8

Nanotechnology: Regulatory
Perspective for Drug
Development in Cancer
Therapeutics
N. Sadrieh and T. J. Miller
CONTENTS
8.1 Introduction ......................................................................................................................... 139
8.2 FDA Experience with Nanotechnology Product Applications........................................... 140
8.3 FDA Denition 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 Scientic 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 .................................................................................................................................... 151
8.1 INTRODUCTION
In the last decade, remarkable scientic progress in the development of novel, nanoscale tech-
nologies has generated rising expectations for this enabling technology to advance our efforts in the
prevention, diagnosis and treatment of human disease. These nanotechnologies, commonly referred
to as nanomedicines when applied to the treatment, diagnosis, monitoring, and control of biological
systems, incorporate a multitude of diverse and often unique nanosized products including new
and/or improved therapeutic drugs, diagnostic/surgical devices, and targeted drug delivery
systems.
1
The list of nanoparticle medicines approved and/or currently being developed is quite
large; these products range from early forms of drug-encapsulating liposomes (e.g., liposomes
containing doxorubicin for treatment of breast and ovarian cancer) and simple polymeric structures
(e.g., actinomycin D adsorbed on poly(methylcryanoacrylate) (PMCA) and poly(ethylcryanoacry-
late) (PECA) nanosized particles)
2
to more intricate multifunctional nanoplatforms and
139
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diagnostic 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
developed to improve early detection of cancer and/or to provide alternative clinical therapeutic
approaches to ghting cancer, some of these products have been approved by the Food and Drug
Administration for clinical use.
75
Although there have been many articles published on the in vitro toxicity of certain nanoma-
terials, very little in vivo safety data evaluating the general toxicity of these novel products is
available in the published literature. Many in vitro assays (cell-based, organelle-based, and cell/or-
ganelle-free systems) have been used to evaluate the cytotoxicity of nanomaterials to help predict
the relative safety and general biocompatibility of the nanoproducts in vivo. Several such studies
include viability assays in vascular endothelial cells exposed to C
60
;
76
fullerene induction/inhi-
bition of oxidative stress and lipid peroxidation in isolated microsomes, dermal broblasts, and
cultured cortical neurons;
7779
cytotoxicity of metal oxide nanoparticles to BRL 3A liver cells;
80
and macrophage apoptosis after exposure to carbon nanomaterials and ultrane particles.
8183
Although a vast amount of useful information has been obtained from these various in vitro
models, the relevance and application of these ndings to human drug safety remain uncertain
until validated with in vivo studies with identical nanomaterials.
Targeted in vivo efcacy data is readily available for many of the novel, potential nanother-
apeutics; however, necessary in vivo data indicating mechanism of action, general
pharmacology/toxicity proles, 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 ultrane 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 sh
species, respectively, have important but limited value in drug discovery in the absence of systemic,
whole animal toxicology data
67,89
.
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 Drug
Administration (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 scientic considerations that raise unique concerns for nanotechnology-
based therapeutics?
8.2 FDA EXPERIENCE WITH NANOTECHNOLOGY PRODUCT APPLICATIONS
Historically, the FDA has encountered and approved many products with particulate materials
characteristic of a nanomedicine or nanoproduct (e.g., small size, mechanism of delivery, increased
Nanotechnology for Cancer Therapy 140
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TABLE 8.1
Nanomedicines: Drugs/Devices FDA Approved and in Development
Name Structure Company Size (nm) Phase Indication Reference
a,b
Magnevist
wc
PIO Shering AG !1 APP MRI tumor imaging 35
Feridex
wc
SPIO Adv.Magnetics 120180 APP MRI tumor imaging 59
Rapamune
wc
Nanocrystal drug Wyeth 1001,000 APP Immunosuppressant agent 1012
Emend
wc
Nanocrystal drug Merck 1001,000 APP Nausea 13,14
Doxil
wc
Liposome-drug encapsulation Ortho Biotech z100 APP Metastatic ovarian cancer 1517
Abraxane
wc
Nanoparticulate albumin American Pharmaceutical
Partners
z130 APP Non-small-cell lung cancer, breast cancer,
others
1820
SilvaGard
w
Silver nanoparticles AcryMed z10 APP Antimicrobial surface treatment (medical
devices)
2123
AmBisome
wc
Liposome-drug encapsulation Gilead Science 4580 APP Fungal infections 2426
Leunesse
w
Solid lipid nanoparticles Aano-therapeutics N/A On market Cosmetics N/A
NB-001
d
Nanoemulsion NanoBio Corp z150 Phase II Topical microbicide for herpes labialis 2730
VivaGel
w
Dendrimer Starpharma Holdings Ltd. N/A Phase I Vaginal microbicide (STI and HIV
prevention)
3134
INGN-401
c
Drugliposome complex Introgen Therapeutics N/A Phase I Metastatic lung cancer 3538
Combidex
wc
USPIO Advanced Magnetics 2050 NDA led MRI tumor imaging 3942
IT-101
c
Drugpolymer complex Insert Therapeutics N/A IND led Metastatic solid tumors 43,44
Dendrimers
c
Polymeric spheres, multifunctional Dendritech Nanotech.,
Starpharma
O1 to !500 IDV Diagnostic, contrast agents, microbicide,
drug delivery, B neutron capture
4554
Nanoshells
c
Metal shell, SiO
2
core Nanospectra 100200 IDV Photo-thermal ablation therapy /imaging
tumors
5558
Fullerenes
c
Carbon sphere, C
60
, multifunctional C Sixty 1 IDV MRI contrast agent, antiviral, antioxidant 5967
Quantum dots
c
CdSe
a
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 immunodeciency 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 reect general properties about the product.
c
Drugs with proposed or proven diagnostic or therapeutic benet to cancer patients.
d
Unable to locate peer-reviewed publications. References listed are press releases found during internet search.
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surface area, specialized function related to size and increased surface area, etc.). Although the eld
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 identication, 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 nished 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 (Magnevist
w
, tumor contrast agent),
35
ferumoxides (Feridex
w
, tumor contrast
agent),
59
liposomal doxorubicin (Doxil
w
, chemotherapeutic),
1517
and albumin-bound paclitaxel
(Abraxane
w
, 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, Magnevist
w
, a paramagnetic, gadolinium-based contrast
medium, and Feridex
w
, 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-specic adverse sensitivity and pharmacology/toxicology
proles in patients.
39
Another early nanomedicine, liposomal encapsulated doxorubicin (Doxil
w
), 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 proles, 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
efcacy compared to the free form of the drug.
1517
This increased efcacy 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
denition of a nanomedicine.
Nanoparticlized, albumin-bound paclitaxel, Abraxane
w
, is one of the rst FDA-approved
(January, 2005) cancer drugs that was submitted to the FDA with specic claims regarding
nano-related characteristics that improved this particular formulation over previous sub-
missions.
1820
Initially identied as (ABI-007), this chemotherapeutic agent that is approved for
the treatment of metastatic breast cancer eliminates the excipient Cremophor
w
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 hypersensitivity
reaction that limited the amount of paclitaxel that could be safely administered.
20
Unlike the
previous three agents, the approximate diameter of Abraxane is 130 nm, slightly larger than the
Nanotechnology for Cancer Therapy 142
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requirements described in the National Nanotechnology Initiative (NNI) denition of nanotech-
nology (!100 nm), and thus originally was determined not to t the size requirement of a
nanomedicine. 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-
technology is dened as the following: In case of these devices, nanoscale objects were dened 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-
interface. A discussion regarding the denition of nanotechnology is currently an active topic
among various organizations. However, while a denition 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 denition. 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 denition of nanotechnology at the FDA has been consistent with the denition of nano-
technology as reported by the NNI. As such, the FDA currently denes nanotechnology with the
following denition:
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, efcacy 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 they
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 signicant enhancement of public
health. 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 FDAfor approval, the
FDAreleased the Critical Path Initiative (http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.
html) 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
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costly. The Critical Path Initiative at the FDA is a serious attempt to bring attention and focus to the
need for targeted scientic efforts to modernize the techniques and methods used to evaluate the
safety, efcacy, and quality of medical products as they move from product selection and design to
mass manufacture. It is intended to integrate newscience into the regulatory process. As such, a list of
opportunities for the Critical Path Initiative was published by the FDA, and nanotechnology was
identied 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 Ofce of Science and Health Coordination
manages the regular interaction and discussion of nanotechnology between the various agency
centers and ofces, and the nanotechnology working groups within each center, and address the
concerns about the regulation of nanosized drugs and materials submitted to the individual centers.
Basic
research
Safety
Medical
utility
Industrial-
ization
D
i
m
e
n
s
i
o
n
s
Prototype
design or
discovery
Material selection
structure
activity
relationship
In vitro
and animal
testing
Human
and animal
testing
In vitro and
computer
model
evaluation
In vitro
and animal
models
Human
efficacy
evaluation
Physical
design
Characterization
small-scale
production
Manunfacturing
scale-up
refined
specifications
Mass
production
Safety
follow
up
Preclinical
development
Clinical development
FDA filling/
approval &
launch
preparation
FIGURE 8.1 Ahighly generalized description of activities that must be successfully completed at different points
and in different dimensions along the Critical Path. Many of these activities are highly complexwhole industries
are devotedtosupportingthem. Not all the describedactivities are performedfor everyproduct, andmanyactivities
have been omitted for the sake of simplicity. (From http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.
html.)
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8.5 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 specic 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 specic projects that are currently ongoing are listed below. The research projects,
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. TiO
2
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
TiO
2
and ZnO that may or may not be in the nano size range. Therefore, to assess the
particle size of TiO
2
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 sometimes
occurs 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
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incorporated 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 Ofce 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 ofce broad responsibilities covering the regulatory life cycle of
drugdevice, drugbiologic, and devicebiologic combination products. However, the primary
regulatory responsibilities for, and oversight of, specic 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
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 nal rule dening 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 nal
rule denes 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 specic 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-
cally, 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 and
lactation), 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
Nanotechnology for Cancer Therapy 146
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induce tumors in animal models) and other possible studies (specic 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, xed, 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 specic 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-specic 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-
nology applications that it is only possible to assess the safety of nanomaterials when the material
under 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 conrmation 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 proles. Published data
show that slight modications of a nanoparticle have resulted in different toxicity proles. For
example, several in vitro studies with Starburst
w
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 ndings of dimin-
ished toxicity were observed in J774 macrophages upon conjugation of polysaccharides to polymer
nanoparticles and in broblasts 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, and
overall stability of the nanomaterials in vivo.
9799
When injected into rodents, several generations
of dendrimers with different surface congurations displayed contrasting organ distribution
Regulatory Perspective in Nanotechnology Products 147
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patterns and plasma clearance proles in vivo, typically depositing within the liver, kidney, and
pancreas.
98100
PEG-conjugation to the dendrimer particle surface signicantly 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
ndings of these studies and the collection of pulmonary inhalation data with environmental
ultranes 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 denition 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? Specically, 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 modied without signicantly 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 specic 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
characterization of the nanomaterials? Does the preclinical testing need to be repeated
for each modication of the multifunctional molecule, or can there be limited testing to
Nanotechnology for Cancer Therapy 148
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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?
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-
fore, 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-specic 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 specic 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-specic 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, specic questions include:
a. What are the differences in the ADME prole 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?
8.8 CONCLUSIONS
In this chapter, we have tried to highlight some of the steps being taken by the FDA to meet the
challenges of nanotechnology products. The FDA has engaged in an open discussion with numer-
ous groups and organizations, has participated in and sponsored workshops, has established internal
working groups, has outlined a path for the review of combination nanotechnology products and has
initiated research projects in nanotechnology. All these efforts have been geared towards a better
understanding of the science and towards assessing the adequacy of existing regulations for the
types of products that are expected to be regulated by the FDA.
Regulatory Perspective in Nanotechnology Products 149
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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-specic guidances, no new guidance documents applicable specically 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 rst 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 efcient drug development plan.
Basic
research
Prototype
design or
discovery
Pre-IND meeting
Industry - FDA
interactions
during
development
Initial
IND
submissions
Ongoing
submission
IND review phase Application
review
phase
Pre-BLA or NDA
meeting
End of phase
2 meeting
End of
phase
2a meeting
Market
application
submission
Safety update
Preclinical
development
Clinical development
FDA filing/
approval &
launch
preparation
Phase 1 Phase 2 Phase 3
FIGURE 8.2 This gure depicts the extensive industryFDA interactions that occur during product develop-
ment, using the drug development process as a specic example.* Developers often meet with the agency
before submitting an investigational new drug (IND) application to discuss early development plans. An IND
must be led 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 efcacy, 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.)
Nanotechnology for Cancer Therapy 150
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8.9 TRADEMARK LISTING
1. Magnevist
w
(Schering Aktiengesellschaft, Berlin, Germany)
2. Feridex
w
(Advanced Magnetics, Inc., Cambridge, Massachusetts, U.S.A.)
3. Rapamune
w
(Wyeth, Madison, New Jersey, U.S.A.)
4. Emend
w
(Merck & CO., Inc., Whitehouse Station, New Jersey, U.S.A.)
5. Doxil
w
(Ortho Biotech Products, L.P., Bridgewater, New Jersey, U.S.A.)
6. Abraxane
w
(American Pharmaceutical Partners, Inc., Schaumburg, Illinois, U.S.A.)
7. SilvaGard
w
(AcryMed, Beaverton, Oregon, U.S.A.)
8. AmBisome
w
(Gilead Sciences, Inc., Foster City, California, U.S.A.)
9. Leunesse
w
(Nanotherapeutics, Inc., Alachua, Florida, U.S.A.)
10. VivaGel
w
(Starpharma Holdings, Ltd., Melbourne, Australia)
11. Combidex
w
(Advanced Magnetics, Inc., Cambridge, Massachusetts, U.S.A.)
12. Cremophor
w
(BASF Aktiengesellschaft, CO., Ludwigshafen, Germany)
13. Starburst
w
(Dendritic Nanotechnologies, Inc., Mount Pleasant, Michigan, U.S.A.)
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