w
hat k
ind
of d
ata
are
requ
ired
at e
ach
step
of t
he n
anom
edic
al tr
ansl
atio
nal p
roce
ss.
•Ea
rly s
pons
or in
tera
ctio
n w
ith th
e FD
A in
the
deve
lopm
ent p
roce
ss is
hel
pful
to id
entif
y ap
prop
riat
e pa
thw
ays
to b
e na
viga
ted.
Fi
le p
aten
t app
licat
ions
(re
gula
r an
d pr
ovis
iona
l) at
an
early
sta
ge to
cap
ture
ups
trea
m a
spec
ts o
f nan
omed
ical
pro
duct
s an
d em
ploy
an
inte
rdis
cipl
inar
y te
am o
f pat
ent a
ttor
neys
or p
aten
t age
nts t
o dr
aft a
pplic
atio
ns. T
he re
gula
tory
revi
ew p
roce
ss, p
aten
t pr
osec
utio
n at
pat
ent o
ffice
s, an
d bu
sine
ss d
evel
opm
ents
shou
ld a
ll be
coor
dina
ted
thro
ugho
ut R
&D
and
tran
slat
ion.
•Si
nce
ther
e ar
e fe
w p
roto
cols
to
char
acte
rize
nan
omed
icin
es a
t th
e ph
ysic
oche
mic
al, b
iolo
gica
l, an
d ph
ysio
logi
cal l
evel
s, it
is
esse
ntia
l to
deve
lop
a re
sear
ch s
trat
egy
that
invo
lves
ADM
E st
udie
s. An
impr
ovem
ent o
f phy
siol
ogic
ally
bas
ed m
odel
s fo
r th
e pr
edic
tion
of th
e im
pact
of f
orm
ulat
ion
chan
ges
on d
rug
expo
sure
and
its
vari
abili
ty is
in o
rder
. A c
ompr
ehen
sive
app
roac
h to
un
ders
tand
ing
ADM
E ca
n be
rea
lized
thro
ugh
the
inte
grat
ion
of m
echa
nist
ic A
DME
data
thro
ugh
the
mat
hem
atic
al a
lgor
ithm
s th
at u
nder
pin
phys
iolo
gica
lly b
ased
pha
rmac
okin
etic
(PBP
K) m
odel
ing,
rout
inel
y ut
ilize
d to
sup
port
regu
lato
ry s
ubm
issi
ons
for
conv
entio
nal m
edic
ines
in th
e US
by
the
FDA
and
in E
urop
e by
the
EMA.
Alth
ough
adv
ance
s in
PBP
K re
flect
sig
nific
ant a
dvan
ces
in th
e pr
edic
tabi
lity
of cr
itica
l PK
para
met
ers f
rom
phy
sica
l che
mis
try,
in v
itro
dat
a an
d so
ftwar
e pl
atfo
rms/
data
base
s, ch
alle
nges
pe
rsis
t with
res
pect
to m
akin
g cr
itica
l dec
isio
ns in
ear
ly a
nd c
linic
al d
evel
opm
ent a
nd in
the
sele
ctio
n of
indi
vidu
aliz
ed d
osin
g re
gim
ens.
Bench-to-Bedside Translation of Nanomedicine
(Con
tinu
ed)
10� Drug Delivery at the Nanoscale
•To
xico
logy
test
s sho
uld
be d
evel
oped
and
phy
sico
chem
ical
char
acte
riza
tion
(PCC
) stu
dies
for n
anom
ater
ials
cond
ucte
d. A
lthou
gh
com
plex
ity an
d di
vers
ity o
f nan
omed
icin
es p
ose a
pro
blem
, bio
com
patib
ility
and
imm
unot
oxic
ity m
ust b
e tak
en in
to co
nsid
erat
ion
duri
ng p
recl
inic
al a
sses
smen
t. Al
so, s
tand
ards
that
corr
elat
e th
e bi
odis
trib
utio
n of
var
ious
nan
omat
eria
ls w
ith sa
fety
/effi
cacy
(by
usin
g pa
ram
eter
s su
ch a
s si
ze, s
urfa
ce c
harg
e, s
tabi
lity,
surf
ace
char
acte
rist
ics,
solu
bilit
y, cr
ysta
llini
ty, a
nd d
ensi
ty) n
eed
furt
her
asse
ssm
ent.
•In
tegr
atin
g an
d le
vera
ging
cum
ulat
ive
know
ledg
e re
gard
ing
tran
slat
iona
l bar
rier
s w
ill le
ad t
o im
prov
ed h
ealth
out
com
es fo
r pa
tient
s. In
tern
atio
nal r
egul
ator
y har
mon
izat
ion
effor
ts an
d fo
rmal
trea
ties w
ith re
leva
nt st
akeh
olde
rs sh
ould
be f
urth
er ex
plor
ed.
The
uniq
ue e
ntiti
es th
at h
ave
been
rece
ntly
est
ablis
hed
mus
t lev
erag
e ex
pert
ise
and
pool
thei
r exp
erie
nces
des
pite
geo
grap
hica
l di
vers
ity o
r org
aniz
atio
n-sp
ecifi
c man
date
s.
•Al
low
gre
ater
pat
ient
inpu
t in
to d
rug
deve
lopm
ent,
regu
lato
ry p
roce
sses
and
clin
ical
tri
al d
esig
n. M
anuf
actu
rers
sho
uld
seek
pa
tient
per
spec
tive
early
on
in p
rodu
ct d
evel
opm
ent.
Furt
herm
ore,
pat
ient
info
rmat
ion
and
data
sho
uld
be m
ore
read
ily s
hare
d fo
r re
sear
ch, e
spec
ially
with
resp
ect t
o ch
roni
c di
seas
es. I
t is
esse
ntia
l to
find
appr
opri
ate
bala
nce
betw
een
safe
guar
ding
acc
ess
to a
n in
divi
dual
’s he
alth
info
rmat
ion
and
shar
ing
that
dat
a fo
r pu
blic
hea
lth w
ith g
uara
ntee
d an
onym
ity. H
owev
er, f
or t
hese
re
com
men
datio
ns to
bec
ome
a re
ality
, cle
arer
pol
icie
s an
d gu
idel
ines
may
be
need
ed v
ia g
over
nmen
tal a
ctio
n so
that
com
pani
es
do n
ot ri
sk le
gal i
ssue
s, pa
tient
pri
vacy
is sa
fegu
arde
d, a
nd d
ata
secu
rity
is e
nsur
ed.
•En
hanc
e an
d st
ream
line
inst
itutio
nal r
evie
w b
oard
(IRB
) app
rova
l pro
cess
to m
inim
ize
unne
cess
ary
dela
ys a
nd re
dund
ancy
.
•In
tern
atio
nal h
arm
oniz
atio
n eff
orts
rega
rdin
g bi
osim
ilar v
ersi
ons o
f bio
logi
cs n
eed
to b
e un
dert
aken
as m
any
nano
med
icin
es a
re
biol
ogic
s. Th
e EM
A gu
idel
ines
(div
ided
into
thre
e se
ctio
ns) v
ersu
s th
e FD
A is
sued
dra
ft gu
idan
ce (c
lear
ly id
entif
ying
a s
tepw
ise
appr
oach
) ne
ed to
be
reco
ncile
d. C
lear
er r
egul
ator
y gu
idel
ines
from
the
FDA
and
the
EM
A re
gard
ing
nano
sim
ilars
and
NBC
D fo
llow
-ons
are
urg
ently
requ
ired
.
Copy
righ
t © 2
020
Raj B
awa.
All
righ
ts r
eser
ved.
Tabl
e 1.
� (C
onti
nued
)
10�
Nan
omed
icin
ens
from
Acad
emic
, Gov
t and
Indu
stria
lRes
earc
h
lity,
ESa
fety
,va
te/P
ublic
Fu
ndin
g, P
roto
type
s, F
reed
om-t
o-O
pera
te
FDA
Regu
lato
ryAp
prov
al
VC E
xit:
n,IP
O
Clin
ical
Care
Fina
ncia
l Sup
port
by
-Frie
ndsa
ndFa
mily
-Ang
el In
vest
ors
-Ven
ture
Cap
ital (
VC)
Diag
nos
Ther
apse
Acce
ptan
ce b
y-P
ayer
s-P
rovi
ders
/M
edic
al
Basi
cSc
ienc
e, R
&D
Busi
ness
, Pat
ents
, Tra
onIm
pact
Figu
re 1
.1�
From
Bas
ic S
cien
ce to
Bu
sin
ess
and
Com
mer
cial
izat
ion
: An
ove
rvie
w.
Mod
ified
by
the
auth
or, o
rigi
nal f
rom
Pan
Sta
nfor
d Pu
blis
hing
, Sin
gapo
re.
Bench-to-Bedside Translation of Nanomedicine
110 Drug Delivery at the Nanoscale
Disc
over
yor
Inve
non
Drug
, Dev
ice,
Inte
rven
on
Basi
cSc
ienc
e-C
linic
-Lab
orat
ory
Curio
sity
Sere
ndip
ityKn
owle
dge
Men
torin
gEn
trep
rene
urs
Appl
ied
Scie
nce
-Clin
ic-L
abor
ator
y
Tran
sla
onal
Scie
nce
Figu
re 1
.1�
Vir
tuou
s Cy
cle.
An
itera
tive
proc
ess t
hat p
rodu
ces n
ew k
now
ledg
e, b
iolo
gica
l app
licat
ions
, and
med
ical
inte
rven
tions
. So
urce
: [99
].
111
1.1� Concluding Remarks and Future Prospects
You see things; and you say ‘Why?’ But I dream things that never were; and I say ‘Why not?’”
—George Bernard Shaw (1856–1950), English/Irish playwright
Tomorrow’s science is today’s science fiction.
—Stephen W. Hawking (1942–2018), English physicist
We know what we are, but know not what we may be.—William Shakespeare (1564–1616), English playwright
Transformative advances in genomics, complex combination products (see pages 26 and 71), real-word evidence (see Chapter 36 in this volume), artificial intelligence (AI), innovative clinical trial design, precision medicine, and novel biomarker research are some of the global issues that will impact drug design, regulatory science, and healthcare policy in the US in the next decade. I expect that in the next decade there will be an intense competition for targets, introduction of second- and third generation nanodrugs
Concluding Remarks and Future Prospects
11� Drug Delivery at the Nanoscale
and biologics, and their follow-on versions. Also, expiration of blockbuster patents, spotty patent examination at patent offices, nomenclature confusion, regulatory gaps, third-party payor pressures, sky-rocketing prices, and governmental pricing pressures will all impact and reshape the drug industry landscape as well as healthcare policy. I also expect that due to limited current experience with the evaluation of first-generation nanodrugs and biologics, manufacturers, regulatory agencies, clinicians, patients, and patent offices will face challenges not only regarding second- and third generations of these two drug classes but also on the biosimilars, nanosimilars, and NBCD generics front.
ADRs, including immune reactions, will be common (Box 1.17) and regulatory agencies will continue drug approval based on an analysis of the risk–benefit ratio that changes significantly depending on the treatment modality. However, as more nanodrugs and nanomedical products are developed, information will accumulate on their structure and biofunction. As a result, their description and understanding and their functionality will be revised, as applicable, and supported with characterization data. Moreover, as the intricacies of the human immune system are further elucidated, we will learn more about the interactions of nanodrugs with immune cells. In the meantime, nanodrugs and biologics will continue to be evaluated by regulators on a case-by-case basis, often non-optimally.
Due to long timeline (10–17 years), high attrition rate, and enormous R&D costs (average pre-tax cost per approved drug, including cost of failure, is $2.6 billion) involved in the approval of a new drug [100], pharma has increasingly turned to computational and mathematical modeling at all levels—modeling drug–receptor interactions, PK and pharmacodynamic (PD) modeling, in silico clinical trials. Given this trend, I predict that we will glean greater information regarding pharmacology and toxicology of nanodrugs and biologics as we expand our arsenal of both in vitro, in silico, and in vivo analytical methods as well as instrumentation. Computer-driven computational methods followed by in vitro and/or in vivo testing of potentially adverse epitopes will help in minimizing ADRs. In future, due to the great cost and time needed for comprehensive animal studies, researchers will increasingly develop various ex vivo mimics of in vivo biological environments to study drug interactions. AI is expected to change the drug
11�
discovery process as machine learning and other technologies are likely to make the hunt for new drugs quicker, cheaper and more effective [101]. Specifically, AI will be employed in the nanodrug R&D arena to analyze large data sets from clinical trials, health records, gene profiles, and preclinical studies. Technically, a sufficiently large medicinal chemistry database of transformations could provide novel approaches to improving drug discovery, irrespective of the specific drug arena [102].
Nomenclature, technical specifications, standards, guidelines and best practices are critically needed to advance nanomedicine in a safe and responsible manner. Contrary to some commentators, terminology does matter because it prevents misinterpretation and confusion. However, defining nano from any perspective (scientific, regulatory, patent law, ethics, policy), is no easy task. So far, no real consensus has been reached on basic “nano” terms. In fact, finding a consensus on nano-nomenclature is a challenge, especially with the diversity and scope of scientific disciplines, voices and technologies encompassed by the nano-umbrella. An official, scientifically credible and legally workable definition as applied to nanodrug delivery systems does not currently exist. Nano as applied to drug delivery does not need to have any unique size cut-off for the simple fact that such artificial boundaries are completely irrelevant from an efficacy or formulation perspective. Viable sui generis definition of nano having a bright-line 100 nm size range as applied to nanodrugs blurs with respect to what is truly nanoscale. The NNI definition of nanotech needs to be dropped, especially in the context of nanodrug delivery (Section 1.3).
Efforts are underway to bridge the translational gap between benchtop preclinical research and bedside medial applications with nanoproducts, nanomaterials, and nanotherapeutics (Section 1.12). Practical considerations should be at the forefront to streamline and improve translational nanomedicine (Table 1.8). This, in turn, will enable delivering more therapies rapidly, safely, and effectively for patients globally. It is also important to optimally integrate healthcare, academia, and industry to achieve changes at various levels along the translational path (Table 1.8). These are critical to improving the performance of its supply chain for the benefit of all stakeholders. In a big pharma and biotech setting, enhancing translational nanomedicine will require a corporate
Concluding Remarks and Future Prospects
11� Drug Delivery at the Nanoscale
cultural change, and senior leadership commitment to advocate and implement the changes. I believe that issues such as effective patent reform, adaptive regulatory guidance, robust governmental efforts, and consumer health are all intertwined and require special attention while addressing nanomedicine translation from the bench to the bedside. In this regard, science-based governance that promotes translation on one hand and balances consumer health on the other is crucial. It is imperative that governmental regulatory agencies enhance interaction with developers and drug sponsors early in the R&D cycle. This will help identify bottlenecks and priority areas, monitor emerging scientific trends, update “draft” regulatory guidances, develop new regulatory competence in emerging areas and reduce the translational gap.
A concerted international approach is the only way to overcome the complex barriers confronting translational medicine, and by extension, translational nanomedicine. No one entity, organization, or institution can operate in isolation or undertake the task individually. Serious efforts in the past decade involve streamlining the research approval process and reducing regulatory burdens to push translational medicine. In the US, the National Center for Advancing Translational Sciences (NCATS) was established in 2012 with its mission to “catalyze the generation of innovative methods and technologies that will enhance the development, testing, and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions” [103]. Similarly, there are other entities dedicated to serving as “adapters” and “deriskers” between basic research entities and commercial organizations. These key players must come together on a global platform to address issues affecting translational efforts. Despite geographic diversity and organization specific mandates, they must leverage expertise, share best practices, and pool their experiences. Obviously, integrating and leveraging their cumulative knowledge will lead to improved health outcomes for patients.
It is important that some order, central coordination and uniformity be introduced globally to address the rise of diverse nano terms seen in the patent literature, journal articles and the press. This is also critical to prevent a significant scientific, legal, and regulatory void from developing. It is apparent to me that
11�
this has contributed to the evolving patent thicket in certain sectors along with a lack of specific protocols for preclinical development, slower nano-characterization and confusion in the scientific literature.
In summary, in the coming decade, various other issues pertaining to R&D, IP, ADRs, regulation, translation, and commercialization will spill over from pharma and biotech into the nanomedicine space. Irreproducible preclinical data will continue to plague biomedical research (Box 1.18). Safety of generics due to oversights by the FDA or EMA will be another major concern for patients and health-care systems (Box 1.19). Public acceptance of nanomedicine will continue to be strongly influenced by the perception of the associated ethical and societal aspects [104–106]. Numerous other issues that today appear on the backburner will directly or indirectly impact the trajectory of nanomedicine development. Some of these include: • scientific integrity, including research misconduct and
plagiarism [107–112], • pressure to publish (or perish) [113, 114], • open access publishing (OAP) of journals [115], • the pollution of science by predatory/fake journals
[116–121], • over-reliance on and the semi-sanctified status of impact
factors [122, 123], • the self-citation fraud [124–127], • catastrophic blemish of pseudoscience [128, 129], • the pervasive conflict-of-interest with respect to FDA
advisory committees [130–138], • the continued irrelevance of PhD courses [139], • the rise of academic bullying in the scientific community
[140–143], • national security concerns and anti-espionage policies at
universities [144, 145], and • limited access to scientific research data [146, 147].
Stakeholders ranging from physicians, scientists, patent professionals, lawyers, regulatory bodies, drug and biotech companies, academia, policymakers, the venture community, disease advocacy groups, consumer-patients, and governmental agencies must converge on a global platform to address various
Concluding Remarks and Future Prospects
11� Drug Delivery at the Nanoscale
pending issues in nanomedicine as elaborated in this chapter. Specifically, they must formulate formal definitions for nano terminology, draft effective regulatory guidelines, ensure issuance of valid patents, formulate clearer safety protocols, provide transparency to the R&D process, and be fully committed to translational and commercialization efforts. In the meantime, this chapter should provide guidance and a roadmap to these stakeholders.
Box 1.1� The Crisis of Reproducibility in Biomedical Research and Its Lethal Consequences
We are in the midst of a widening research crisis. The current pervasive culture of science focuses on rewarding flashy, eye-catching, and positive findings. There is an increased emphasis on making provocative statements rather than presenting technical details or reporting basic elements of experimental design. These are some of the factors that have resulted in irreproducible preclinical research in biomedicine, mainly from academia. Reports indicate that less than one-third of biomedical papers can be reproduced; this is due to sloppy science blamed in part on scientific culture, training, and incentives. A survey of nearly 900 members by the American Society for Cell Biology in 2015 found that more than two-thirds of respondents had been on at least one occasion unable to reproduce published results. These results are strikingly similar to another online survey of 1,576 researchers by Nature conducted in 2016 that reported that 70% of researchers have tried and failed to reproduce another scientist’s experiments, and more than half have failed to reproduce their own experiments. Irreproducible research delays treatments, wastes time, and squanders research dollars. It is clearly widespread. In fact, it is seen in all disciplines of biomedical research, with the area most susceptible being research work that employs animal models. Research institution administrators, faculty members, and trainees all share blame here. Most institutions will, however, not make the necessary moves unless forced by a regulatory or funding body. However, note that there is no evidence to suggest that irreproducibility is caused by scientific misconduct. Obviously, human clinical trials are less at risk from irreproducibility because they are already governed by various regulations that stipulate rigorous
11�
design and independent oversight. Big pharma is particularly concerned about this irreproducibility crisis plaguing biomedical research. Drug companies have reported that one-quarter or fewer of high profile papers are reproducible. In the past, drug screening was mainly performed at pharma and supported internally by outstanding teams of chemists. Over the years, there has been a growing reliance on academia for this upstream drug R&D. In fact, this collaborative innovation between pharma and the academic community is credited with producing key enabling discoveries underlying many marketed blockbusters. Today, preclinical drug discovery research is still primarily conducted and managed by pharma. However, academia now contributes to this effort by conducting basic research into fundamental and mechanistic aspects of human disease biology and discovery of targets whose modulation could have therapeutic potential. The resultant “gold nuggets” that are thus generated by academia are then plucked by pharma to discover and develop drugs that modulate those targets, thereby driving the drug discovery engine. However, this common arrangement is in trouble and the collaborative paradigm is breaking down as much of the research published in academia has proven not to be reproducible by drug companies. Basically, academic target discovery research reproducibility has become suspect. One important factor for the imperfect marriage between academia and industry with respect to drug R&D is the absence of an outstanding support structure in academic drug research where researchers are typically not trained to separate “hits” into compounds good, bad, and ugly. Many contend that, as a result, naivety about promiscuous, assay-duping molecules is polluting the literature and wasting resources. Shortcuts taken by antibody manufacturers and researchers alike have resulted in a crisis of reproducibility in antibody performance. The American Statistical Association (ASA) issued principles to guide use of the P-value and warned that P-values cannot be used to determine whether a hypothesis is true or whether the results are important. According to the ASA, misuse of P-values is also contributing to this irreproducibility mess. Irreproducibility of biomedical research is costly. According to a report, about US$28 billion are annually spent on irreproducible preclinical research in the US.Source: R. Bawa [21].
Concluding Remarks and Future Prospects
(Continued)
11� Drug Delivery at the Nanoscale
“Biomedical science—the research that underlies our treatments and cures—is in deep crisis. Every year, American taxpayers spend more than $30 billion funding it. About half of that work, by some estimates, is wrong. As award-winning science journalist Richard Harris reveals in Rigor Mortis, this is not simply the result of trial and error, which is an essential part of the scientific
process. The economic imperative for researchers to get and keep jobs and funding encourages dubious behaviour, from poor experimental design to sloppy statistics and shoddy analysis. Add to that a bunch of mislabelled cell lines and mishandled ingredients, and what seems like a potential cure becomes an unreliable mess. Some 900 breast-cancer studies were conducted with cells that weren’t breast-cancer cells at all, new “treatments” for ALS developed in rodent models failed when retested properly in mice, and only 1.2 percent of early papers in genomics stand the test of time. These problems aren’t the exception. They are commonplace. This crisis of reproducibility—when studies done in one lab fail when another tries to reproduce their results—isn’t just holding back scientific progress; it’s a devastating blow for patients everywhere, who are hoping that medical science will give them longer, healthier lives. Rigor Mortis explores these urgent issues through vivid anecdotes, personal stories, and interviews with the nation’s top biomedical researchers, some of whom are now struggling to set things right. An unsparing investigation that lays bare the dysfunctions in our research system, this book represents the first step toward fixing it.”
Source: Harris, R. F. (2017). Rigor Mortis: How Sloppy Science Creates Worthless Cures, Crushes Hope, and Wastes Billions. Basic Books, New York. [Book Cover Copyright © 2017 Basic Books. All rights reserved.]
Box 1.1� (Continued)
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Box 1.1� FDA’s Broken Quality Control System for Generics: Patients Beware!
“Carcinogens have infiltrated the generic drug supply in the U.S. and an FDA quality-control nightmare reveals how impurities end up in America’s blood pressure pills. The FDA has a rigorous approval process for new drugs. Companies conduct clinical trials in humans over several years to prove a drug is safe and effective. But 90% of all medications prescribed to Americans are generics. They’re
cheaper, they’re supposed to work the same way, and they receive less scrutiny right from the start. Companies manufacturing generic drugs have to show only that patients will absorb them at the same rate as the name-brand medications they mimic. At least 80% of the active pharmaceutical ingredients, or APIs, for all drugs are made in Chinese and Indian factories that U.S. pharmaceutical companies never have to identify to patients, using raw materials whose sources the pharmaceutical companies don’t know much about. The FDA checks less than 1% of drugs for impurities or potency before letting them into the country. Surveillance inspections of overseas factories have declined since 2016, even as the agency is under pressure to get more generics to market more quickly. In 2008 the FDA opened three posts in China and announced plans to dramatically increase the number of inspectors there. By 2014, it had closed its offices in Shanghai and Guangzhou, leaving only the Beijing office with inspectors who could visit Chinese factories on short notice…. Quality-control problems in the generic drug industry go beyond the visible lapses….Where the FDA’s [non-generic or branded] drug approval process is founded on testing and more testing, the regulatory system for generics is built on trust, specifically trust in manufacturers.”
Source: Edney, A., Burfield, S., Yu, E. (2019). Can you trust generics? Bloomberg Businessweek. September 23 Issue, pp. 36–43. [Magazine Cover Copyright © 2019 Bloomberg L.P. All rights reserved.]
Concluding Remarks and Future Prospects
1�0 Drug Delivery at the Nanoscale
Abbreviations
ADCs: antibody–drug conjugatesADME: adsorption, distribution, metabolism, and excretionADRs: adverse drug reactionsAFM: atomic force microscopeAI: artificial intelligenceANDA: Abbreviated New Drug ApplicationAPI: active pharmaceutical ingredientASA: American Statistical AssociationASTM: American Society for Testing and MaterialsAUC: area under the curve BCS: Biopharmaceutical Classification SchemeBLAs: Biologics License ApplicationsBPCI Act: Biologics Price Competition and Innovation Act of 2009CAFC: US Court of Appeals for the Federal CircuitCAGR: compound annual growth rateCAR-T: chimeric antigen receptor T-cell therapyCARPA: C activation-related pseudoallergyCBER: Center for Biologics Evaluation and ResearchCDC: Centers for Disease Control and PreventionCDER: Center for Drug Evaluation and ResearchCDRH: Center for Devices and Radiological HealthCFR: Code of Federal RegulationsCFSAN: Center for Food Safety and NutritioncGMP: current Good Manufacturing PracticeCNTs: carbon nanotubesCTP: Center for Tobacco ProductsCVM: Center for Veterinary MedicineDDS: drug delivery systemDEA: Drug Enforcement AdministrationEMA: European Medicines AgencyENMs: engineered nanomaterialsEPA: Environmental Protection AgencyEPR: enhanced permeability and retentionEU: European Union
1�1
f-CNTs: functionalized carbon nanotubesFD&C Act: Federal Food, Drug, and Cosmetic ActFDA: US Food and Drug AdministrationFIH: first-in-humanGAO: US Government Accountability OfficeGCP: good clinical practiceGLP: good laboratory practiceGMP: good manufacturing practiceGRAS: generally recognized as safeGPCR: G protein-coupled receptorHOS: higher-order structureIBD: inflammatory bowel diseaseIDE: Investigational Device ExemptionIMPs: Investigational Medicinal ProductsIND: Investigational New DrugIP: intellectual propertyIRB: institutional review boardISO: International Organization for StandardizationISO/TC229: ISO Technical Committee on NanotechnologyIUPAC: International Union of Pure and Applied ChemistryKS: Kaposi sarcomaMNT: molecular nanotechnologyMS: multiple sclerosisMW: molecular weightNASA: National Aeronautics and Space AdministrationNBCD: nonbiologic complex drugNBEs: new biological entitiesNCATS: National Center for Advancing Translational SciencesNCEs: new chemical entitiesNCPs: nano-combination productsNDAs: New Drug ApplicationsNDDS: nanoscale drug delivery systemsNIH: National Institutes of HealthNIOSH: National Institute for Occupational Safety and HealthNMEs: new molecular entities
Abbreviations
1�� Drug Delivery at the Nanoscale
NMOFs: nanoscale metal organic frameworksNRC: National Research CouncilNNI: National Nanotechnology InitiativeNPs: nanoparticlesNSF: National Science FoundationOAP: open access publishingOCP: Office of Combination ProductsOECD: Organization for Economic Co-operation and Development OTC: over-the-counterPBPK: physiologically based pharmacokineticPCC: physicochemical characterizationPD: pharmacodynamicPEG: polyethylene glycolPhRMA: Pharmaceutical Research and Manufacturers of AmericaPHS: Public Health ServicePK: pharmacokineticsPMA: premarket approval applicationPMOA: primary mode of actionPTO: US Patent and Trademark OfficeQA: quality assuranceRA: rheumatoid arthritisROI: return on investmentSBIR: Small Business Innovation ResearchsiRNA: small interfering RNASPR: surface plasmon-resonance STM: scanning tunneling microscopeTEM: transmission electron microscopeTM: translational medicineTMAbs: therapeutic monoclonal antibodiesTTOs: technology transfer officesUSC: United States CodeUSPION: ultrasmall superparamagnetic iron oxide nanoparticleUSTR: US Trade RepresentativeWHO: World Health OrganizationWIPO: World Intellectual Property Organization
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Disclosures and Conflict of Interest
This work was supported by Bawa Biotech LLC, Ashburn, VA, USA. The author is a scientific advisor to Teva Pharmaceutical Industries, Ltd., Israel. No writing assistance was utilized in the production of this chapter and no payment was received for its preparation.
Corresponding Author
Dr. Raj BawaBawa Biotech LLC21005 Starflower WayAshburn, VA 20147, USAEmail: [email protected]
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