7194_C008

8.1 INTRODUCTION

In the last deca

nologies has ge

prevention, diag

to as nanomedic

systems, incorp

and/or improv

systems.1 The

large; these pro

xo

y

)containing do

(e.g., actinom

late) (PECAq 2006 by Taylor & Frade, remarkable scientific progress in the development of novel, nanoscale tech-

nerated rising expectations for this enabling technology to advance our efforts in the

nosis and treatment of human disease. These nanotechnologies, commonly referred

ines when applied to the treatment, diagnosis, monitoring, and control of biological

orate a multitude of diverse and often unique nanosized products including new

ed therapeutic drugs, diagnostic/surgical devices, and targeted drug delivery

list of nanoparticle medicines approved and/or currently being developed is quite

ducts range from early forms of drug-encapsulating liposomes (e.g., liposomes

rubicin for treatment of breast and ovarian cancer) and simple polymeric structures

cin D adsorbed on poly(methylcryanoacrylate) (PMCA) and poly(ethylcryanoacry-

nanosized particles)2 to more intricate multifunctional nanoplatforms and8 Nanotechnology: RegulatoryPerspective for DrugDevelopment in CancerTherapeutics

N. Sadrieh and T. J. Miller

CONTENTS

8.1 Introduction ......................................................................................................................... 139

8.2 FDA Experience with Nanotechnology Product Applications........................................... 140

8.3 FDA Definition of Nanotechnology ................................................................................... 143

8.4 FDA Initiatives in Nanotechnology .................................................................................... 143

8.5 Research at the FDA on Nanotechnology .......................................................................... 145

8.6 Regulatory Considerations for Nanotechnology Products ................................................. 145

8.6.1 Jurisdiction of Nanotechnology Products ............................................................... 145

8.6.2 Existing FDA Regulations That Apply to Nanomaterial-Containing Products ..... 146

8.7 Scientific Considerations for the Development of Nanotechnology Products .................. 147

8.7.1 Characterization of Nanoparticles........................................................................... 147

8.7.2 Safety Considerations.............................................................................................. 149

8.8 Conclusions ......................................................................................................................... 149

8.9 Trademark Listing ............................................................................................................... 151

References .................................................................................................................................... 151139

ncis Group, LLC

developed to improve early detection of cancer and/or to provide alternative clinical therapeutic

approaches to fighting cancer, some of these products have been approved by the Food and Drug

Administration for clinical use.75

A a-

teria is

avail r-

gane ct

the r es

inclu i-

bition of oxidative stress and lipid peroxidation in isolated microsomes, dermal fibroblasts, andcultured cortical neurons;7779 cytotoxicity of metal oxide nanoparticles to BRL 3A liver cells;80

and macrophage apoptosis after exposure to carbon nanomaterials and ultrafine particles.8183

Although a vast amount of useful information has been obtained from these various in vitro

models, the relevance and application of these findings to human drug safety remain uncertain

until validated with in vivo studies with identical nanomaterials.

Targeted in vivo efficacy data is readily available for many of the novel, potential nanother-

apeutics; however, necessary in vivo data indicating mechanism of action, general

pharmacology/toxicity profiles, and optimal product characterization efforts rarely appear in the

published literature. Much of our current understanding of the biocompatibility of nanomaterials

comes from focused inhalation and dermal studies using nanosized products and ultrafine contami-

nants, as a model of environmental and occupational risk.8487 However, there are questions

regarding the level of applicability of these studies to human drug safety assessment due to the

variability in size and purity of the chemical or structural composition reported or not reported in

these studies, the route of primary exposure, and the complex differences in the structure and

function of the affected organs.88 In addition, other in vivo studies, which identify intrinsic anti-

oxidant and oxidative stress-inducing properties of unsubstituted fullerenes in a rodent and fish

species, respectively, have important but limited value in drug discovery in the absence of systemic,

whole animal toxicology data67,89.

While the enthusiasm and expectations for success in utilizing nanomaterials and nanometer-

sized structures in biomedical applications grow, so do the concerns regarding the potential impact

of such products on the environment and human health.88 The absence of available safety infor-

mation for a vast majority of these novel nanosized materials and nanoparticlized drugs in

biological systems only further supports the need for additional research into any potential toxic

mechanisms in humans. The questions that appear most often in deciding the safety of any nanos-

cale material include:

Are nanomaterials and nanotechnology new to the United States Food and DrugAdministration (FDA)?

How do existing regulations ensure the development of safe and effective nanotech-nology-based drugs and how is the FDA preparing to deal with nanotechnology?

What are the scientific considerations that raise unique concerns for nanotechnology-based therapeutics?

8.2 FDA EXPERIENCE WITH NANOTECHNOLOGY PRODUCT APPLICATIONSHisto

char

q 2006lthough there have been many articles published on the in vitro toxicity of certain nanom

ls, very little in vivo safety data evaluating the general toxicity of these novel products

able in the published literature. Many in vitro assays (cell-based, organelle-based, and cell/o

lle-free systems) have been used to evaluate the cytotoxicity of nanomaterials to help predi

elative safety and general biocompatibility of the nanoproducts in vivo. Several such studi

de viability assays in vascular endothelial cells exposed to C60;76 fullerene induction/inhdiagnostic devices, including polymeric dendrimers, nanocrystal quantum dots, carbon-based full-

erenes, and nanoshells, to name a few (see Table 8.1). The vast majority of these products are being

Nanotechnology for Cancer Therapy140rically, the FDA has encountered and approved many products with particulate materials

acteristic of a nanomedicine or nanoproduct (e.g., small size, mechanism of delivery, increased

by Taylor & Francis Group, LLC

TABLE 8.1Nanomedicines: Drugs/Devices FDA Approved and in Development

Name Structure Company Size (nm) Phase Indication Referencea,b

Magnevistwc PIO Shering AG !1 APP MRI tumor imaging 35

Feridexwc SPIO Adv.Magnetics 120180 APP MRI tumor imaging 59

Rapamunewc Nanocrystal drug Wyeth 1001,000 APP Immunosuppressant agent 1012

Emendwc Nanocrystal drug Merck 1001,000 APP Nausea 13,14

Doxilwc Liposome-drug encapsulation Ortho Biotech z100 APP Metastatic ovarian cancer 1517

Abraxanewc Nanoparticulate albumin American Pharmaceutical

Partners

z130 APP Non-small-cell lung cancer, breast cancer,

others

1820

SilvaGardw Silver nanoparticles AcryMed z10 APP Antimicrobial surface treatment (medical

devices)

2123

AmBisomewc Liposome-drug encapsulation Gilead Science 4580 APP Fungal infections 2426

Leunessew Solid lipid nanoparticles Aano-therapeutics N/A On market Cosmetics N/A

NB-001d Nanoemulsion NanoBio Corp z150 Phase II Topical microbicide for herpes labialis 2730

VivaGelw Dendrimer Starpharma Holdings Ltd. N/A Phase I Vaginal microbicide (STI and HIV

prevention)

3134

INGN-401c Drugliposome complex Introgen Therapeutics N/A Phase I Metastatic lung cancer 3538

Combidexwc USPIO Advanced Magnetics 2050 NDA filed MRI tumor imaging 3942

IT-101c Drugpolymer complex Insert Therapeutics N/A IND filed Metastatic solid tumors 43,44

Dendrimersc Polymeric spheres, multifunctional Dendritech Nanotech.,

Starpharma

O1 to !500 IDV Diagnostic, contrast agents, microbicide,

drug delivery, B neutron capture

4554

Nanoshellsc Metal shell, SiO2 core Nanospectra 100200 IDV Photo-thermal ablation therapy /imaging

tumors

5558

Fullerenesc Carbon sphere, C60, multifunctional C Sixty 1 IDV MRI contrast agent, antiviral, antioxidant 5967

Quantum dotsc CdSea nanocrystal Evident Technologies 210 IDV Optical imaging, tumor imaging,

photosensitizer

6874

APP, approved; IDV, in development; PIO, paramagnetic iron oxide; SPIO, superparamagnetic iron oxide; USPIO, ultrasmall superparamagnetic iron oxide; STI, sexually transmitted

infection; HIV, human immunodeficiency virus; N/A, not available.

a Most typical semiconductor metal used, however can also be composed of nearly any other semiconductor metal (e.g., CdS, CdTe, ZnS, PbS, etc.).b References do not necessarily refer to the product described, and may reflect general properties about the product.c Drugs with proposed or proven diagnostic or therapeutic benefit to cancer patients.d Unable to locate peer-reviewed publications. References listed are press releases found during internet search.

q 2006 by Taylor & Francis Group, LLC

Regu

latory

Persp

ectivein

Nan

otech

nolo

gyPro

ducts

141

surface area, specialized function related to size and increased surface area, etc.). Although the field

of nanomedicine may be new, the submission of applications for products containing novel dosage

forms or drug delivery systems, including nanomaterials, nanoparticlized drugs and medical

devices, is not particularly new to this agency. Products are reviewed on a product-by-product

basis, and as such, various concepts of risk management (i.e., risk identification, risk analysis, risk

control, etc.) are often implemented to support the drug review process.

The FDA is aware of several FDA regulated products that employ nanotechnology. However,

to date, few manufacturers of regulated products have claimed the use of nanotechnology in the

manufacture of their products or made any nanotechnology claims for the finished product.

The FDA is aware that a few cosmetic products and sunscreens claim to contain nanoparticles

to increase the product stability, modify release of ingredients, or change the opacity of the

product by using nanoparticles of titanium dioxide and zinc oxide. Similarly, several drugs

such as Gd-DTPA (Magnevistw, tumor contrast agent),35 ferumoxides (Feridexw, tumor contrast

agent),59 liposomal doxorubicin (Doxilw, chemotherapeutic),1517 and albumin-bound paclitaxel

(Abraxanew, chemotherapeutic),1820 to name a few, have all been approved for human clinical

use in the diagnosis and treatment of a variety of patient tumors and metastatic cancers. For public

information regarding FDA approval letters, label information, and review packages for each

of these drugs and others listed in Table 8.1, please visit the following website: http://www.

accessdata.fda.gov/scripts/cder/drugsatfda/.

Of the many drugs listed in Table 8.1, tumor contrast agents comprise some of the earliest

nanosized products to receive FDA approval for human clinical use. Critical to therapeutic

outcome, diagnostic imaging of nanosized contrast agents using non-invasive magnetic resonance

imaging (MRI) and positron emission tomography (PET), have shown advanced utility for early

detection of small tumors, metastatic lymph nodes, and altered tumor microenvironments.90

The leading MR contrast agent, Magnevistw, a paramagnetic, gadolinium-based contrast

medium, and Feridexw, a superparamagnetic iron oxide contrast agent, received primary FDA

approval for clinical use in 1988 and 1996, respectively. Each contrast agent has a different

mean particle size (!1 nm and 120180 nm, respectively), is approved for different clinical indi-cations, and demonstrates product-specific adverse sensitivity and pharmacology/toxicology

profiles in patients.39

Another early nanomedicine, liposomal encapsulated doxorubicin (Doxilw), is regulated by the

FDA and has been available in the clinic for treatment of various cancers since 1995. Drug

incorporation inside the hydrophilic core or within the hydrophobic phospholipid bilayer coat of

liposomes, has been shown to improve drug solubility, enhance drug transfer into cells and tissues,

facilitate organ avoidance, and modify drug release profiles, minimizing toxicity.91 The liposomal

formulation of the popular anthracyline, doxorubicin, which is commonly used to treat metastatic

breast and ovarian cancer, is reported to have diminished cardiotoxicity and enhanced therapeutic

efficacy compared to the free form of the drug.1517 This increased efficacy is most likely due to the

passive targeting of solid tumors through the enhanced permeability and retention effect inherent to

tumor vasculature and aberrant tumor morphology.17 The approximate diameter of the doxoru-

bicinliposomal product is reported to be 100 nm, near the size limits described in the FDA

definition of a nanomedicine.

Nanoparticlized, albumin-bound paclitaxel, Abraxanew, is one of the first FDA-approved

(January, 2005) cancer drugs that was submitted to the FDA with specific claims regarding

nano-related characteristics that improved this particular formulation over previous sub-

missions.1820 Initially identified as (ABI-007), this chemotherapeutic agent that is approved for

the treatment of metastatic breast cancer eliminates the excipient Cremophorw by overcoming

intrinsic insolubility with nanoparticlization of the active paclitaxel ingredient. Although widely

used in many drug formulations, Cremophor has been associated with an adverse hypersensitivity20

Nanotechnology for Cancer Therapy142reaction that limited the amount of paclitaxel that could be safely administered. Unlike the

previous three agents, the approximate diameter of Abraxane is 130 nm, slightly larger than the


technology is defined as the following: In case of these devices, nanoscale objects were defined as

molecules or devices within the size range of one to hundreds of nanometers that are the active

component or object, even within the frame-work of a larger micro-size device or at a macro-

need to use medicines and foods to improve their health. Towards this end, the FDA needs to

proactively pursue those innovations that would result in a significant enhancement of publichealth. Therefore, it falls directly within the mandate of its mission for the FDA to understand

and help to speed innovations that promise to improve many products that will be regulated by the

FDA, such as those resulting from nanotechnology.

In response to a slowdown in innovating medical therapies submitted to the FDA for approval, the

FDA released the Critical Path Initiative (http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.interface. A discussion regarding the definition of nanotechnology is currently an active topic

among various organizations. However, while a definition is always useful, the FDA has tradition-

ally dealt with products on a case-by-case basis. This approach is likely to continue for

nanotechnology products, regardless of the definition. However, we are actively involved in the

various organizations and committees dealing with issues regarding terminology, such as the

American Society for Testing and Materials (ASTM) International.

The definition of nanotechnology at the FDA has been consistent with the definition of nano-

technology as reported by the NNI. As such, the FDA currently defines nanotechnology with the

following definition:

1. The existence of materials or products at the atomic, molecular, or macromolecular

levels, where at least one dimension that affects the functional behavior of the drug/de-

vice product is in the length scale range of approximately 1100 nm.

2. The creation and use of structures, devices, and systems that have novel properties and

functions because of their small size.

3. The ability to control or manipulate the product on the atomic scale.

8.4 FDA INITIATIVES IN NANOTECHNOLOGY

The FDA is responsible for protecting the health of the public by assuring the safety, efficacy and

security of human and veterinary drugs, biological products, medical devices, our nations food

supply, cosmetics, and products that emit radiation. The FDA is also responsible for advancing the

publics health by helping to speed innovations that make medicines and foods more effective, safer

and more affordable; and by helping the public get the accurate, science-based information theyrequirements described in the National Nanotechnology Initiative (NNI) definition of nanotech-

nology (!100 nm), and thus originally was determined not to fit the size requirement of ananomedicine. However, the fact that the exact particle size exceeds 100 nm may not necessarily

preclude Abraxane and other similarly-sized or larger products from being

considered nanotechnology.

8.3 FDA DEFINITION OF NANOTECHNOLOGY

As described on the NNI website (http://www.nano.gov/index.html), Nanotechnology is the

understanding and control of matter at dimensions of roughly 1100 nm, where unique phenomena

enable novel applications. Encompassing nanoscale science, engineering and technology, nano-

technology involves imaging, measuring, modeling, and manipulating matter at this length scale.

Similarly, in a recent publication by the European Science Foundation on Nanomedicine,92 nano-

Regulatory Perspective in Nanotechnology Products 143html) in March 2004. The report describes the urgent need to modernize the medical product

development processthe Critical Pathto make product development more predictable and less


costly. The Critical Path Initiative at the FDA is a serious attempt to bring attention and focus to the

need for targeted scientific efforts to modernize the techniques and methods used to evaluate the

safety, efficacy, and quality of medical products as they move from product selection and design to

mass manufacture. It is intended to integrate new science into the regulatory process. As such, a list of

opportunities for the Critical Path Initiative was published by the FDA, and nanotechnology was

identified as one of the elements under the Critical Path Initiative. Figure 8.1 illustrates the three

dimensions of the Critical Path (safety, medical utility and industrialization).

However, the Food and Drug Administration is only one of several government agencies that

currently regulates and evaluates a wide range of products that utilize nanotechnology and/or

contain nanomaterials, including foods, cosmetics, drugs, devices, and veterinary products. As a

member of both the National Science and Technology Council (NSTC) Committee on Technology,

and the Nanoscale Science, Engineering and Technology (NSET) Working Group on Nanomater-

ials Environmental and Health Implications (NEHI), the FDA coordinates with other government

agencies, including the National Institute for Environmental Health Sciences (NIEHS), the

National Toxicology Program (NTP), and the National Institute of Occupational Safety and

Health (NIOSH) to develop novel strategies for the characterization of and safety evaluation

standards for nanomaterials. The FDA also works closely with the National Cancer Institute

(NCI) and the National Institute of Standards and Technology (NIST) in the Interagency Oncology

Task Force, Nanotechnology subcommittee, to pool knowledge and resources to facilitate the

development and approval of new cancer drugs and to address the use of nanotechnology in

cancer therapies and diagnostics. Within the FDA, the Office of Science and Health Coordination

manages the regular interaction and discussion of nanotechnology between the various agency

centers and offices, and the nanotechnology working groups within each center, and address the

Nanotechnology for Cancer Therapy144concerns about the regulation of nanosized drugs and materials submitted to the individual centers.

Basicresearch

Safety

Medicalutility

Industrial-ization

Dim

ensi

ons

Prototypedesign ordiscovery

Material selectionstructureactivity

relationship

In vitroand animal

testing

Humanand animal

testing

In vitro andcomputer

modelevaluation

In vitroand animal

models

Humanefficacy

evaluation

Physicaldesign

Characterizationsmall-scaleproduction

Manunfacturingscale-uprefined

specifications

Massproduction

Safetyfollow

up

Preclinicaldevelopment Clinical development

FDA filling/approval &

launchpreparation

FIGURE 8.1 A highly generalized description of activities that must be successfully completed at different pointsand in different dimensions along the Critical Path. Many of these activities are highly complexwhole industries

are devoted to supporting them. Not all the described activities are performed for every product, and many activitieshave been omitted for the sake of simplicity. (From http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.

html.)


which happen to be conducted by the Center for Drug Evaluation and Research (CDER), include:1. Particle size determination in marketed sunscreens with TiO2 and ZnO nanoparticles.

Sunscreens are considered drugs in the U.S., and although some undergo a premarket

FDA review, others are marketed under over-the-counter (OTC) monographs that outline

the active ingredients that the FDA has found to be safe and effective, as well as labeling

that is truthful and not misleading. TiO2 and ZnO used in sunscreens are therefore

manufactured according to OTC monographs, and these monographs do not specify

particle size. As a result, a manufacturer can formulate a sunscreen using particles of

TiO2 and ZnO that may or may not be in the nano size range. Therefore, to assess the

particle size of TiO2 and ZnO in currently marketed sunscreens, CDER has undertaken a

research project, in collaboration with NIST.

2. Another project focuses on manufacturing various nanoformulations in our laboratories

and characterizing the physical and chemical properties of the nanoparticles in these

formulations, including evaluating the effects of excipients on the measured parameters,

the effects of preparation methodology on the measured parameters, and the impact (if

any) that process and formulation variables may have on nanotechnology product

characteristics and stability.

3. Another project is studying the in vivo effects of selected nanoparticles, using validated

animal models. The toxicity of the same nanoparticles will also be evaluated, using

various in vitro systems.

8.6 REGULATORY CONSIDERATIONS FOR NANOTECHNOLOGY PRODUCTS

8.6.1 JURISDICTION OF NANOTECHNOLOGY PRODUCTS

There has been much interest in the question of whether nanotechnology products will be

considered drugs, devices, biologics or a combination of the three for regulatory purposes and

assignment of work. This has been extensively discussed internally within the FDA and the current

thinking is that many of these products will be considered combination products.

Combination products (i.e., drugdevice, drugbiologic, and devicebiologic products) are

increasingly incorporating cutting edge, novel technologies that hold great promise for advancing

patient care. For example, innovative drug delivery devices have the potential to make treatments

safer, more effective, or more convenient to patients. For example, drug-eluting cardiovascular

stents have the potential to reduce the need for surgery by preventing the restenosis that sometimes8.5 RESEARCH AT THE FDA ON NANOTECHNOLOGY

Although the FDA is a regulatory agency, it is also engaged in a number of research activities.

However, the FDA recognizes that science supported by research provides the foundation for sound

regulation. As such, the FDA is interested in research projects that can address specific regulatory

needs. As an example, FDA has a grants program in support of orphan products research and

development. The FDA does not have a grants program to support other research in non-FDA

laboratories. Nevertheless, in several of its Centers the FDA conducts research to understand the

characteristics of nanomaterials and nanotechnology processes. Research interests include any

areas related to the use of nanoproducts that the FDA needs to consider in the regulation of

these products.

Although many FDA Centers are engaged in some nanotechnology research activities, only

some of the specific projects that are currently ongoing are listed below. The research projects,

Regulatory Perspective in Nanotechnology Products 145occurs following stent implantation. Drugs and biologics can be used in combination to potentially

enhance the safety and/or effectiveness of either product used alone. Biologics are being


which they are assigned.A combination product is assigned to an agency center or alternative organizational component

that will have primary jurisdiction for its premarket review and regulation. Under section 503(g)(1)

of the act, assignment to a center with primary jurisdiction, or a lead center, is based on a

determination of the primary mode of action (PMOA) of the combination product. For

example, if the PMOA of a devicebiological combination product is attributable to the biological

product, the agency component responsible for premarket review of that biological product would

have primary jurisdiction for the combination product.

A final rule defining the PMOA of a combination product was published in the August 25, 2005

edition of the Federal Register, and is available at http://www.fda.gov/oc/combination/. The final

rule defines PMOA as the single mode of action of a combination product that provides the most

important therapeutic action of the combination product.

8.6.2 EXISTING FDA REGULATIONS THAT APPLY TO NANOMATERIAL-CONTAINING PRODUCTS

The FDA has specific guidance/requirements in place for most products. These guidance docu-

ments can be accessed on the FDAs website (http://www.fda.gov/oc/industry/default.htm). These

requirements apply to all products, whether they contain nanomaterials or not. Existing require-

ments are therefore considered to be adequate at this time for most nanotechnology

pharmaceutical products.

In the following section, there will be a brief description of the current preclinical requirements

for the submission of most drugs, to highlight why we believe that our current regulations are

adequate for the evaluation of the types of nanotechnology products that have been reported as

being close to submission to the agency as an investigational new drug (IND).

Within CDER, the preclinical requirements for approval to market pharmaceutical products

include both short-term and long-term toxicity testing in rodent and non-rodent species. Speci-

fically, the types of studies conducted by pharmaceutical manufacturers prior to New Drug

Application (NDA) submission include pharmacology (mechanism of action), safety pharmacology

(functional studies in various organ systems, most notably the cardiovascular system), absorption,

distribution, metabolism, and excretion (ADME), genotoxicity (potential to cause mutations in both

in vivo and in vitro assays), developmental toxicity (to assess effects on reproduction, fertility andincorporated into novel orthopedic implants to help facilitate the regeneration of bone required to

permanently stabilize the implants.

Because combination products involve components that would normally be regulated under

different types of regulatory authorities, and frequently by different FDA centers, they also raise

challenging regulatory, policy, and review management issues. A number of criticisms have been

raised regarding the FDAs regulation of combination products. These include concerns about the

consistency, predictability, and transparency of the assignment process; issues related to the

management of the review process when two (or more) FDA centers have review responsibilities

for a combination product; lack of clarity about the postmarket regulatory controls applicable to

combination products; and lack of clarity regarding certain Agency policies, such as when appli-

cations to more than one agency center are needed.

To address these concerns, FDAs Office of Combination Products (OCP) was established on

December 24, 2002, as required by the Medical Device User Fee and Modernization Act of 2002

(MDUFMA). The law gives the office broad responsibilities covering the regulatory life cycle of

drugdevice, drugbiologic, and devicebiologic combination products. However, the primary

regulatory responsibilities for, and oversight of, specific combination products will remain in

one of three product centersthe Center for Drug Evaluation and Research, the Center for

Biologics Evaluation and Research, or the Center for Devices and Radiological Healthto

Nanotechnology for Cancer Therapy146lactation), irritation studies (to assess local irritation effects), immunotoxicology (to assess effects

on the components of the immune system), carcinogenicity (to assess the capacity of drugs to


nology applications that it is only possible to assess the safety of nanomaterials when the materialunder study is adequately characterized. If two or more laboratories are working on what they think

is the same material, then in order for the data from one laboratory to be compared with data from

another laboratory, there needs to be some confirmation that in fact the nanomaterials being studied

are actually identical. It has been mentioned by many that for nanomaterials, small differences in

product characteristics (such as size, surface charge, hydrophobicity, or a number of other attri-

butes) may impact product behavior and thus result in vastly different safety profiles. Published data

show that slight modifications of a nanoparticle have resulted in different toxicity profiles. For

example, several in vitro studies with Starburstw polyamidoamine (PAMAM) dendrimers and

Caco-2 cells have shown decreased cytotoxicity of cationic dendrimers upon addition of lauroyl

or polyethylene glycol (PEG) to the surface of the macromolecules.9394 Similar findings of dimin-

ished toxicity were observed in J774 macrophages upon conjugation of polysaccharides to polymer

nanoparticles and in fibroblasts and CHO cells with the addition of PEGsilica to the surface of

CdSe and CdSe/ZnS nanocrystals.9596

Although much less toxicity data is available in vivo, it is evident that surface chemistry is of

similar importance to the toxico- and pharmacokinetics, toxico- and pharmacodynamics, and9799induce tumors in animal models) and other possible studies (specific studies for a product being

developed). The current battery of tests, as listed above, is therefore considered to be adequate

because of the following reasons: the studies use high dose multiples of the drug (usually three

doses, one that results in low, one that results in medium and one that results in high toxicity), at

least two animal species are used (usually one rodent and one non-rodent), extensive histopathology

is conducted on most organs (where most organs are removed, fixed, stained and viewed under the

microscope to assess if there are structural changes that may have resulted from damage to the

organs), functional tests are conducted to assess if there are effects on specific organ systems (such

as the heart, brain, respiratory system, reproductive system, immune system, etc.) and drug treat-

ments in animals can be for extended periods of time (up to two years for carcinogenicity studies).

Additional studies might be requested based on drug-specific considerations and on a case-

by-case basis. Therefore, as for other drugs, nanotechnology products will be handled on a case-

by-case basis, depending on the characteristics of the particular product being developed. As

research provides additional understanding with regards to the toxicity of nanomaterials, the

FDA may require additional toxicological tests to ensure the safety of the products it regulates.

8.7 SCIENTIFIC CONSIDERATIONS FOR THE DEVELOPMENT

OF NANOTECHNOLOGY PRODUCTS

Ensuring the safety of nanomaterials in drug applications is one of the most important concerns for

regulators and drug developers. However, as important as safety is, it is also important to

adequately characterize the nanomaterials used in drug products. Proper characterization and

manufacturing procedures will ensure that a consistent product is being used, both during precli-

nical and clinical development, and after approval. Some of the questions that have been raised

internally regarding the assurance of safety of nanomaterial-containing products, as well as ques-

tions regarding characterization, are listed below. It is not within the scope of this chapter to address

questions regarding manufacturing and scale-up; however, it should be noted that this is an issue

that needs serious consideration, because unique characteristics of nanotechnology products are

likely to require unique manufacturing procedures.

8.7.1 CHARACTERIZATION OF NANOPARTICLES

It has become clear to most of those involved in research or development of potential nanotech-

Regulatory Perspective in Nanotechnology Products 147overall stability of the nanomaterials in vivo. When injected into rodents, several generations

of dendrimers with different surface configurations displayed contrasting organ distribution


patterns and plasma clearance profiles in vivo, typically depositing within the liver, kidney, and

pancreas.98100 PEG-conjugation to the dendrimer particle surface significantly increased the blood

half-life and diminished the liver accumulation of dendrimer particles.99 Similarly, quantum dots

coated with a complex polymer with carbon alkyl side chains demonstrated greater in vivo stability

and less genotoxicity than those coated with a simpler polymer or lipid coating.101 Based on the

findings of these studies and the collection of pulmonary inhalation data with environmental

ultrafines and other in vitro cytotoxicity results obtained with different nanomaterials (e.g.,

quantum dots, fullerenes, and nanoshells, etc.), it appears that a thorough characterization of the

nanomaterial is essential to the interpretation and understanding of toxicity data collected from

in vitro and in vivo studies.

To summarize some of the ongoing discussions within CDERs nanotechnology working

group, a list of questions has been put together regarding the characterization of nanomaterial-

containing products. At this time, it appears that there are no adequate answers to these questions.

However, it may be that in the future, to satisfy regulatory requirements for nanomaterial-

containing products, the questions listed below will need to be addressed by product sponsors.

1. What are the forms in which particles are presented to the organism, the cells and the

organelles? Are these particles soluble or insoluble, are the nanomaterials organic or

inorganic molecules, are the nanomaterials described as nanoemulsions, nanocrystal

colloid dispersions, liposomes, nanoparticles that are combination products (drug

device, drugbiologic, drugdevicebiologic), or something else? Does the product

fall within the currently established definition of nanotechnology?

2. What are the tools that can be used to characterize the properties of the nanoparticles?

Can standard tools that are used of other types of products (for example, spectroscopic

tools) be used to characterize nanomaterial-containing products, or do these products

require specialized tools that are not widely available for product characterization

(atomic force microscopy, tunneling electron microscopy, or other specialized modal-

ities)?

3. Are there validated assays to detect and quantify nanoparticles in the drug product and in

tissues?

4. How can long- and short-term stability of nanomaterials be assessed? Specifically, how

can the stability of nanomaterials be assessed in various environments (buffer, blood,

plasma, and tissues)?

5. What are the critical physical and chemical properties of nanomaterials in a drug product

and how do residual solvents, processing variables, impurities and excipients impact

these properties?

6. How do physical characteristics impact product quality and performance? Within what

range can these physical properties be modified without significantly affecting product

quality and performance?

7. What are the critical steps in the scale-up and manufacturing process for nanotechnology

products? How could manufacturing procedures for nanomaterials differ from those for

other types of drugs?

8. How are issues concerning the characterization and manufacturing procedures for nano-

technology products assessed, when considering the development of personalized

therapies? In this context, personalized therapies refer to those multifunctional products

that will be custom made for specific patients, depending on issues such as the

expression of a certain receptor on a tumor or the response of the tumor to a particular

chemotherapeutic agent. For these types of therapies, what should be the level of

Nanotechnology for Cancer Therapy148characterization of the nanomaterials? Does the preclinical testing need to be repeated

for each modification of the multifunctional molecule, or can there be limited testing to


8.7.2 SAFETY CONSIDERATIONS

Other than characterization, the other major consideration has to do with safety. However, it is only

within the context of adequately characterized products that safety studies provide value. There-

8.8 CONCLUSIONS

In this chapter, we have tried to highlight some of the steps being taken by the FDA to meet the

ch r-

ou al

wo as

ini er

un

typ

q 2allenges of nanotechnology products. The FDA has engaged in an open discussion with nume

s groups and organizations, has participated in and sponsored workshops, has established intern

rking groups, has outlined a path for the review of combination nanotechnology products and h

tiated research projects in nanotechnology. All these efforts have been geared towards a bettfore, although safety is instinctively the primary concern, adequate characterization of

nanomaterials has to precede any studies on safety.

As particle size decreases, there may be size-specific effects. These effects may impact safety if

the materials are more reactive. It has been mentioned in numerous discussions that, as particle size

decreases, reactivity is expected to rise. The increased reactivity combined with the decreased size

has led us to pose many questions. Some of these questions are listed below:

1. Will nanoparticles gain access to tissues and cells that normally would be bypassed by

larger particles?

2. If nanoparticles enter cells, what effects do they have on cellular and tissue functions?

Are the effects transient or permanent? Might there be different effects in different cell

types, depending on specific tissue targets or receptors?

3. Once nanoparticles enter tissues, how long do they remain there and where do they

concentrate?

4. What are the mechanisms by which nanoparticles are cleared from tissues and blood and

how can their clearance be measured?

5. What are some route-specific issues for nanomaterials, and how are these issues different

than for other types of materials that are not in the nanoscale?

6. With regards to ADME, specific questions include:

a. What are the differences in the ADME profile for nanoparticles versus larger particles

of the same drug?

b. Are current methods used for measuring drug levels in blood and tissues adequate for

assessing levels of nanoparticles (appropriateness of method, limits of detection)?

c. How accurate are mass balance studies, especially if the levels of drug administered

are very low; i.e., can 100% of the amount of the administered drug be accounted for?

d. How is clearance of targeted nanoparticles accurately assessed?

e. If nanoparticles concentrate in a particular tissue, how can clearance be accurately

determined?

f. Can nanoparticles be successfully labeled for ADME studies?cover certain aspects of the product behavior, such as the ADME, the toxicology (a

bridging study for the acute and/or repeat dose toxicology studies)? What aspects of

the chemistry, manufacturing and controls (CMC) studies need to be repeated and what

should be the extent of physical characterization?

Regulatory Perspective in Nanotechnology Products 149derstanding of the science and towards assessing the adequacy of existing regulations for the

es of products that are expected to be regulated by the FDA.

006 by Taylor & Francis Group, LLC

At this point, and based on internal discussions, the FDA feels that its current regulations are

adequate to address the types of nanotechnology products that are being developed as drugs or drug

delivery systems. The reasons for this have been outlined in this chapter. Although there have been

requests by investigators and developers of nanotechnology products for the FDA to issue nano-

technology-specific guidances, no new guidance documents applicable specifically to

nanotechnology products will be issued at this time. This is because it is felt that all existing

Guidance documents apply to these products. All products being developed, whether nanotech-

nology-based or not, are unique and therefore likely to have unique issues requiring consideration.

As such, and as for all other products reviewed by the FDA, nanotechnology products will be

reviewed on a case-by-case basis.

As shown in Figure 8.2, the drug development process is multiphasic and along the path, there

are numerous opportunities for meetings between the sponsor and the FDA. The first meeting is the

pre-IND meeting, and it is highly recommended that sponsors of nanotechnology products take the

opportunity to meet with the FDA at this early stage. An early meeting with the FDA can avoid

unnecessary or unfocussed studies that could result in a waste of sponsor resources. During early

meetings, sponsors can present, with minimal data, their preclinical plans to the FDA and obtain

guidance on how to focus the studies submitted in the IND package. This type of interaction

between the FDA and the sponsor will be valuable to both parties and will pave the way for the

most efficient drug development plan.

Basicresearch

Prototypedesign ordiscovery

Pre-IND meetingIndustry - FDA End of Safety update

Preclinicaldevelopment

Clinical development FDA filing/approval &

launchpreparationPhase 1 Phase 2 Phase 3

Nanotechnology for Cancer Therapy150interactionsduringdevelopment Initial

INDsubmissions

Ongoingsubmission

IND review phase Applicationreviewphase

Pre-BLA or NDAmeeting

End of phase2 meeting

phase2a meeting

Marketapplicationsubmission

FIGURE 8.2 This figure depicts the extensive industryFDA interactions that occur during product develop-ment, using the drug development process as a specific example.* Developers often meet with the agency

before submitting an investigational new drug (IND) application to discuss early development plans. An IND

must be filed and cleared by the FDA before human testing can commence in the United States. During the

clinical phase, there are ongoing submissions of new protocols and results of testing. Developers often request

additional meetings to get FDA agreement on the methods proposed for evaluation of safety or efficacy, and

also on manufacturing issues. *Note: Clinical drug development is conventionally divided into three phases.This is not the case for medical device development. (From www.fda.gov/oc/initiatives/criticalpath/white-

paper.html.)


superparamagnetic iron oxide MR contrast agents and commonly used transfection agents, Academy

of Radiology, 9 (Suppl. 2), S484S487, 2002.7. Shapiro, E. M., Skrtic, S., Sharer, K., Hill, J. M., Dunbar, C. E., and Koretsky, A. P., MRI detection of

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States of America, 101 (30), 1090110906, 2004.

8. Daldrup-Link, H. E., Rudelius, M., Oostendorp, R. A., Settles, M., Piontek, G., Metz, S.,

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9. Kostura, L., Kraitchman, D. L., Macka, A. M., Pittenger, M. F., and Bulte, J. W., Feridex labeling of

mesenchymal stem cells inhibits chondrogenesis but not adipogenesis or osteogenesis, NMR in

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10. LaVan, D. A., Lynn, D. M., and Langer, R., Moving smaller in drug discovery and delivery, National

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12. Aspeslet, L. J. and Yatscoff, R. W., Requirements for therapeutic drug monitoring of sirolimus, an

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2000.8.9 TRADEMARK LISTING

1. Magnevistw (Schering Aktiengesellschaft, Berlin, Germany)

2. Feridexw (Advanced Magnetics, Inc., Cambridge, Massachusetts, U.S.A.)

3. Rapamunew (Wyeth, Madison, New Jersey, U.S.A.)

4. Emendw (Merck & CO., Inc., Whitehouse Station, New Jersey, U.S.A.)

5. Doxilw (Ortho Biotech Products, L.P., Bridgewater, New Jersey, U.S.A.)

6. Abraxanew (American Pharmaceutical Partners, Inc., Schaumburg, Illinois, U.S.A.)

7. SilvaGardw (AcryMed, Beaverton, Oregon, U.S.A.)

8. AmBisomew (Gilead Sciences, Inc., Foster City, California, U.S.A.)

9. Leunessew (Nanotherapeutics, Inc., Alachua, Florida, U.S.A.)

10. VivaGelw (Starpharma Holdings, Ltd., Melbourne, Australia)

11. Combidexw (Advanced Magnetics, Inc., Cambridge, Massachusetts, U.S.A.)

12. Cremophorw (BASF Aktiengesellschaft, CO., Ludwigshafen, Germany)

13. Starburstw (Dendritic Nanotechnologies, Inc., Mount Pleasant, Michigan, U.S.A.)

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Table of ContentsChapter 8: Nanotechnology: Regulatory Perspective for Drug Development in Cancer Therapeutics8.1 INTRODUCTION8.2 FDA EXPERIENCE WITH NANOTECHNOLOGY PRODUCT APPLICATIONS8.3 FDA DEFINITION OF NANOTECHNOLOGY8.4 FDA INITIATIVES IN NANOTECHNOLOGY8.5 RESEARCH AT THE FDA ON NANOTECHNOLOGY8.6 REGULATORY CONSIDERATIONS FOR NANOTECHNOLOGY PRODUCTS8.6.1 JURISDICTION OF NANOTECHNOLOGY PRODUCTS8.6.2 EXISTING FDA REGULATIONS THAT APPLY TO NANOMATERIAL-CONTAINING PRODUCTS

8.7 SCIENTIFIC CONSIDERATIONS FOR THE DEVELOPMENT OF NANOTECHNOLOGY PRODUCTS8.7.1 CHARACTERIZATION OF NANOPARTICLES8.7.2 SAFETY CONSIDERATIONS

8.8 CONCLUSIONS8.9 TRADEMARK LISTINGREFERENCES

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