Drug Delivery at the Nanoscale: A Guide for Scientists ... · institutional corruption, “draft”...

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

� Drug Delivery at the Nanoscale

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.

Nano Frontiers


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

Nano Frontiers

(Continued)


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.).

Nano Frontiers


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.

Nano Frontiers

10 Drug Delivery at the Nanoscale

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.

The Arrival of Modern Nanotechnology

1� Drug Delivery at the Nanoscale

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


(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,



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.



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


�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 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


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


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.



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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.



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



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)



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.



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



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

ty

Med

ical

ity

Indu

str-

ializ

aon

Basi

cR&

D

Prot

otyp

eDe

sign

or

Disc

over

y

Prec

linic

alDe

velo

pmen

tCl

inic

alDe

velo

pmen

t

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<TYPESETTER: FIGURE 1.2 HERE. PLEASE INSERT FIGURE 58.3A FROM HANDBOOK OF CLINICAL NANOMEDICINE VOLUME 2.>


�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.

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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.


Figure 1.� Drug Sponsor’s Clinical Studies/Trials.Modified by the author, original courtesy of the FDA.


�� 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

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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.



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?


(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


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.



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.



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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?


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?


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?


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


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


(Continued)


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.



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


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


(Continued)


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).



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


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.

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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



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

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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



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).



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



(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.



Box

1.1�

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imal

s an

d P

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he

Mou

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hat

Wen

t to

Har

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!

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idea

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life

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str

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of G

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l’s n

ovel

198

4. H

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then

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on

June

22,

198

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nive

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file

d a

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pplic

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the

US

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ffice

for

the

Har

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and

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nam

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hat

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ses

it to

dev

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brea

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r. Th

e ap

plic

atio

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itled

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ansg

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non

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amm

als,”

was

aw

arde

d US

Pat

ent

No.

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36,8

66 o

n Ap

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12, 1

988

(exp

ired

in

2005

). Th

is i

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e fir

st p

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t on

an

anim

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mile

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bio

tech

nolo

gy

pate

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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

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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

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g a

livin

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imal

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u be

t. Th

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still

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nd th

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prob

ably

alw

ays

will

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the

outs

ide

obse

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not

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of p

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thin

g sm

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of

scie

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ts a

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busi

ness

men

pla

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God

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how

did

this

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supp

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The

see

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the

land

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upre

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ond

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rul

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that

for

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first

tim

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the

hist

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of p

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stab

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at l

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as p

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upre

me

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t st

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tha

t “a

pat

ent

can

be g

rant

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n an

ythi

ng

unde

r th

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n w

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can

be

mad

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man

” an

d “t

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elev

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pat

enta

bilit

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not

bet

wee

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imat

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ings

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whe

ther

livi

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can

be s

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as ‘h

uman

-mad

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vent

ions

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rior

to 1

980,

the

US P

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t Of

fice

did

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t pa

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s on

mic

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and

cells

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echn

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em t

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fac

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rout

inel

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aten

t ap

plic

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ns p

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g to

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-form

s as

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subj

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mat

ter

unde

r th

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aditi

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trin

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fined

by

35 U

SC §

101

. Alth

ough

no

pate

nts

wer

e gr

ante

d on

livi

ng o

rgan

ism

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r se

at

this

tim

e, c

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ns c

onta

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g liv

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thin

gs, s

uch

as v

acci

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cont

aini

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atte

nuat

ed b

acte

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wer

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able

. A b

oom

in t

he U

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otec

hnol

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indu

stry

follo

wed

the

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krab

arty

dec

isio

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larg

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due

to t

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ntel

lect

ual p

rope

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prot

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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.

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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.



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.



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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


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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



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)



–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)



–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)



–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.



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.



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)



•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.


(Con

tinu

ed)


•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

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sin

ess

and

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mer

cial

izat

ion

: An

ove

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ified

by

the

auth

or, o

rigi

nal f

rom

Pan

Sta

nfor

d Pu

blis

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, Sin

gapo

re.



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

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torin

gEn

trep

rene

urs

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Vir

tuou

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cle.

An

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rodu

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ew k

now

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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


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



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



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].


(Continued)


“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)

11�

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.]


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

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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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