nanomedicine: governing uncertainties · nanomedicine is a promising and revolutionary field to...
TRANSCRIPT
“NANOMEDICINE: GOVERNING UNCERTAINTIES”
by
Antonella Trisolino
A thesis submitted in conformity with the requirements
for the degree of Master of Laws
Graduate Department of Law
University of Toronto
2010
© Copyright by Antonella Trisolino (2010)
ii
“Nanomedicine: Governing Uncertainties”
Antonella Trisolino
Master of laws
Faculty of Law
University of Toronto
2010
Abstract
Nanomedicine is a promising and revolutionary field to improve medical diagnoses and
therapies leading to a higher quality of life for everybody. Huge benefits are expected from
nanomedicine applications such as in diagnostic and therapeutic field. However, nanomedicine
poses several issues on risks to the human health. This thesis aims to defense a perspective of
risk governance that sustains scientific knowledge process by developing guidelines and
providing the minimum safety standards acceptable to protect the human health. Although
nanomedicine is in an early stage of its discovery, some cautious measures are required to
provide regulatory mechanisms able to response to the unique set of challenges associated to
nanomedicine. Nanotechnology offers an unique opportunity to intensify a major interplay
between different disciplines such as science and law. This multidisciplinary approach can
positively contributes to find reliable regulatory choices and responsive normative tools in
dealing with challenges of novel technologies.
iii
Acknowledgements
First I would like to express a special thank you to my Professor Trudo Lemmens who was
always willing to assist me in the elaboration of this thesis. His suggestions and comments
were valuable for a more in-depth analysis of this fascinating and complex topic.
I also would like to express my gratitude to my parents who always helped me during this
academic year in managing the difficult task of being a mother and a student at the same
time. I felt inspired and motivated by their constructive suggestions.
I also would like to thank Ms. Jody Firestone that made a significant contribution to the
revision of this thesis.
iv
Table of Contents Abstract ................................................................................................................................................. ii
Aknowledgements ............................................................................................................................... iii
Chapter 1: What is Nanomedicine? ................................................................................................ 1
1.1: Introduction ............................................................................................................................. 1
1.2: Thesis structure ....................................................................................................................... 1
1.3: Ambiguities in the Definition of Nanotechnologies. ................................................................ 2
1.4.: Properties of Nanotechnologies. ............................................................................................. 3
1.5: Characteristics of Nanomedicine Applications. ....................................................................... 3
1.5.1: Optical Imaging. ................................................................................................................... 4
1.5.2: Drug Delivery System. .......................................................................................................... 4
1.6: Potential Risks in Nanomedicine. ............................................................................................ 5
Chapter 2: How to Manage Risks in Uncertain Science. ................................................................. 8
2.1: Introduction ............................................................................................................................. 8
2.2: The Inadequacy of Classical Model of Risk- Benefit Analyses in Nanomedicine and Other Novel
Technologies ......................................................................................................................................... 9
2.3: Is the Precautionary Principle the Answer to Uncertain Science? ......................................... 12
2.3.1: Introduction ....................................................................................................................... 12
2.3.2: Origins and Various Interpretations of the Precautionary Principle. ................................. 12
2.4: The Precautionary Principle in the Context of Nanotechnologies. ........................................ 15
2.5: Conclusive Considerations on Precaution in Nanomedicine .................................................. 21
Chapter 3: Legal Considerations on Nanomedicine in Light of the Existing European and Canadian
Legal Systems ………………………………………………………………………………………………………………………………….22
3.1: Introduction ........................................................................................................................... 22
3.2: Nanoproducts and the Current Legal Regime in Europe. ....................................................... 22
3.2.1: Nanoparticles are “New Substances” Compared to their Bulk Chemicals. ........................ 25
3.3: Nanoproducts and the Current Legal System in Canada........................................................ 30
3.3.1: Introduction ........................................................................................................................ 30
3.3.2: Challenges for Nanoproducts under the Canadian Drug Regulatory System. .................... 30
3.3.3: Challenges for Nanoproducts under the Canadian Medical Device Regulatory System. ... 31
3.4: Role and Scope of Guidelines in the Context of Nanomedicine. ............................................ 34
Chapter 4: Recommendations and Conclusive considerations ..................................................... 35
4.1 Recommendations ................................................................................................................. 35
4.2 Conclusive Considerations ..................................................................................................... 37
1
Chapter 1: What is Nanomedicine?
1.1 Introduction
Nanotechnology is a revolutionary way of understanding technology and the process of
manufacturing it in different sectors of industries such as transportation, nuclear weapons,
detection systems, and telecommunications to name few sectors which nanotechnology will
have a major impact. Specifically, nanomedicine, which is the application of
nanotechnologies to medicine, is considered the field where nanotechnologies may
noticeably improve medical practice for prevention and therapeutic purposes. The vastness
of nanotechnology applications leaves many unanswered questions on the hazards related to
human health from exposure of nanoparticles on the human body. The novelty of
nanotechnologies demands a new approach in order to fully understand its broad
applications, evaluate potential benefits, and assess potential risks on human health.
However, because nanomedicine is a nascent science its risks and benefits are only
hypothetically assessed at this stage. The lack of consolidated knowledge and the extensive
medical literature of experimental data do not allow a clear assessment of the risks-benefits
associated to this new technology. This lack of knowledge that currently surrounds the area
of nanomedicine makes it difficult to anticipate adequate regulatory responses in
nanomedicine and raises several regulatory questions. This thesis aims to raise awareness on
the main challenges that nanomedicine applications encounter from a regulatory perspective.
Exploring different strategies and methods to deal with nanomedicine, this thesis will
attempt to provide an answer on what is the appropriate regulatory approach at the early
stages of this novel technology.
1.2. Thesis Structure.
Chapter 1 will discuss the notion, characteristics, and properties associated to nanomedicine
with a specific attention to their effects on human health. Chapter 2 will mainly examine the
limitations of the classical model of risk-benefit analyses in assessing and evaluating the
risks associated to novel technologies like nanomedicine. Focusing on a relative and
multidimensional concept of risk inborn in nanomedicine, chapter 2 will provide a revision
of the traditional risk-benefit analyses with the purpose of identifying more responsive and
2
reliable regulatory tools in the risk management. Chapter 3 will examine various
interpretations of the Precautionary Principal in the general context of health law and the
current debate on the Precautionary Principle in the specific context of nanomedicine.
Chapter 3 will examine whether or not the European and Canadian current legal systems are
suitable to cover and adequately regulate nanomedicine applications. This chapter will use
nanomedicine drug delivery system as an example to highlight how the existing European
and Canadian legislations are not sufficiently responsive to the challenges of nanomedicine
applications. The conclusive sections of chapter 3 will focus on the need of developing or
implementing guidelines to clarify how the legal requirements of the existing normative
systems should apply to nanoproducts or nanomedicine applications. Chapter 4 will provide
some recommendations and proposals in managing the challenges of nanomedicine.
1.3. Ambiguities in the Definition of Nanotechnologies.
Nanomedicine is a generic term to indicate products, processes, and properties at the
nano/micro scale. Finding a general definition of nanomedicine is a difficult task because of
its hybrid nature and broad range of applications in different fields such as biology,
chemistry, mathematics, and bio-engineering. Therefore, different definitions exist on
nanomedicine. The European Science Foundation on nanomedicine defines nanomedicine
as follows:
“the science and technology of diagnosing, treating and preventing disease and traumatic
injury, of relieving pain, and of preserving and improving human health, using molecular
tools and molecular knowledge of the human body.“
Also, the National Nanotechnology Initiative (NNI) and the American Society for Testing
and Materials International have defined nanotechnology as a term that refers to technologies
that manufacture and manipulate materials with a dimension between 1 and 100 nanometers
(nm) for exploiting their novel properties. This broad application of nanomedicine creates
challenges in identifying nanomedicine but also in evaluating its novelty. At this stage,
nanomedicine is not a delineated field because it could converge with drugs, with medical
devices or it could be a combination of the two. From this perspective, one of the main
challenges encountered in nanomedicine is the identification and thus the legal evaluation of
a final medical product that can result from the combination of different types of
components. In fact, most of the nanomedicine technologies challenge the boundaries
3
between different areas of science such as chemistry, biology or engineering because they do
not fall in the traditional classifications of drugs or medical devices. Conversely,
nanomedicine applications demand an accurate understanding of the complex processes that
involve different expertise and disciplines.
1.4. Properties of Nanotechnologies.
The characteristics of nanoparticles are the ultra small size, large surface area to mass ratio,
high reactivity and, ultimately, no solubility. The small size property means that they deal
with structures measuring less than 100 nanometers –about a thousand of the diameter of a
human hair. These properties allow nanomedicine to differ completely from equally shaped
macroscopic structures and to perform exceptional tasks in medical practice. Furthermore,
these properties make nanoparticles significantly innovative in the sense that they are able to
overcome some of the limitations that affect traditional diagnostic and therapeutic agents.1
In fact, at this scale nanoparticles match the typical size of natural functional units in living
organisms. The small size property provides nanoparticles an extreme mobility and the
capacity to interact with the biology of living organisms. However, several research studies
have shown that the “smaller nanoparticles are the more reactive and toxic they are.”2
These properties of nanoparticles have raised safety issues about the risks related to
nanomedicine; in fact, initial findings have shown that nanoparticles can easily penetrate and
propagate into living organisms without control. From comparative analyses, the succeeding
sections will examine studies that have shown potential benefits in better diagnostic and cure
diseases, such as the risks to human health coming from the exposure to nanoparticles
especially to the immune system, lungs, digestive mucosa and skin.
1.5. Characteristics of Nanomedicine Applications.
Nanomedicine carries a great hope for the cure of life-threatening and disabling diseases.
Numerous benefits have been discovered in nanomedicine such as the improvement of
diagnostic, techniques and imaging, biomaterials, drug development and delivery,
regenerative medicine, stem cell therapy, implants, and cosmetic applications.
1 A. El-Ansary and S. Al-Daihan, “On the Toxicity of Therapeutically Used Nanoparticles: An Overview,” J
1 A.
El-Ansary* and S. Al-Daihan, “On the Toxicity of Therapeutically Used Nanoparticles: An Overview,” J Toxicol.
2009; 2009: 754810. Published online 2009 January 25. doi: 10.1155/2009/754810.
2 Ibidem
4
Nanomedicine holds great expectations for scientific advances in the area of regenerative
medicine - tissue engineering - and cancer therapy enabling techniques that cannot be
performed otherwise. The use of nanomedicine has made tremendous advances for the
treatment of severe and disabling diseases. Nanomedicine applications relate to novel
therapies and diagnostic techniques in three major areas such as molecular imaging agents,
drug delivery systems and biosensors. The description of the novel medical applications in
the following sections is not exhaustive but is intended to illustrate some advances obtained
by the use of nanotechnologies in medicine.
1.5.1 Optical Imaging.
Nanotechnologies can provide improvements in imaging the human body by using
fluorescence microscopy or magnetic resonance imaging (MRI). Quantum dots (QDs) are
inorganic particles with luminescence properties which are employed for novel diagnostic
purposes. These types of nanoparticles are able to emanate strong fluorescent light under
ultraviolet (UV) illumination, and the wavelength (color) of the fluorescent light emanated
depends sensitively on particle size. The main advantages associated to quantum dot
technologies are to image tissues and cells such as lymph nodes and tumors. Other types of
nanoparticles known as superparamagnetic iron oxide (SPIO) have recently been recognized
as a capable way of detecting cancer. Some studies conducted on human patients affected by
prostate cancer have employed SPIO to detect metastases in lymph node. The outcomes of
these studies have shown that SPIO nanoparticles can accurately detect metastases that
otherwise would be undetectable.3As a result of this, patients are being treated for their
cancers at an early stage and thus this is impeding the proliferation of other metastases. In
addition to that, patients have the option to treat the cancer detected at an early stage with
surgery intervention rather than having radiation therapy which is commonly used in
advanced cancer process.
1.5.2 Drug Delivery System.
3 Harisinghani M.G.et al.” Noninvasive Detection of Clinically Occult Lymph-node Metastases in Prostate
Cancer” in N. Engl. J. Med. 2003 Jun 19;348(25):2491-9.
5
Different studies in different areas of medicine have shown that nanoparticle- based drug
delivery systems can be employed in different ways to improve the efficacy and performance
of drugs and to eliminate the adverse effects of drugs already in use today. Some studies
have shown that nano-sized polymer based pharmaceuticals are successful for the treatment
of several types of cancer such as skin, ovarian and lung cancer.4 Nanoparticles used in
cancer therapies have the ability to carry the drug only to treat the cancerous cells without
interfering with the surrounding parts or organs. In addition to this, some studies have shown
how nanoparticle- based drug delivery can be employed in different ways to improve the
performance of cancer therapy.5 An illustrative example of this is given by a well-known
cancer agent called Paclitaxel which in 2005 was used with nanoparticles of albumin. This
form of Paclitaxel has the ability to eliminate adverse effects associated with another cancer
drug such as Cremophor. Nanotechnologies strategies have reached important discoveries in
the treatment of neurodegenerative, cerebrovascular and inflammatory diseases. In fact, one
of the major challenges for drug delivery system to the brain is the presence of the blood
brain barrier (BBB) which is a natural brain protection against foreign substances and blood
infections. As a result, it becomes necessary to administer higher doses of drugs with an
increase in adverse effects. Conversely, the use of polymer nanoparticles in drug delivery to
the brain has demonstrated the potential to administer non- invasive nanotechnologies to
penetrate the BBB. 6 Moreover, one of the major challenges affecting the efficacy of HIV
anti –viral agents is the poor water solubility. Some experiments conducted on dogs were
successful in demonstrating that the employment of nanoparticles is a more efficient way to
distribute HIV anti -viral agents.7
1.6. Potential Risks in Nanomedicine.
Research on nanostructures has shown potential benefits coming from their applications in
nanomedicine but has also shown risks of adverse effects on living organisms exposed to
nanoparticles. Researchers and experts are concerned that manufactured nanoparticles could
4 De Giorgi U., Amadori D.“Fluorodeoxyglucose Positron Emission Tomography for Outcome Prediction of
Mammalian Target of Rapamycin Inhibitor Therapy” (2010) J. Clin. Oncol. 28(15):e236-7. 5 Shashi, K. Murthy “Nanoparticles in Modern Medicine: State of the Art and Future Challenges” (2007) Int. J.
Nanomedicine. 2(2): 129–141published online June 2007.
6 Garcia-Garcia E., Andrieux K., Gil.S., Couvreur P. “Colloidal Carriers and Blood-Brain Barrier (BBB)
translocation: a Way to Deliver Drugs To the Brain.”(2005) Int. J. Pharm.;298(2):274-92. 7 De Jaeghere F.et al.”Oral Bioavailability of a Poorly Water Soluble HIV-1 Protease Inhibitor Incorporated into
PH Sensitive Particles: Effects of the Particles Size and Nutritional State“ (2000) J. Controlled Release 68(2):291-
8.
6
be dangerous for the human body and the environment. However, the risk analyses of
nanoapplications are complicated by two considerations: 1) nanoparticles already exist in
nature (e.g. volcanic ash, ocean sprays and forest fire-smoke) and some of them are highly
toxic 2) some nanoparticles contain the same molecules that are present in other already
existing chemicals (e.g. carbon nanotubes are made of carbon). Some scholars have pointed
out that the exposure of the human body to the toxic effect of natural nanoparticles is not a
new phenomenon considering that some human activities such as mining, cooking and
combustion are responsible for contaminating the environment with nanoubstances. 8
Therefore, the question at hand is how much and to what extent the risks associated to
manufactured nanoparticles are different from nanoparticles already existing in nature and
from other already existing chemicals. Although uncertainties are still surrounding the risk-
analyses of nanoapplications, important toxological studies conducted on the interaction
between nanoparticles with living organisms have given us significant information regarding
nanoparticles exposure and the human health. Studies on nanoparticles have shown that 1)
ultra small size property and extreme mobility of manufactured nanoparticles means more
propagation in living organisms without control of them 2) ultra small size nanoparticles can
be more toxic per unit compared to larger particles of the same chemicals 3) ultra small size
particles are more quickly absorbed by cells compared to larger particles 4) ultra small size
particles can move more quickly and thus contaminating the environment through air, soil,
and water causing damages to plants and animals.9 With specific attention to the interaction
between nanoparticles and the human body, some studies on humans have shown the
deposition of nanoparticles in the lungs may increase with a decreasing particle size and the
toxicity of inhaled insoluble nanomaterials increase with decreases particle size and
increasing particle surface area. In addition to that, certain classes of nanoparticles could be
responsible for the destructive inflammatory processes in the lungs eg. carbon black
nanoparticles such as quantum dots or polymeric nanoparticles cannot be considered uniform
groups of nanomaterials because each of them interact and behave differently depending on
several factors. Notwithstanding this heterogeneity of nanoparticles, the overall interaction
of nanoparticles in the human body can in general be described as follows: 1) nanoparticles
enter into the human body through inhalation, dermal exposure, ingestion or intra venous; 2)
8 Anne Ingebord Myhr and Roy Ambli Dalmo “Nanotechnology and Risk: What are the issues?”In ”Nanoethics:
The Ethical and Social Implications on Nanotechonology” New Jersey, Jhon Wiley & Sons Inc 2007 at 150. See
also Cristina Buzea & alt. Nanomaterials and Nanoparticles: Sources and Toxicity,” (2007) Biointerphases Vol.4,
n.2 at 21. 9 Ibidem, at 150
7
absorption is when nanoparticles interact with biological components (i.e. proteins and
cells); 3) distribution is when nanoparticles propagate through different organs; 4) they may
maintain the same structure, they may be modified or they may be metabolized; 5) they enter
into the cells of the organs and they remain for an unknown period of time before they
propagate to another organ or to be excreted.10
With specific regard to quantum dots, the
previous sections have already mentioned that they are inorganic particles with an organic
coating such as polyethylene glycol that enhances their biocompatibility. However, some
experiments in vivo have shown a potential toxicity in quantum dots caused by the
deterioration of the organic coating.11
Furthermore, the same studies have shown that “QD
absorption, distribution, metabolism, excretion, and toxicity depend on multiple factors
derived from both inherent physicochemical properties and environmental conditions.”12
With specific regard to some nanostructures used in drug delivery systems for therapeutic
purposes, deliveries of drugs to the brain and cancer- killer genes in the tumor therapy are
being investigated. These novel technologies are challenging because they have shown that
nanoparticles can damage normal cells or tissues. Although experiments in vivo and in vitro
have expanded the level of knowledge about how nanoparticles interact with living
organisms, more extensive studies on physiochemical, molecular, and physiological activity
of nanostructures are required in order to assess manufactured nanoparticles properties and
risks. With specific regard to this, two important European Reports such as SCENIHR
Report and the White Paper Nanotechnologies Risk published in June 2006 by the
International Risk Governance Council address this issue. Both these reports have
emphasized the lack of data on potential risks associated with nanomedicine and
nanotechnologies with regard to the human body and the environment. Moreover, the U.S.
NIH is evaluating the issue of safety including how particle pathways affect the human body.
Ultimately, the current state of scientific knowledge cannot yet answer the following
questions:
- How nanoparticles pathways affect the human body?
- How long nanoparticles remain in the human body?
- What are the nanoparticles effects on cellular and tissue functions?
10
El-Ansary and Al-Daihan, supra note 1. 11 Ibidem 12 Ibidem
8
The lack of scientific data to answer to these questions important to the human health should
stimulate more extensive toxological studies with the purpose of better understanding what
the peculiar properties that characterize manufactured nanoparticles are and to what extent
these properties are responsible in generating new risks for the human health.
Chapter 2: How to Manage Risks in Uncertain Science.
2.1Introduction
Science has always been the ideal tool by which man explores, knows, and interacts with
nature. However, the advents of new scientific technologies have marked the age in which
scientists have progressively acquired an active role in manufacturing nature. This new
characterization of man-nature relationship has raised many ethical and philosophical
implications. The reality is that every scientific discovery carries with itself unavoidable
doubts and risks because science is for its nature unable to provide definitive answers to our
questions and perplexities. In 1958 a famous philosopher, Hanna Arendt, pointed out that
paradoxically, on the one hand science improves our technological knowledge but on the
other hand it does not allow us to control the consequences of human activities.13
From this
perspective, the improvement of human skills to create technologies that copy nature is not
accompanied with an adequate improvement of knowledge to manage uncertainties that
accompany these technologies. The reality is that we have to face the ubiquity of risk; risks
are even present when drinking water or eat fruits - because of the risks coming from
carcinogen elements that may be contained in pesticides.14
However, what characterizes the
most nanotechnologies like other emergent technologies are the complexity, variability and
unpredictability of risk class associated with them. These challenging features of risk
combined with a fragmented and limited scientific knowledge have led experts and policy
makers to develop normative frameworks able to assess hazards and evaluate side effects of
human activities with the ultimate goal of defining a level of acceptable risk. In pursuing
these purposes, one of the most accepted regulatory tool is the risk-benefit analyses, which
main goal is to provide strategies and methods to control risks and evaluate activities,
products, or technologies as low or high risk activities. The following section outlines the
13
Hanna Arendt, “The Human Condition” Chicago, The University of Chicago Press, 1958 at 230-232. 14
W. Kip, Viscusi, “Rational Risk Policy: The 1996 Arne Ride Memorial Lectures” Oxford, Clarendon-Press
Oxford University Press, 1998 at .84
9
classical model of risk-benefit analyses to underline the reasons why this model seems to be
inadequate in giving a full account of the risks and the benefits associated to nanomedicine.
2.2.: The Inadequacy of Classical Model of Risk-Benefit Analyses in
Nanomedicine and Other Novel Technologies.
Risks-benefits analyses is a regulatory tool which provides a qualitative and quantitative
account of the risks and the benefits involved in a given activity. The conventional model
of risk -benefit analyses is set up on two stages. The first step is the risk-benefit
assessment which is a purely factual estimation of the magnitude of the risks. The second
stage is known as risk-benefit evaluation which is a normative determination of the
acceptability of the risk. While the first stage is free from values and completely based on
scientific facts, the second stage is not free from normative, ethical and social values. In
addition, the second stage is influenced by the public perception and acceptability of the
risks involved. The interplay and the influence between risk-assessment analyses and the
public acceptability of risks are intense; in fact, the lower estimation of risk is equal to the
higher acceptability of risk or vice versa. 15
With regard to this, the gap existing between
science and public perception has been an issue in nascent biotechnologies like in the case of
genetically modified organisms or gene therapy. In fact, the uncertainty and the knowledge
gap that usually surround emergent technologies are factors that have contributed to
characterize them as “high risk” technologies.16
The failure of adequate public awareness on
the benefits and the risks of emerging technologies may lead to the conclusion a lower rate
of acceptability from the public with the possibility of no further development. From this
perspective, it is of fundamental importance that the risk-benefit analysis be conducted in an
accurate way that mirrors the complexity of all factors and variables associated to a risk
class. For all these reasons, it is clear that risk-benefit analyses has became a challenging
task in nascent technologies since it is a crucial regulatory phase that has to manage
scientific uncertainties, several gaps in the information and even conflicting data. The
question is how risk-benefit analyses can effectively overcome these incognita inborn in
novel technologies in the endeavor to provide sustainable bases for the elaboration and
15 Duff R.Waring and Trudo Lemmens “Integrating Values in Risk Analysis of Biomedical Research: The Case for
Regulatory and Law Reform.“ In “Law and Risk “ Vancouver , University of British Columbia Press (2005) at 160. 16
National Institutes of Health Advisory Committee on Oversight of Clinical Gene Transfer Research, Enhancing
the Protection of Human Subjects in Gene Transfer Research at the National Institutes of Health (12 July 2000) at
Appendix D, <http://www.nih.gov./about/director/07122000.htm>
10
development of policies. What clearly emerges from emergent technologies such as
nanomedicine or gene therapy is that managing these uncertainties is no longer only a
scientific task. However, it is progressively becoming an interdisciplinary activity among
different fields of knowledge and expertise. From a regulatory perspective, this
interdisciplinary approach required in nanomedicine as in other novel technologies
challenges the classical model of risk-benefit analysis and in particular its strict separation
between risk-assessment and risk-evaluation or in more general terms between pure facts and
values.17
As mentioned above, the classical model holds a net distinction between the risk -
assessment which is descriptive of the magnitude of risks and the risk-evaluation which is a
judgment on safety and risk acceptability associated to a product or technology. Particularly,
this separation between facts and values has been criticized by some scholars especially
because it has been considered not helpful in overcoming uncertainties coming from novel
technologies where often data availability is limited and estimations are not yet reliable.
Proliferation of research data and divergent results depending on different factors and
variables involved in research on emergent science have to be based on quantitative but also
a qualitative risk analyses. In fact, only a risk analysis that not only aims at the pursuit of an
assessment of magnitude of risks but also investigates on more complex questions can
capture critical issues related to the type of risks associated to emergent technologies.
Questions that are crucial from a management risk perspective cannot be responded by a
risk- assessment based on pure scientific data. Critical questions such as what are the factors
that most likely produce adverse effect? What is the dose of the administration relationship?
What kind of causal relationship may link important variables present in a given research?
What is the threshold level below which a substance can be considered not harmful to human
health? What are the most important factors to be considered to frame a “reasonable worst-
case “scenario”? These questions unavoidably trigger normative values in the risk-
assessment. Explaining the limitations that affect the classical model of risk-benefit analyses,
Conrad G. Brunk affirms that “…scientific data do not interpret themselves; to determine
what the data indicate concerning the risk of a product, the assessor has no alternative but to
employ an interpretative point of view.”18
These considerations do not intend to undermine
the role of science but instead they aim to underline a dimension of relativity that
17
R. Steven Turner, “Of Milk and Mandarins RBST, Mandated Science and the Canadian Regulatory Style”(2001)
36 J. Can. Stud.107 at 126-27. 18 Conrad G. Brunk, Lawrence Haworth and Brenda Lee “Values Assumptions in Risk-Assessment: a case study in
alachlor controversy,” Waterloo, Canada, Wilfrid Laurier University Press (1991) at 26
11
characterizes science in novel technologies. Conversely, the current model of risk-benefit
analyses fails when it considers the scientific data as “absolute” regardless of the concrete
scenarios in which the risk needs to be investigated. This has a general negative impact on
the entire process of risk-benefit analysis. First, the risk- assessment will be partial and not
even realistic from a scientific framework since it is unable to completely describe the risk in
its dynamics. Secondly, a non reliable risk-assessment will affect negatively the risk-
evaluation that grounds its judgment on the risks as assessed in this first stage. Ultimately,
this compromises the chance of finding responsive regulatory tools that are able to delineate
adequate and reliable margins of safety. What really emerges from nascent technologies is
that they introduce a dynamic and relative concept of risk that is interconnected with real and
concrete situations in which risks are investigated. Furthermore, the concept of risk should
not be considered as a rigid outcome of research but more correctly as a variable element
belonging to a given research. In the attempt to provide an example of how some risk
features can differently impact on the outcome of research, it is important to take into
consideration the outcome coming from experiments involving carbon nanotubes in rats and
mice. In addition, these studies have shown that carbon nanotubes nanoparticles determined
pulmonary diseases and deaths of several animals. Nevertheless researchers have pointed
out that these adverse effects have not been considered as specific hazards of carbon
nanotubes but only as a result of high doses of administration. 19
Several studies have
highlighted the importance of the relationship between high-doses of administration and
harms occurring in assessing the adverse effects of nanoparticles.20
In fact, the probability
rate of harms occurrence changes depending on the higher or lower dose administered.
While higher doses of chemicals can be harmful or even lethal, lower doses of the same
chemical are not harmful. From this it is possible to elaborate the following considerations:
1) even the same sub-category of nanoparticles does not show uniform adverse effects; 2)
same class of risk can simply vary because of the interaction between nanoparticles and cell
or molecules in living organisms; 3) study of risk variability pushes towards an analysis that
takes into account risks in real and concrete situations rather than perceived risks; 4)
assessment and management risks in nanomedicine could not be a simplistic evaluation of
adverse effects of final products but instead it is the risk evaluation of a specific process in
which the product was examined; 5) a risk-assessment that takes into account quantitatively
19
Gunter Oberddrster, et al., "Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine
Particles” (2005) 113 Environmental Health Perspectives at pp.823-839, at 823. 20
D. B. Warheit, et al., "Comparative Pulmonary Toxicity Assessment of Single-Wall Carbon Nanotubes in Rats “
(2004) 77 Toxicological Science pp.117-125 at 117.
12
and qualitatively all subsets of risks and their variable determinants can ensure a more
accurate and realistic risk-benefit relationship and thus define a more accurate margin of
safety. The classical model cannot capture how the level of risk and, oppositely, the
standards of safety can be sensitive depending on different factors such as a lower or higher
dose administration of the potentially harmful substance. In other words, it cannot properly
take into consideration the degree of relativity that surrounds the concept of risk and safety
standards associated with nascent technologies. Conversely, a risk-benefit analyses that
includes normative and ethical values even in the risk-assessment can be more responsive to
regulatory issues such as what is the administration dose rate that indicates a threshold level
below which a potential harmful substance can be considered not harmful?
2.3: Is the Precautionary Principle the Answer to Uncertain Science?
2.3.1. Introduction
The Precautionary Principle is a legal tool that commonly is invoked to manage the scientific
uncertainties coming from novel technologies such as cloning, genetically modified
organisms, and nanotechnologies just to name a few. As explained above, these new
technologies show a new class of risks and hazards that are difficult to quantitatively and
qualitatively estimate since they depend on numerous variables and they are sensitive to the
specific methods used. From this perspective, the Precautionary Principle is a legal and
social response in order to manage and lessen uncertainties coming from the so- called
“modernization risks”21
which are identified as those risks generated by the industrialization
of society. To properly examine the Precautionary Principle in the specific context of
nanotechnologies, it is fundamental to analyze the origins and various interpretations of this
principle in the public health.
2.3.2.: Origins and Various Interpretations of the Precautionary Principle.
Although the Precautionary Principle has developed in the field of environmental health, it
has been invoked and applied in several areas of the public health. The Precautionary
Principle has been invoked as a tool to provide a preventive action in order to avoid harm to
human health in situations where scientific uncertainties exist. The primary foundation of the
Precautionary Principle is the Rio Declaration on Environment and Development (1992) that
21 Ulrich Beck “Risk Society: Towards a New Modernity” London, Sage Publication Ltd.1992, at.76.
13
provides a definition which is internationally accepted. The Principle 15 of Rio Declaration
states that:
"In order to protect the environment, the precautionary approach shall be widely applied
by States according to their capabilities. Where there are threats of serious or irreversible
damage, lack of full scientific certainty shall not be used as a reason for postponing cost-
effective measures to prevent environmental degradation."
The Precautionary Principle has been also adopted by the European Union and it is included
in the Treaty of Maastricht of 1992. According to the European Commission, the
Precautionary Principle is based on the assumption that uncertainty enables regulatory
authorities to take preventive action when there are scientific uncertainties and associated
risks but a direct causal link cannot be established. In Canada, a precautionary approach is
invoked in the Canadian Environmental Protection Act of 1999. Health Canada recognizes
an important role to the Precautionary Principle in the science-based of risk management.22
The Royal Society of Canada report’s (2001) underlines the importance of the Precautionary
Principle in assessing the safety of genetically modified organisms of food. The
Precautionary Principle is being extensively applied in the context of preventing harm to the
human health. However, there is not an unanimous consensus on the meaning of the
Precautionary Principle since nineteen different formulations of the Precautionary Principle
exist. 23
Although a unique definition of the Precautionary Principle does not exist, there are
three elements on which scholars commonly agree: 1) uncertainty cannot be used as a pretext
to delay action; 2) the burden of proof might be reversed from “recipients” to prove that a
given chemical agent or technology is harmful to “proponents” to prove that the chemical
agent or technology is innocuous; 3) it is important to evaluate different actions to avoid
harm, preferably at early stages of the process. However, the precaution raises some issues
even in its different linguistic expressions whereas at times it is expressed as the
Precautionary Principle and other times it is expressed only as a more general proposition.
As some scholars have pointed out, this distinction is important because it implies different
effects; in fact, while a principle is understood as a source of law with a compulsory
enactment an approach means generally a suggested way in dealing with a particular subject.
From this perspective, it is interesting to notice that the European Union often refers to the
22
Health Canada online source available at http://www.hc-sc.gc.ca7english.protection.precaution.html last visited
on July 18, 2010. 23
G.E. Marchant and D. J. Sylvester, "Transnational Models for Regulation of Nanotechnology," (2006) Vol.34
n.4 Journal of Law, Medicine & Ethics at pp. 714-725.
14
Precautionary Principle as a general principle of law while U.S does not apply the
Precautionary Principle but only a precautionary approach.24
Particularly, the Advocate
General of the European Court of Justice has stated that the Precautionary Principle applies
when no threat has yet been demonstrated but initial findings indicate a possible risk” and
also “the principle requires risks to be reduced to the lowest level reasonably imaginable.”
The Precautionary Principle, which can be defined by the following statement: “’Better safe
than sorry!” entails that even a lack of scientific evidence for harmful events is not a
justification to refuse regulation. Among its several formulations, Cass. R. Sunstein has
identified a strong and a weak version of the Precautionary Principle.25
The strong version of
the Precautionary Principle states that regulation is required when there are potential risks to
the human health even if the cause-effect relationship is not established. In addition this
formulation of the principle places the burden of proof to manufacturers that have to provide
proof of safety before a product or technology approval is granted. An illustrative example
of the Precautionary Principle strong version is given by the Wingspread Statement that was
drafted and finalized at the International Conference of Wingspread of 1998. This statement
declares that:
“When an activity raises threats of harm to human health or the environment,
precautionary measures should be taken, even if some cause and effect relationships are
not established scientifically. In this context the proponent of the activity, rather than the
public, should bear the burden of proof.”26
Furthermore, the extreme formulation of the Precautionary Principle leads to prohibitions
and bans of potentially harmful activities or products. The weak version of the
Precautionary Principle holds that the lack of scientific proof on serious harm is not a
justification to refuse regulation. Particularly, this formulation invokes precautious measures
when serious and irreversible risks exist and require at least some evidence of likelihood of
harm occurrence. The weak version of the Precautionary Principle has been accepted by Rio
Declaration that at principle 15 states that:
“in order to protect the environment, the precautionary approach shall be widely applied
by States according to their capabilities. Where there are threats of serious or irreversible
damage, lack of full scientific certainty shall not be used as a reason for postponing cost-
effective measures to prevent environmental degradation."
24 Miguel Recuerda “Dangerous Interpretations of the Precautionary Principle and the Foundational Values of
European Food Law: Risk Versus Risk” (2008) Vol.4 n.1 Journal of Food & Law Policy, at. pp.1-44 25
Cass R. Sunstein, “Laws of Fear: Beyond the Precautionary Principle” Cambridge, University Press 2005, at
pp.18-19-21 26 “Wingspread Conference on the Precautionary Principle “The Science and Environmental Network online
source available at http://www.sehn.org/wing.html last visited on August 26, 2010.
15
The Precautionary Principle has been subject to an intensive debate and attracted a lot of
criticism from those scholars that have pointed out that the ambiguities that surround this
principle do not allow answering to important questions. Such as what is the level of risk
acceptability for products or technologies before they enter the market or which kind of
hazards have to be taken into consideration for enacting precautionary measures. 27
In
addition to that, the wide range of different interpretations of the same principle leaves space
for discretional evaluations of risks and measures to adopt in order to eliminate or reduce
them. Some scholars have argued that this discretionarily can generate negative effects on
the development of nascent technologies since regulators and governmental authorities
should have the power to influence the social acceptability on some new technologies rather
than others.
2.4.: The Precautionary Principle in the Context of Nanobiotechnologies.
Nanotechnology is an illustrative example of what challenges are implied when
new technologies are discovered. In fact, when new technologies emerge scientists and
regulators have to discern what type of action is appropriate to undertake especially in the
early stages of their discovery and what are the most important priorities to take into
consideration when governing a situation of uncertainty that usually characterizes the
newest technologies. The possible answers provided to these questions are significantly
different since they reflect the different contexts in which they are conceived. From this
perspective, nanotechnology, cloning, or gene therapy are revolutionary in the sense that
nascent technologies are no longer subject to a science monopoly but they attract the
attention from other disciplines such as philosophy, ethics, and sociology. Nanotechnology
is being subject to an intensive debate on the manner and the degree of how to proceed in the
early stages of its discovery. This ongoing debate on nanomedicine shows an array of
different opinions from scholars, government agencies and professional organizations. In
2006 the lack of regulations on nanotechnologies has led some U.S. environmental groups
and citizens to seek for a more precautionary approach from nanoproducts manufacturers
and require to federal government to start regulating nanomaterials. Conversely, private
corporations sustained that government agencies should not presume potential adverse
events of nanotechnologies products in absence of data that demonstrate a real risk of
27
E.G. Marchant, and D. J. Sylvester, "Transnational Models for Regulation of Nanotechnology,"(2006) Vol.34
n.4 Journal of Law, Medicine, & Ethics at pp. 714-725.
16
harmful events. With considerable differences, opinions oscillate along a bi-polar spectrum.
On one side, there are supporters of a “science-based approach” that aim to advance the
scientific knowledge in order to demonstrate real risks for the human health; on the opposite
side there are advocates for public safety and protection of the human health even against
putative hazards not based on an established scientific causal relationship. The current
debate on how to manage new technologies is going to be preeminently defined by two
opposing views such as a more cautious approach or a more risk-taking approach. Recalling
this debate, Renn that Precautionary Principle critics argue that the strong interpretation of
the precautionary principle could provide a justification to ban everything that might be
harmful and thus arbitrarily be applied to any new substance or human activity.28
Along the
same line, Doering pointed out that “the precautionary principle has another fundamental flaw:
it can be used to support any side of an issue because it is all in how you define the
hazard.”29
Addressing the feature of arbitrariness in the precautionary principle, Doering
added that:
“A principle that is this malleable cannot be a reliable guide to decision making, but it is
still often used as a justification for a decision taken for other reasons.”30
Ostiguy and other scholars have elaborated the first comprehensive risk guide on how to
apply the Precautionary Principle on nanotechnology and how to manage risks even in a
situation of uncertainty. The guide is intended to support companies and researchers to
promote a risk prevention culture and a responsible development of nanotechnologies.
Interestingly, the guide gives practical advice on how to manage safety challenges in a
university’s research laboratory. By encouraging responsibility in controlling risks and
preventing harmful events, the guide emphasizes the role of the researcher in reducing risk.
For example, the guide suggests to take procedural steps “to develop a prevention culture in
his laboratory” such as naming the person responsible for safety issues concerning the
laboratory or properly training all students to better handle nanoparticles challenges.31
Other
scholars have argued that advocates for the precautionary principle neglect the role of
28 Ortwin Renn, “Precaution and Analyses: Two Sides of the Same Coin? Introduction to Talking Point on the
Precautionary Principle”(2007) 8 EMBO Reports at pp.303-304
<http:www.nature.comembor/journal/v8/n4/full/7400950.html>last visited on July 22, 2010 29 Ronald Doering, “Food Law: The Precautionary Principle is not The Answer”(2009) online source available at
<http:www.canadianmanufacturing.com>last visited on July 19, 2010. 30
Ibidem 31
Ostiguy et al. “Best Practices Guide to Synthetic Risk Nanoparticles Management” (2009) at p.56 online source
available at www.safenano.org last visited on July 22, 2010.
17
science and they may come to unrealistic policies based on perceived and hypothetical risks
rather than real risks. With respect to this, Wilson states that:
“It is not surprising that existing statutes do not work particularly well with
nanotechnology because the normal scheme of events is to regulate after the fact, as our
experiences with the Cayahoga River (which precipitated the CWA) and Love Canal
(which preceded the superfund statute) illustrate. Regulation after an adverse event has its
advantages: the event highlights the need for regulation, crystallizes the policy choices we
face, allows us to consider real, not perceived costs of regulating or choosing not to
regulate, and the regulations we adopt are more meaningful.“32
In opposition to this approach, other scholars have invoked the adoption of the precautionary
principle as an effective instrument to deal with uncertainties in the new nanotechnologies.
According to Heselhaus, the Precautionary Principle is an instrument to protect public safety
as a central part of the consumer protection.33
Focusing on the main challenges of
nanomedicine, some scholars have argued that the challenges of nanotechnology generated
by enormous uncertainties that surround these novel applications cannot be solved by
traditional risk management tools such as cost-benefit analysis or the Precautionary
Principle. However, they recognize that:
“Yet, simply waiting for these uncertainties to be resolved before undertaking risk
management efforts would not be prudent, in part because of the growing public concerns
about nanotechnology driven by risk perception heuristics such as affect and
availability.”34 They suggest a more helpful risk management approach in dealing with
challenges coming from nanotechnology applications and other future emerging.35
On the other side, Stirling supporting a precautionary approach has underlined that a
precautionary approach does not automatically mean a ban but rather it means a step by step
approach to prevent harms generated by risky technologies.36
He explained that:
“precaution does not automatically entail bans and phase-outs, but calls instead for
deliberate and comprehensive attention to contending policy or technology pathways. Far
from being in tension with science, precaution offers a way to be more measured and
rational about uncertainty, ambiguity and ignorance.”37
32
Robin Fretwell Wilson, “Nanotechnology: The Challenge of Regulating Known Unknown
Risks”(2006) Vol.4, Issue n.34 Journal of Law, Medicine & Ethics at pp. 704-713. 33
Sebastian Heselhaus, “Nanomaterials and the Precautionary Principle in the EU ”(2010) 33 Journal of
Consumer Policy at pp.91-108. 34
E.Gary Marchant , J. Sylvester Douglas and W. Abbott Kenneth “Risk Management Principles for
Nanotechnologies” (2008) Vol.2, n.1 Nanoethics at pp.43-60. 35
Marchant et al., ibidem at pp. 43-60. 36
Andrew Stirling, “Risk, Precaution and Science: Towards a More Constructive Policy Debate. Talking point on
the Precautionary Principle. 2007) EMBO Reports at pp.303-304 on line source
<http:www.nature.comembor/journal/v8/n4/full/7400950.html>last visited on July 22, 2010. 37
Ibidem.
18
The debate outlined above shows how conflicting the strategies and methods are in dealing
with nanomedicine. Linked to this debate is the discussion whether or not nanomedicine
applications are adequately covered by the existing regulatory framework provided for drugs
and medical devices or do they require a separated oversight model. In addition to that, even
among supporters who invoke regulation on nanomedicine there is a current debate on
providing an oversight model for nanomedicine applications or single regulatory regimes for
selected applications. However, the bottom line of the discussion is how much
nanotechnologies products and applications can be considered different from the already
existing chemical substances contained in already known drugs and technologies. Those
scholars who consider nanotechnology as a new science have addressed the need for an
immediate regulation of nanotechnologies. Indeed, a large part of academics, government
agencies and professional organizations are invoking an oversight framework on
nanotechnologies that establishes adverse effects and benefits, reporting procedures, and
safety standards. Conversely, scholars that follow a more “science based approach” refuse
early regulation on nascent technologies because they believe that the anticipation of rules
and bans is seen as an impediment to a further scientific development. On one hand, an
oversight model that aims to prevent any potential risks by providing too strict standards and
bans on new technologies in their early stage can profoundly affect a further development of
new technologies. On the other hand, a laissez-faire approach in dealing with novel
technologies is not a responsible approach in protecting the public safety. Between these two
extremes, there are a variety of different regulatory choices in managing novel technologies.
It is important to mention the direct influence between the regulatory approach used in
managing challenges of novel technologies and public acceptability. Some illustrative
examples coming from the past experiences of genetically modified organisms in food
(OGM) or the gene transfer research in human beings called “gene therapy” will highlight
some aspects of the relationship between regulatory choices and public perception. Gene
therapy is an experimental technique to correct defective genes which are responsible for
various diseases. In 1999, gene therapy research came to a halt after the death of eighteen
years old Jesse Gelsinger. On September 13, 1999 during a clinical trial, Jesse was injected
with a dose of adenoviruses transporting correct genes. As a result of this experiment, he
developed a genetic disease of the liver called ornithine transcarbamylase deficiency
(OTCD) and four days later he died. The death of Gelsinger has generated among the public
anxiety and mistrust on the scientific development of new technologies and also on the
19
ability of regulators to prevent adverse effects by developing adequate oversight models. In
the Gelsinger case, there has been a failure of reporting system adverse effects on gene
therapy and a complete lack of communication between researchers and regulatory agencies.
Basing their opinions on Gelsinger case, some scholars have pointed out that past experience
from gene therapy experimentations suggests that more efficient and coordinated oversight
mechanisms are also required in nanobiotechnologies. Furthermore, they point out that the
lack of communication on adverse effects between researchers and the relevant oversight
bodies such as FDA and Recombinant DNA Advisory Committee (RAC) was one of the
main causes that may have contributed in generating harms and death. They believe that a
major coordination and inter-agency communication between the relevant agencies could not
only eliminate communication gaps on adverse effects but also enhance safety evaluations
from different perspectives. 38
With respect to nanotechnologies, they underline that
coordination and inter-agency communication are of fundamental importance in new
technologies like nanotechnologies that “stretch the jurisdictional boundaries and expertise of
existing oversight bodies.” 39 Others have also argued that even if it is possible to characterize
risks to human health then the system is not “able to reliably assess their probability of
occurrence.”40
They point out that an efficient monitoring system that reliably assesses
safety “will require a long-term follow up of a large number of patients”41
With respect to
the case of genetically modified organisms, some scholars have addressed a parallelism
between OGM and nanotechnology since both these new technologies have generated
among the public anxiety and skepticism on how governments and regulators adequately
regulate these nascent technologies. 42
In the Canadian context, Metha has pointed out that:
“Example of how Canada has failed to include the public in discussions on how to regulate
biotechnology are instrumental for understanding the possible pitfalls associated to future
with future regulation of nanotechnology.”43
38 Jordan Pradise et al., ”Developing Oversight Frameworks for Nanobiotechnologies” (2009) Vol. 37 n.4 The
Journal of Law, Medicine, and Ethics at .608-705. 39 Ibidem 40
Duff R.& Trudo Lemmens see supra note 15 at 168 41
Ibidem 42
Kenneth H. David and Paul B. Thompson , “What Can Nanotechnology Learn from Biotechnology: Social an
Ethical Lessons for Nanoscience from the debate over Agrifood Biotechnology and GMOs. Burlington USA,
Academic Press, 2008 at 120.
43 Michael D. Metha “From Biotechnology to Nanotechnology: What we Can Learn from Earlier Technologies?”
(2004) Vol. 4 n.1 Bulletin of Science, Technology and Society (2004) at 38
20
Particularly, Metha explains how the regulatory tools used to assess safety on OGM - such
as substantial equivalence and artificial distinction between product and process - have
resulted in the exclusion of the public from participating in an open debate on this novel
technology. 44
Metha has argued that this exclusion of the public is directly reflected in the
labeling system of OGM . On the issue of labeling OGM, the Canadian Biotechnology
Advisory stated that it was too early for a mandatory labeling system on OGM. On this
point, they stated that “All OGM products on the market have been approved as safe for
health and environment by the responsible regulatory authority.”45
After an approval is
granted for a food product, it is put on the market and no labeling is required. Arguing on
this point, Metha has pointed out that:
“Canadians regulators prohibit labeling that gives consumers an opportunity to
discriminate against approved foods based on process rather on product distinctions. In
reality, many consumers see product and process as important to decisions to make on a
wide range of items.” 46
In Mehta’s view the regulatory approach used in the labeling regime on OGM is an example
of how the public was excluded to an open discussion on a novel biotechnology such as
OGM . Nonetheless, this is an instructive example of what needs to be avoided in dealing
with novel technologies like nanotechnology. 47
The past experiences coming from OGM and
gene therapy cases allow us to argue that in the early stages of new technologies it is
important to choose a regulatory approach that is proactive in stimulating innovation but at
the same time capable of providing guidance to ensure margins of safety. With respect to
nanotechnologies, even if relevant regulatory agencies are recognizing the importance of
providing guidelines and procedures on nanotechnologies applications the current approach
is still towards provisions that regulate specific products instead of providing oversight
models on nanotechnology. Currently, governmental agencies such as The United Nation
Environmental Program, the Australian Government’s Nanotechnology Taskforce, the
United States Environmental Protection Agency, and the U.S. NGO Environmental Defense
did not mention in their reports a precautionary principle or at least a precautionary
44
Ibidem 45
Canadian Biotechnology Advisory Committee on“Improving the Regulation of Genetically Modified Food and
other Novel Foods in Canada” Report to the Government of Canada, Biotechnology Ministerial Coordinating
Committee (2002) in Metha supra note 40 . 46 Metha, supra note 40 at 37 47
Ibidem
21
approach. 48
Furthermore, even the 2008 report EU Scientific Committee on Emerging and
Newly identified Health Risks related to the precautionary principle on page 54 stating
that:49
“In the absence of suitable hazard data a precautionary approach may need to be adopted
for nanoparticles which are likely to be highly biopersistent in humans and/or in
environmental species." Hardly a clarion call for the precautionary principle to underpin
the development of a technology predicted to literally reshape the world.”50
Ultimately, this thesis agrees with Sterling’s view that regulation on new technologies51
does
not automatically mean bans and prohibitions on new technologies but it could provide
instead guidelines to protect the public safety in the path of scientific development.
2.5. Conclusive Considerations on Precaution in Nanomedicine.
Regulatory choices can be different in dealing with nascent technologies and significantly
vary from general guidelines to more strict regulatory frameworks with different
consequences on the further development of a given technology. As some scholars have
pointed out,52
regulation does not mean automatically strict bans and prohibitions on new
technologies but it can significantly vary from general guidelines to more strict regulatory
frameworks with a consequent different impact on the further development of a given
technology. Therefore, in the early stages of nascent technologies general guidelines are
suggested to protect the public safety along the path of scientific development. Accordingly
to this perspective, challenges inherent nanomedicine applications such as unknown
toxological effects, uncertain adverse effects to the human body, and novel properties and
unique functions of nanoparticles should require the elaboration and development of
guidelines capable of providing guidance on how to proceed under conditions of uncertainty
and ambiguity. Such regulatory approach in dealing with uncertainties is not in conflict with
the scientific goal of advancing knowledge but instead it becomes complementary to science
in the sense of providing a different perspective on challenging issues. To what extent the
48
Georgia Miller, “Who’s afraid of the Precautionary Principle?”online source available at http://nano.foe.org.au/
last accessed July 6, 2010 49
Ibidem 50
Ibidem 51
Stirling, supra note 32. 52
Ibidem .
22
guidelines helpful us deal with the challenges to nanomedicine will be better explained in the
following sections.
Chapter 3: Legal Considerations on Nanomedicine in Light of the Existing
European and Canadian Legal Systems.
3.1 Introduction
Premising that no country worldwide has a specific regulation on nanomedicine, the existing
European and Canadian legislations and regulatory systems on drugs and medical devices
contain provisions that include nanoproducts. The issue here is how adequate the regulatory
and normative systems are in dealing with challenges associated
to nanomedicine applications. The analyses of the drugs and medical devices regulations in
North America and in Europe is essential to fully understanding what are the main
challenges encountered in nanomedicine. The first section will examine the current legal
system on drugs and medical devices in North America and in Europe to analyze whether or
not nanoproducts can fall into the regulatory classifications provided for drugs and medical
devices. The second section will analyze whether or not the existing legal systems in North
America and in Europe can adequately regulate and cover the field of nanomedicine. The
third section will examine what is the regulatory approach of some key Agencies in order to
classify nanoproducts as new substances or an application of already known substances or
technologies. As already mentioned above, the answer to this question is profoundly
influenced by the discussion on whether or not nanoparticles are considered as new
substances compared to drugs and medical devices already existing on the market.
However, the discussion on novelty in nanomedicine applications implies a full
understanding of the properties and functions that define a nanoproduct. This is of
fundamental importance because the European and North American regulatory regimes
depend on how bioproducts are classified as drugs or medical devices.
3.2. Nanoproducts and the Current Legal Regime in Europe.
From the existing normative system perspective, nanobiotechnologies creates a unique set of
challenges. One of the major challenges that experts and regulators have encountered in
nanomedicine applications is the ability to adapt them to the existing normative model. This
has relevant consequences in how nanomedicine applications should or should not fit into
23
the regulatory system of drugs and medical devices provided in Europe. Although
nanomedicine employs different methods and technologies, nanoproducts are usually
associated to traditional medical devices. Therefore, it is important to examine one of the
most relevant European provisions that regulate medical devices which is Directive
93/42/ECC. Specifically, Directive 93/42/ECC is relevant to nanomedicine applications
since it provides at article 1 the following definition of medical device:
“any instrument, apparatus, appliance, material other article, whether used alone or in
combination, including the software necessary for its proper application, intended by the
manufacturer to be used for human beings for the purpose of (a) diagnosis, prevention,
monitoring, treatment or alleviation of disease; (b) diagnosis, monitoring, treatment,
modification of the anatomy or of a physiological process; (d) control of conception; (e)
and pharmacological , immunological or metabolic means, but which may be assisted in its
function by such means.”
A careful examination of medical devices definition provided by Directive 93/42/ECC leads
us to argue that some nanomedicine applications do not seem to be completely covered by
the definition. For instance, a drug delivery system that employs a medical device with the
purpose of carrying a drug for the treatment of cancer cells is substantially a combination of
a medical device and a drug. Therefore, drug delivery system refers to the European
regulation on medicinal products which is articulated by Council Directive 65/65/ECC too.
Article 1 of this directive defines a medicinal product as follows:
“any substance or combination of substances presented for treating or preventing disease
in human beings or animals; any substance or combination of substances which may be
administered to human beings or animals with a view to making a medical diagnosis or to
restoring , correcting or modifying physiological functions in human beings or in animals
is likewise considered a medicinal product. “
However, nanotechnology applications that perform novel drug delivery systems seem to go
beyond both regulations of medicinal products and medical devices. In the case that a
medical device and a drug are combined to form a product, Directive 93/42/ECC at article 1
states that:
“Where a device is intended to administer a medicinal product within the meaning of
Article 1 of Directive 65/65/EEC, that device shall be governed by the present Directive,
without prejudice to the provisions of Directive 65/65/EEC with regard to the medicinal
product. If, however, such a device is placed on the market in such a way that the device
and the medicinal product form a single integral product which is intended exclusively for
use in the given combination and which is not reusable, that single product shall be
governed by Directive 65/65/EEC.”
24
Therefore, the traditional regulatory model for combined products shows that when a
medical device and a drug form a product not divisible in its components this product is
regulated by Directive 65/65/EEC instead when the product is separable in its two
components then it is subject to Directive 93/42 EEC is applied. It is clear that directives on
medicinal products and on medical devices cannot be applied cumulatively to regulate a
combined product. To determine whether a product falls under one or the other of the above
directives, identifying the primary action of the product is key. With respect to
nanotechnology drug delivery system, this criterion of the primary action performed by a
nanoproduct is challenging due to the complex mechanisms of action that usually
characterizes these applications. From a regulatory perspective, drug delivery system is a
revolutionary application that challenges the traditional normative boundaries between drugs
and medical devices. Therefore, nanomedicine applications that show unique features like
drug delivery system should require either a separate regulatory model or an implementation
of guidelines to adapt the existing normative system to nanomedicine applications. Another
legal issue related to nanoproducts or nanotechnologies emerges from the classification
made by the European system on medical products. In fact, under the European regulation
medical products are classified in each category based on their level of risk. Directive
93/42/ECC classifies medical devices in three different classes: Class I, Class II which is
sub-divided in Class II a e Class II b, and Class III in accordance of Annex IX of directive.
Accordingly to the classificatory system provided in Annex IX, Class I is intended for non-
invasive devices with a low risk, Class II(a) relates to low-medium risk non-invasive devices
which come into contact with injured skin principally intended to manage the micro-
environment wound; Class II (b) relates to medium-high risk surgical devices applied for
transient use; Class III is for high-risk implantable and long-term surgically devices. The
Directive 93/42/ECC puts different safety standards and conformity assessment procedures
depending on the risk level that characterizes each class of medical devices. For instance,
under the generals rule low risk medical devices in Class I are approved under the sole
responsibility of the manufacturer, Class II (a) medical devices require the intervention of an
official body designated by the member State during the production phase, and Class II (b)
and Class III require inspection from an official body since they pose high potential risks to
human safety. In classifying medical devices and their risks, the system takes into
consideration the degree of invasiveness, the duration of contact to the human body and how
the human body is affected. This normative system is based on the principle that higher
25
potential risks require a higher degree of safety standards. However, as we have already
discussed in the preceding sections one of the main challenges with nanoproducts and
nanotechnologies is the difficulty to identify quantitatively and qualitatively the class of risk.
Therefore, obstacles emerge in the effort to adapt nanoproducts or nanotechnologies to the
traditional normative system based ultimately on a categorization of different risk levels.
From this perspective, it is clear that challenging features such as complexity, variability and
unpredictability that define risks associated to nanotechnologies have an impact on the
normative system that does not seem sufficiently adequate to solve nanoproducts challenges.
More recently, the European Union has enacted the Directive 20001/95/ECC on general
product safety. The General Product Safety Directive (GPSD) which is called “horizontal” is
intended to be applicable to all products placed into the market or made available to the
public. This includes nanoproducts. This directive has the main purpose to ensure that
manufacturers produce safe medical devices and fulfill all regulatory requirements.
However, some scholars have pointed out that this directive refers only to human health and
not the safety in the environment.53
Ultimately, a communication from the Commission of
the European Communities (CEC 2008) has stated that the European legislation covers to the
large extent the risks associate to nanoproducts.
3.2.1.: Nanoparticles are “New Substances” Compared to their Bulk
Chemicals.
Relevant to nanoproducts is the European legislation on chemicals known as Registration,
Evaluation, Authorization and Restrictions of Chemicals (REACH) that came into effect on
June 1, 2007. Although REACH does not mention specifically nanosubstances, this
legislation applies to all chemical substances including nanosubstances. The main purpose of
the European legislation on chemicals is to develop higher standards of human health and
environmental safety through an earlier identification of properties and chemical substances
of products before they are put in the market. How and to which extent nanotechnology is
covered by this legislation needs to be analyzed. Examining whether or not REACH
adequately covers nanomaterials is a starting point from which to develop more responsive
legal tools to adapt the revolutionary field of nanotechnology. As Hansen well pointed out:
53 Graeme A. Hodge et al.”New Global Frontiers in Regulation: The Age of Nanotechnology” Cheltenham-
Massachusetts, Edward Elgar Publishing, (2007) at 223
26
“Understanding the limitations of the current regulation in regard to nanomaterial
is a starting point in the process towards adapting existing laws and facilitate
discussion about which kind of regulatory option is best to address these.”54
As we already mentioned in the preceding sections, one of the main challenges coming from
nanotechnology is that nanoparticles contain the same molecules that are present in other
already existing chemicals. In fact, most of the existing nanoproducts are a manipulation of
already well-known chemicals at atom or molecular scale as listed below:
Carbon: carbon black, carbon nanotubes and fuellerenes;
Silver
Silicon dioxide: amorphous and crystalline
Aluminum oxide
Zinc oxide
Iron oxides
Cerium oxide
Titanium dioxide
Although nanoproducts are made of the same chemicals existing in nature, bulk chemicals in
nanoproducts are modified and transformed to serve different market sectors such as food,
cosmectics and personal care products. REACH is intended to provide alternative methods
of risk assessment of chemical substances contained in products before they enter the
market. Based on the principle “no data, no market,” article 13 of REACH imposes on
producers, importers and down-stream users the requirement to prove that what they produce
and intend to put in the market is not harmful to human health and the environment.
Therefore, REACH is a clear application of the Precautionary Principle. For all substances
manufactured or imported in volumes of one tone per year or more a registration is required
under REACH. Registrants for nanoform and bulk form have to submit to European
Chemical Agency (ECA) a technical dossier with all relevant data on the toxic and ecotoxic
properties of substance and uses, classification, and labeling of products. At or above 10 tons
per year the registrant is obliged to submit a chemical safety report on risks, hazards and
exposure of substances manufactured or imported in quantities of 10 tons or more per year.
In addition to that, registrants have the obligation to constantly update the information
54 Steffen Foss Hansen, “Regulation and Risk-Assessment of Nanomaterials -Too little Too late?” (2009) Technical
University of Denmark, at 19 source available at www.env.dtu.dk., last visited on August 13, 2010.
27
related to changes in quantities manufactured or imported or knowledge of new adverse
effects to human health. Article 3.1 of REACH states that:
“substance: means a chemical element and its compounds in the natural state or obtained
by any manufacturing process, including any additive necessary to preserve its stability
and any impurity deriving from the process used, but excluding any solvent which may be
separated without affecting the stability of the substance or changing its composition."
Although article 3.1 does not make a specific reference to nanoproducts, REACH includes
nanomaterials since it is applied to all substances regardless to their shape, properties or size.
However, manifactured nanoparticles properties differ completely from equally shaped
macroscopic structures. Some scholars have argued that:
“Nor is it clear the extent to which we can rely on our existing knowledge about
conventional chemicals to predict risks of nanomaterials. The defining character of
nanotechnology – the emergence of wholly novel properties when materials are reduced to
or assembled at the nano-scale – carries with it the potential for novel risks and even novel
mechanisms of toxicity that cannot be predicted from the properties and behavior of their
bulk counterparts.”55
For instance, aluminum is an inert substance in its bulk form but it is highly explosive at its
nanoscale. Under REACH, most of the substances are identified on the base of their
chemical composition; however, other substances like nanosubstances need a more careful
observation depending on additional criteria able to properly identify them. From this
perspective, nanomaterials seem to be identifiable not only by their chemical composition
but also by other various criteria. In 2007, the Technical Guidance Document on
Identification and Naming of Substances in REACH (TGD) has stated that:
"The current developments in nano-technology and insights in related hazard effects may
cause the need for additional information on size of the substances in the future. The
current state of development is not mature enough to include guidance on the identification
of substances in the nanoform in this TGD."56
Therefore, additional information on nanomaterials is required for the purpose of conducting
an analysis of equivalence between the nanoform and its bulk form. Also guidelines should
be implemented in order to evaluate when a nanoproduct can be deemed as a separate
substance or as a simple variation of bulk substance. These clarifications are important
55 Richard A. Denison, ”A proposal to increase federal funding of nanotechnology risk research to at least $100
million annually”(2005) on line source available at http://.myaccess.library.utoronto.ca
www.enironmentaldefense.org/documents/4442_100milquestionl.pdf last visited on July 8, 2010. 56
Guidance for Identification and Naming of Substances in REACH at 28 online source available at guidance.
echa. europa.eu/guidance_en.htm ,last visited on July 20, 2010.
28
because depending on how a substance is defined it will require a different classification,
labeling and long-term review procedures. However, under REACH is not clear when a
nanoform equivalent to a bulk form should be registered. With regard to this, SCENIHR
report on “The appropriateness of the risk assessment methodology in accordance with the
Technical Guidance Documents for new and existing substances for assessing the risks of
nanomaterials” has stated that that current methodologies described in the TGDs are likely
to recognize certain hazards, but modifications are required for the assessment of risks to
human health and the environment. Furthermore, SCENIHR highlights the need to evaluate
hazards of nanoparticles on a case by case basis. In addition to that REACH raises some
concerns about nanomaterials used for medical purposes. More specifically, REACH raises
regulatory concerns on nanomaterials related to medicinal products and medical devices.
Art. 2(5) (a) of REACH excludes from its requirements of registration, evaluation and
authorization substances used in medicinal products. Differently, medical and in-vitro
diagnostic devices that contain chemical substances fall within the scope of REACH.
However, in article 2 (6) of REACH the following exemption is provided:
“Medical devices which are invasive or used in direct physical contact with the human
body in so far as Community measures lay down provisions for the classification and
labeling of dangerous substances and preparations which ensure the same level of
information provision and protection as Directive 1999/45/EC.”
Therefore, it is not clear how the European legislation looks at medical devices that contain
nanomaterials. By the analyses of the various directives, it seems that European legislation
considers nanomaterials from a broad perspective without taking into consideration practical
issues. For example, nanoproducts that are a combination of medical devices and drugs
encounter challenges under the European legislation that is based on a marked regulatory
distinction between medical devices and medicinal products. For example, under REACH
medical device component would fall under within its requirements but the chemical
substance used as medicinal product would fall under the exemption for REACH
applicability. In addition, if the medical device contains dangerous chemical substances and
preparations, it is exempted from REACH requirement and is regulated under Directive
1999/45/EC. The classification of dangerous chemical substances and preparations
according to the degree and nature of the hazards involved are based on the definition of
categories of danger provided by this directive. However, defining dangerous chemical
substances means identifying their intrinsic hazards and their class of risk. Due to lack of
29
insufficient data and limited studies on properties of nanomaterials, the risk classification of
chemical substances in nanoform is challenging. Recently, the European Commission has
provided guidelines “on the borderline between drugs and medical devices.”57
These
provisions have the purpose to lighten the multiplicity of requirements and authorities
involved in the regulatory system that disciplines these combined products. Contained in the
Meddev 2.1/3.358
, these guidelines should give help to manufacturers of combined products
to recognize the regulatory category for their products. Surprisingly, these guidelines do not
contain any reference to medical devices that incorporate nanomaterials. Even a broad
interpretation of these guidelines that includes nanoproducts such as drug delivery products
and devices incorporating an ancillary substance still leaves room for interpretation. For
example, one issue coming from combined nanoproducts is how to discern the primary or
subsidiary action of pharmaceutical on medical device. This analyses involves full
understanding of the process that underlines nanoproducts and nanotechnology applications.
Ultimately, nanotechnology imposes a major convergence of regulatory tools in order to
appropriately regulate its novel nanoproducts and applications. This would allow experts and
regulators to address specific aspects related to novel applications. Examining REACH, we
can extrapolate some considerations concerning nanoparticels. One of the main advantage of
REACH is that it allows gathering, collecting and disseminating relevant information on
properties, adverse effects, and toxicity behavior of nanoparticles. This would facilitate the
task to fulfill the gap communication on adverse effects and enhance the dissemination of
information among researchers, experts, and regulatory agencies. From a risk management
perspective, REACH is an important legal tool that could provide information during the
life-span of nanoproducts and thus be helpful in the safety monitoring system. However,
some limitations have been identified in the applicability of REACH to nanosubstances. In
fact, the requirement of manufacturing or importing chemical substances in tonnage does
not seem to be adequate to nanoparticles that usually are manufactured in lower quantity.
REACH should also implement a system that aims at obtaining data with a specific attention
57 Julia Gillert and Lucy Knight, ”On the borderline between drugs and medical devices”(2009) Europe
Pharmaceutical & Healthcare Newsletter online source available at http://bakerxchange.com/last last visited on
July 22, 2010.
58 MEDDEV 2.1/3.3 “Borderlines products, drugs delivery products and medical devices incorporating, as integral
part, an ancillary medicinal substance or an ancillary human blood derivative,” ( 2009) online source available at
http://ec.europa.eu/consumers/sectors/medical-devices/documents/guidelines/ last visited on August 26, 2010.
30
to nanoproducts. Ultimately, the European legislation should develop a major integration
between REACH and other directives for better classifying nanoproducts that are on the
borderline between medical devices and drugs.
3.3 Nanoproducts and the Current Legal System in Canada.
3.3.1.Introduction
This section will examine the Canadian regulatory system on drugs and medical devices
since nanoproducts will be regulated under these two regulatory systems. The main purpose
of this section is to examine whether or not nanoproducts are adequately and sufficiently
covered by the existing Canadian regulatory system.
3.3.2. Challenges for Nanoproducts under the Canadian Drug Regulatory
System.
Currently, Health Canada is referring to the existing normative system on medical devices
and drugs to regulate nanomedicine applications even if it recognizes that changes and
implementations to both regulations need to be done to ensure specific safety standards on
products. Under the Canadian legal system FDA, FDR and NOC are the regulatory Agencies
responsible for regulatory approval of pharmaceuticals. Numerous nanotechnology
applications are expected to be regulated under drug regulation. With specific attention to
nanotechnology, it is important to underline the importance of the Center for Drug
Evaluation and Research (CDER) at FDA with the main purpose to review “new substances”
contained in drugs and drug delivery systems. Before a regulatory submission, a sponsor has
to conduct all the required necessary clinical trials. Before a pharmaceutical approval is
granted for a drug preclinical trials have to be conducted on animal to test toxicity effects.
Prior of a New Drug Submission (NDS) preclinical tests include safety pharmacology,
toxicity on immune system and reproduction, carcinogenicity, and irritation effects. Some
scholars have argued that existing tests and methods are not adequate to assess novel risks
31
and novel mechanisms of toxicity associated to nanoproducts.59
Addressing the issue how
manufactured nanomaterials can change their properties and behavior, they stated that:
“We have yet to develop the means to sufficiently characterize or systematically describe
such subtle structural changes – a clear prerequisite to being able to consistently and
rigorously apply and interpret the results of toxicological testing.”60
Others have argued that existing preclinical tests on drugs could be considered overall
adequate to nanoproducts unless additional tests are required if single nanoproducts show
particular toxicity profiles. Therefore, FDA may select on a case by case bases single
applications to require additional studies depending on the specific characterization of
hazards and risks associated to these nanoproducts. 61
3.3.3. Challenges for Nanoproducts under the Canadian Medical Device
Regulatory System.
Since a large part of nanoproducts placed into the market fall into the category of medical
devices this section will examine the existing regulatory system on medical devices to argue
that nanoproducts amplify the already existing weaknesses inherent in this system. In the
Canadian context, medical devices were not regulated for a long time until the Medical
Device Amendments (1976) to the Federal Food, Drugs and Cosmetic Act. 62
In 1998, new
regulations were published to enhance safety and effectiveness of medical devices. Under
the Canadian regulation, medical devices are placed into four classes Class I, Class II, Class
III, and Class IV where Class I represents the lowest risk and Class IV represents the highest
risk depending on the level of risks associated to each category. Some scholars have argued
that the system on medical devices provides lower standards compared to the drug system.
Before a sponsor puts a drug on the market they have to show a “substantial evidence of
effectiveness” whereas a sponsor for a medical device has to show a “reasonable assurance
59
Denison, supra note 51 at 4 60
Ibidem 61
Nakissa K.Sadrieh & Parvaneh Espandiari, ”Nanotechnology and FDA: What are the Scientific and Regulatory
Considerations for Products Containing Nanomaterials?”Nanotechnology Law and Business (2006) on line source
available at http://heinonline.org last visited on July 23, 2010. 62 Jonas Zajac Hines et al.”Left to Their Own Devices: Breakdowns in United States Medical Device Premarket
Review”(2001) in Plos Medicine online source available at http://www.plosmedicine.org last visited on July 22,
2010.
32
of safety and effectiveness.”63
Compared to safety requirements prescribed for drugs, the
lower degree of safety standards that regulation demands for medical devices in the stage of
pre-market approval has significant consequences especially in the case of high risk medical
devices incorporating nanoparticles. For example, recent studies have shown toxicity and
biocompatibility issues associated to nanoparticles such as quantum dot. Accordingly to the
classificatory system, quantum dot devices should be classified in the highest class of risk
such as Class III and Class IV. However, the existing regulation on medical devices would
require the sponsor of quantum dot medical devices to show only a “reasonable assurance of
safety and effectiveness” before a pre-market approval is granted on these nanoproducts.
Also the different degree of safety standards prescribed for drugs and medical devices raises
issues about whether a nanoproduct is a combination of a drug and a medical device. Before
March 2006 a combined product had to satisfy the requirements of two regulations. The
Food and Drug Regulation and the Medical Device Regulation. In pursuing a unique set of
regulations for combined products, the Food and Drug Regulations and the Medical Devices
Regulations were amended and a revised policy was enacted on March 2006. 64
However,
this policy is applied only when the two components of a combined product are separable.
Instead when the two components are not separable then the product will be subject to either
Food and Drug Regulation or Medical Device Regulation. As Health Canada has stated:
“Where the principal mechanism of action by which the claimed effect or purpose is
achieved by pharmacological, immunological, or metabolic means, the combination
product will be subject to the Food and Drug Regulations, unless that action occurs in
vitro, without reintroducing a modified cellular substance to the patient, in which case the
product will be subject to the Medical Devices Regulations. Where the principal
mechanism of action by which the claimed effect or purpose is not achieved by
pharmacological, immunological, or metabolic means, but may be assisted in that effect or
purpose by pharmacological, immunological, or metabolic means, the combination product
will be subject to the Medical Devices Regulations.”65
Therefore, the primary mode of action (PMOA) of a combined product is the regulatory
criteria by which a combined product is classified as a drug or a medical device with a
consequent different impact on the regulatory requirements. The policy tends to create a
hierarchical system that distinguishes between a primary function and an ancillary function
inherent a mechanism of action. However, this provision does not seem adequate for
nanomedicine applications. The task to identify what is the primary or ancillary function in
63
Ibidem 64
Health Canada on line source available at www.hc-sc.gc.ca last visited on July 22, 2010. 65 Ibidem
33
nanomedicine is a challenging task since nanoproducts and nanomedicine applications are
across drugs, medical devices, and biologics. What emerges from this is the need to
implement guidelines for a more comprehensive understanding of the underlying dynamics
that govern processes in nanomedicine applications. Also, the lack of clarity on combined
nanoproducts has generated a further jurisdictional issue on which legislation and thus which
authorities are responsible to regulate these products. Recently, FDA has commented on
combined products in the following way :
“Since 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 FDA's regulation of combination products. These
include the following 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 applications to more than
one Agency Center are needed.”66
Recent legislation has created new competencies and offices such as “OCP” Office of
Combination Products to account for jurisdictional challenges coming from combined
products. However, a combined nanoproduct will be assigned to one of the three Agency
Centers - Center for Drug Evaluation and Research, the Center for Biologics Evaluation and
Research, or the Center for Devices and Radiological Health.67
Furthermore, the assignment
to an Agency Center is based on the assessment of the primary mode of action (PMOA) of
the combination product. By examining the existing legislation, it clearly emerges that on the
one hand, nanotechnology applications amplify the challenges that already exist in both
regulatory systems on drugs and medical devices and on the other hand they create novel
challenges that impose more responsive regulatory tools. Issues generated by
nanotechnologies applications confirm that both regulatory systems on drugs and medical
devices are based on a short-term effectiveness and safety of the drug products.68
The
traditional normative system does not seem to adequately assess the safety and effectiveness
on nanoproducts in the premarket approval and in monitoring activities as well. As some
66 FDA, Overview of the Office of Combination Products, FDA.GOV,
http://www.fda.gov/oc/combination/overview.html last visited on July 23, 2010.
67
Ibidem 68
Jocelyne Downie, Timothy Caulfield and Collen M. Flood “Canadian Health Law and Policy “Canada,
LexisNexis, (2007) at.336
34
scholars have pointed out uncertainties and limited knowledge on nanoproducts properties
and behavior have generated concerns on the feasible applicability of regulatory tools to
nanotechnologies. Safety tests for premarket approval and methods to ensure safety during
all life cycle of nanoproducts need to be re-examined to be adapted to the novel challenges
that characterize nanotechnology.
3.4 Role and Scope of Guidelines in the Context of Nanomedicine.
From the analysis conducted in the preceding sections, what has emerged is the applicability
of the existing European and Canadian legislations to nanomedicine applications which
generates concerns and difficulties. Particularly, the classificatory system of risk provided by
both European and Canadian regulatory regimes does not seem applicable to nanomedicine
since it is not yet possible to establish in certain terms the level of risk belonging to
nanomedicine applications. Also, nanomedicine applications such as drug delivery system
have highlighted how the advancement of science is challenging the boundaries between
medical products and devices existing in European and Canadian traditional normative
systems. For example, nanomedicine drug delivery system is blurring the borderline
between medical products and devices. However, legislations and regulatory sources are not
sufficiently responsive in dealing with these challenges. As more nanoproducts and
technologies are introduced into the market, it is extremely important for researchers, jurists,
and manufacturers to know what are the legislative or regulatory framework involved with a
specific product or technology. Currently, the European and Canadian normative systems are
not clear in how to apply the legal requirements and criteria to nanomedicine. Furthermore,
both systems are based on a classical model of drugs, medical devices and combined
products without taking into considerations the novel challenges coming from the
advancement of nanomedicine. From this point of view, detailed guidelines that clarify legal
requirements and criteria for nanomedicine legislation are required. As additional
information sources, guidelines already exist in both European and Canadian systems. For
example, Meddev 2.1/3.3 on borderline products that incorporate medical devices and drugs
is a guideline intended to clarify what requirements a nanomedicine combined product has to
fulfill in order to be considered subject under Medical Devices Directive or Medicinal
Product directive. However, the legal status of this guideline is not legally binding. The
guideline has only consultation purposes on the procedures related to combined products.
What should be the legal status of guidelines on nanoproducts is highly debated among
35
researchers, experts, and stake holders. The European Committee for Standardization is
evaluating the opportunity to introduce nanotechnology standards on quality, safety and
efficacy of naoproducts. However, there is no consensus on whether these standards should
be introduced as soft guidelines or legally binding provisions. The discussion is highlighted
by the EU Directorate General Enterprise and Industry’s consultation on proposals to amend
Directive 2001/83/EC.69
In fact, a large number of stakeholders have expressed the opinion
that Annex I to Directive 2001/83/EC that contains “essential requirements” should be
implemented by soft guidelines and not legally binding provisions that may impede the
advancement of novel products or technologies. At this stage of the advancement of
nanomedicine an appropriate regulatory approach should address flexible guidelines as a
helpful information source on the most challenging nanotechnology applications but with a
regulatory mechanism that enables regulatory bodies and legislators to intervene whereas an
authoritative interpretation on legal provisions is required.
Chapter 4: Recommendations and Conclusive Considerations.
4.1: Recommendations.
What has emerged from the present analyses is that nanotechnology is still in its infancy
since the state of knowledge on hazards and risks associated with nanotechnology is too
limited to elaborate general categories of risk or a comprehensive set of norms to cover
nanotechnology applications. Currently, the ambiguities and scientific uncertainties that
surround nanomedicine are reflected in the normative system which seems not to be
adequate to deal with the challenges coming from this emergent technology. In such a
scenario where scientific uncertainties are dominant it is of fundamental importance to
intensify the tradeoff between science and other disciplines, especially law. On the one side,
the lack of data requires further scientific studies and toxological research on nanoparticles
properties and behavior towards a more comprehensive understanding of this novel
technology in its various applications. On the other side, developing this process of
knowledge is not only a scientific task since it requires other disciplines to be involved. For
69 European Commission – Enterprise and Industry Directorate General, Public Consultation on amendments to
Annex I to Directive 20001/83/EC as regards advanced therapy medicinal products, Brussels 9 July 2008, online
source available at http://ec.europa.eu/index_it.htm last visited on August 28, 2010.
36
instance, jurists and legal scholars should sustain the scientific discoveries by developing
guidelines and providing the minimum safety standards acceptable to protect human health.
From this point of view, as other novel technology, nanotechnology offers an opportunity for
major integration between different disciplines and especially between science and law.
Novel technologies open up a space where science and law should be seen not in conflict but
as complimentary disciplines with the purpose of tracing a technology pathway for a
responsible scientific progress. This approach has important consequences on a regulatory
level. Challenges coming from emergent technologies require a new model of risk-benefit
analyses that calls for a major interplay between science and legal, social, and ethical values
in the risk-assessment and risk-evaluation. In uncertain science, the legal perspective has an
extremely important role in the risk management and ultimately in how to advance the
scientific knowledge by providing methods to control risks and strategies to minimize risks
to human health. A major integration between scientific facts and ethical, social and legal
values even in the risk-assessment is more advantageous because it allows better
investigating and identifying the risk- multidimensionality and its interdependencies in
concrete situations. Secondly, it allows developing regulatory tools that are more responsive
in managing real and not only perceived risks. Also, the multidisciplinary approach is
helpful for the understanding of how scientific ambiguities and uncertainties that surround
nanotechnology can negatively impact the current European and Canadian regulatory
systems. Indeed, these current normative systems take into consideration nanomedicine
applications only from a broad perspective without considering practical issues. Therefore,
in such a scenario in which scientific knowledge is so scarce to properly elaborate legal
definitions and categories but potential risks can be seriously harmful to the human body
some precautionary measures should be required in order to manage challenges and prevent
harmful events. As it was better explained in the previous sections of this thesis, an approach
that aims to develop step by step precautionary measures and guidelines offers a rational
way to sustain science under uncertain and ambiguous conditions. On the contrary, a
comprehensive regulation that aims to cover nanotechnology seems neither appropriate at
this early stage, nor feasible, since nanoparticles behave differently depending on the
specific application or process in which they are employed. More realistically, regulatory
guidelines should be provided in relation to those nanomedicine applications that seem more
risky and invasive to the human body such as nanoparticles employed in drug delivery
systems and optical imaging. This approach that tends to select specific applications might
37
be helpful for researchers and legal experts to investigate critically the dynamics of risk that
govern specific applications. In addition to that, technologies such as “gene therapy” or
OGM are instructive examples on how to avoid in the future some of the pitfalls that have
characterized these emergent biotechnologies. Specifically, the lesson coming from “gene
therapy” could be synthesized as the need of implementing regulatory policies that enhance
the reporting system on adverse effects between researchers and regulatory agencies in
future nanobiotechnologies. Secondly, the OGM experience suggests for more transparent
regulatory choices that include the public in an open discussion on novel technologies and
thus in the process of technological knowledge. Although with some limitations, the
European Legislation on Chemicals (REACH) aims to accomplish these purposes. In fact,
REACH has recognized the importance of developing a data center with the purpose of
collecting, gathering, and disseminating relevant data on nanoparticles properties, adverse
effects and toxological behavior between researchers, regulatory agencies and producers.
From a risk management perspective, exchanging and disseminating data is essential to
provide information on researches and outcomes, adverse effects and toxological issues
related to nanotechnology applications. The challenging features of nanoproducts and
nanotechnology applications should require a safety monitoring system during all their life-
span, so regulatory choices that enhance reporting system on adverse effects are crucial for
this purpose. Ultimately, regulatory choices that favor the dissemination of relevant
scientific data on nanomedicine facilitate a constructive discussion between science and
society and thus build an understanding of risks associated to novel technologies grounded
on scientific data and not on fears generated only by perceptions.
4.2: Conclusive Considerations
Nanomedicine offers the possibility of preventing, diagnosing and treating very disabling
diseases and thus opens up very promising area in the field of medicine. However, limited
knowledge and lack of scientific data on nanomedicine poses novel challenges. The first
challenges that researchers, jurists and legal scholars have encountered with nanomedicine is
how to identify nanomedicine and evaluate its novelty since nanomedicine is across different
disciplines such as biology, chemistry, and bio-engineering. This means that nanomedicine
applications require a deep understanding of the processes involved in each application and
challenges the boundaries between different areas of science. Another challenge comes from
the ultra small size property of nanoparticles which is the most characterizing property of
38
nanomedicine. This property is surprisingly ambivalent in its positive and negative
implications. On the one hand, the ultra small size of nanoparticles is significantly
innovative in the area of diagnosis and therapy because at this scale nanoparticles match the
typical size of natural functional units in living organisms. On the other hand, the ultra small
size of nanoparticles is the most worrying concern for scientists and experts because of the
risks to the human health associated to a more intense interaction between nanoparticles and
living orgamisms. In fact, toxological studies that have focused on this interaction have
found that nanoparticles can be more toxic due to their ultra small size that allow them to
propagate into the living organisms more easily and to be absorbed more quickly compared
to the larger particles. In addition lack of data and limited knowledge does not allow the
answer to relevant issues related to human health such as how and to what extent
nanoparticles properties are responsible in generating novel risks to human health. With
respect to this, two important European Reports such as SCENIHR Report and the White
Paper Nanotechnologies Risk published in June 2006 by the International Risk Governance
Council have addressed this issue. This thesis has argued how challenging features that
surround nanomedicine led experts and policy makers to find regulatory tools able to assess
hazards and evaluate risks in uncertain science. The risk-benefit analyses are the most
accepted regulatory tool that provide strategies and methods to control and manage risks.
However, this thesis has highlighted how the classical model of risk-benefit analyses, which
is based on a strict separation of risk-assessment from risk-evaluation, is inadequate to
properly identify and manage challenges of nanomedicine. The preceding sections have
highlighted how the current model of risk-benefit analyses marks a net line between science
and regulatory, ethical and social values. This strict separation determines the inadequacy of
classical model in properly considering the risk - multidimensionality associated to nascent
technologies like nanotechnology. Conversely, a more reliable and realistic risk-benefit
analyses should integrate scientific data with legal, social and ethical values even in the risk-
assessment. Such an approach aims to pursue an assessment of the magnitude of risks but it
also helps in investigating more complex questions related to the risks and its variable
factors. This approach gives a more realistic picture of risks and its interdependencies
because it takes into consideration concrete situations. The issue of how to manage
uncertainties coming from nanotechnology has drawn the attention from legal scholars and
researchers and generated an intense debate. This thesis has analyzed the main arguments
that characterize this debate and has underlined how this debate is characterized either by a
39
more cautious approach or a more risk-taking approach. This thesis has argued that some
precautionary measures should be applied to sustain scientific discoveries that proceed under
uncertain and ambiguous conditions. Adhering to Sterling’s view, a precautionary approach
does not mean a banning regulation for everything that might be harmful but rather it means
a step by step approach to prevent harms generated by risky technologies.70
This thesis has
considered this regulatory approach far from being in conflict with scientific goals but
instead as complementary to science in the sense of providing a different perspective on
challenging issues. In the last sections, this paper has analyzed whether or not the current
European and Canadian normative systems on drugs and medical devices are adequate to
cover nanomedicine applications. What clearly has emerged from these analyses is that
uncertainties that characterize emergent nanotechnology applications are reflected in the
normative systems. For example, some nanomedicine applications like drug delivery system
are across drugs and medical devices and thus they do not fall into either drug regulatory
system or in medical devices regulatory system. These types of applications challenge the
established normative boundaries between drugs and medical devices drawn in the European
and Canadian legislations. Another limitation coming from the European and Canadian
legislations is the classification of risk made on medical products. These normative systems
are unable to identify quantitatively and qualitatively the risks associated with
nanotechnology. They are not adequate to face challenging features such as complexity,
variability and unpredictability that define risks associated to nanotechnologies. Ultimately,
nanotechnological innovations are transformative in the sense that they result from
assemblage of complex dynamics and variable processes that go beyond the classical way of
understanding science. This revolutionary dimension inborn in nanotechnology but common
to other emergent technologies triggers a more responsive mechanism able to deal with these
challenges. The challenge is to envision a technological pathway in which a fragile and
fragmented scientific knowledge can benefit the value and capability of different disciplines
that continually interact in response to the evolution of knowledge with a positive impact on
policy choices and normative framework.
70 Sterling, supra nota 32.
40
Bibliography
LEGISLATION: EUROPE
Directive 65/65/ECC
Directive 90/385/ECC
Directive 93/42/ECC
Directive 98/79/ECC
Directive 99/45/ECC
Directive 2001/95/ECC
Directive 2001/83/ECC
REACH- Registration, Evaluation, Authorization and Restrictions of Chemicals dated 1 June,
2007.
TEU -Treaty on European Union signed on 7 February, 1992.
LEGISLATION: CANADA:
Canadian Environmental Protection Act of 1999.
FFDCA- Federal Food, Drug, and Cosmetic Act Medical devices Amendment of 1938.
Medical Device Amendments of 1976 to the Federal Food, Drug, and Cosmetic Act.
Policy on Drug/Medical Devices Combination Products dated March 1st, 2006.
INTERNATIONAL SOURCES:
UNCED -Rio Declaration on Environment and Development of 1992.
Wingspread Declaration of 1998 on the Precautionary Principle.
REPORTS AND OTHER RELEVANT DOCUMENTS: EUROPE:
CEC 2008- Communication Commission of the European Communities.
41
European Commission – Enterprise and Industry Directorate General, Public Consultation on
amendments to Annex I to Directive 20001/83/EC, Brussels 9 July 2008, online source available at
http://ec.europa.eu/index_it.htm.
MEDDEV 2.1/3.3 – “Borderlines products, drugs delivery products and medical devices
incorporating, as integral part, an ancillary medicinal substance or an ancillary human blood
derivative” dated December 2009.
SCENIHR REPORT dated June 2006.
TGD-Technical Guidance Document on Identification and Naming of Substances in REACH
WHITE PAPER NANOTECHNOLOGIES RISKS dated June 2006.
REPORTS AND OTHER RELEVANT DOCUMENTS: CANADA:
Canadian Biotechnology Advisory Committee (2002) Improving the Regulation of Genetically
Modified Food and other Novel Foods in Canada”Report to the Government of Canada,
Biotechnology Ministerial Coordinating Committee released on August 26, 2002.
Royal Society of Canada (2001) . Report of the Expert Panel on the future of food Biotechnology.
Royal Society of Canada, Ottawa, Canada.
National Institutes of Health Advisory Committee on Oversight of Clinical Gene Transfer Research,
Enhancing the Protection of Human Subjects in Gene Transfer Research at the National Institutes of Health
(12 July 2000) at Appendix D, http://www.nih.gov./about/director/07122000.htm.
SECONDARY MATERIALS: BOOKS
Arendt, Hanna “The Human Condition” Chicago, The University of Chicago Press (1958).
Beck, Ulrich “Risk Society: Towards a New Modernity” London, Sage Publication Ltd., (1992).
Brunk, C.G., Haworth L. and Lee B.“Values Assumptions in Risk-Assessment: a case study in
alachlor controversy,” Waterloo, Canada, Wilfrid Laurier University Press (1991).
David K.H. and Thompson P.B.,“What Can Nanotechnology Learn from Biotechnology?: Social
an Ethical Lessons for Nanoscience from the debate over Agrifood Biotechnology and GMOs,”
Academic Press (2008).
Downie J., Caulfield T. and Flood C.M., “Canadian Health Law and Policy “LexisNexis, Canada
(2007).
42
Hodge G. A. et al.”New Global Frontiers in Regulation: The Age of Nanotechnology” Cheltenham-
Massachusetts, Edward Elgar Publishing (2007).
Viscusi V.K., “Rational Risk Policy: The 1996 Arne Ride Memorial Lectures” Oxford, Clarendon-
Press Oxford University Press, (1998).
BOOK CHAPTERS:
Myhr A.I. and Dalmo R.A. “Nanotechnology and risk: What are the issues?” In”Nanoethics: The
Ethical and Social Implications on Nanotechonology” New Jersey, John Wiley & Sons Inc.(2007).
Waring R. D.. and Lemmens T.“Integrating Values in Risk Analysis of Biomedical Research: The
Case for Regulatory and Law Reform“ In “Law and Risk” Vancouver, University of British
Columbia Press, (2005).
SECONDARY MATERIALS: ARTICLES
Buzea, Cristina et al. “Nanomaterials and Nanoparticles: Sources and Toxicity,” (2007)
Biointerphases Vol.4, n.2.
Denison, R. A.”A proposal to increase federal funding of nanotechnology risk research to at least
$100 million annually”(2005) on line source available at http://.myaccess.library.utoronto.ca
www.enironmentaldefense.org/documents/4442_100milquestionl.pdf
Doering, R. Food Law: “The Precautionary Principle is not The Answer”(2009), online source
available at <http:www.canadianmanufacturing.com
De Giorgi U., Amadori D.“Fluorodeoxyglucose Positron Emission Tomography for Outcome
Prediction of Mammalian Target of Rapamycin Inhibitor Therapy” (2010) J. Clin. Onco. 28(15):e236-7.
De Jaeghere F.et al.”Oral Bioavailability of a Poorly Water Soluble HIV-1 Protease Inhibitor
Incorporated into PH Sensitive Particles: Effects of the Particles Size and Nutritional State“ (2000)
J. Controlled Release 68(2):291-8.
El-Ansary A. and Al-Daihan S., “On the Toxicity of Therapeutically Used Nanoparticles: An
Overview,” (2009) J Toxicol.; 2009: 754810. Published online 2009 January 25. doi:
10.1155/2009/754810
Garcia-Garcia E., Andrieux K., Gil.S., Couvreur P. “Colloidal Carriers and Blood-Brain Barrier
(BBB) translocation: a Way to Deliver Drugs To the Brain.”(2005) Int. J. Pharm.; 298(2):274-92.
43
Harisinghani M.G.et al.” Noninvasive Detection of Clinically Occult Lymph-node Metastases in
Prostate Cancer” in N. Engl. J. Med. 2003 June 19;348(25):2491-9.
Heselhaus, S., “Nanomaterials and the Precautionary Principle in the EU ”(2010) 33 Journal of
Consumer Policy at 91-108.
Hines Z.J. et al.”Left to Their Own Devices: Breakdowns in United States Medical Device
Premarket Review”(2001) in Plos Medicine online source available at
http://www.plosmedicine.org
Marchant E.G., and D. J. Sylvester, "Transnational Models for Regulation of
Nanotechnology,"(2006) Vol.34 n.4 Journal of Law, Medicine, & Ethics.
Marchant E.G. , J. Sylvester Douglas and W. Abbott Kenneth “Risk Management Principles for
Nanotechnologies” (2008) Vol.2, n.1 Nanoethics.
Metha M.D. “From Biotechnology to Nanotechnology: What we Can Learn from Earlier
Technologies?”(2004) Vol. 4 n.1 Bulletin of Science, Technology and Society.
Murthy S.K “Nanoparticles in Modern Medicine: State of the Art and Future Challenges” (2007)
Int. J. Nanomedicine. 2(2): 129–141. Published online 2007 June.
Oberddrster G., et al., "Nanotoxicology: An Emerging Discipline Evolving from Studies of
Ultrafine Particles” (2005) 113 Environmental Health Perspectives.
Pradise J.et al., ”Developing Oversight Frameworks for Nanobiotechnologies” (2009) Vol. 37 n.4
The Journal of Law, Medicine, and Ethics.
Recuerda M.“Dangerous Interpretations of the Precautionary Principle and the Foundational
Values of European Food Law: Risk Versus Risk” (2008) Vol.4 n.1 Journal of Food & Law
Policy.
Sadrieh N. K. and Espandiari P. ”Nanotechnology and FDA: What are the Scientific and
Regulatory Considerations for Products Containing Nanomaterials?”Nanotechnology Law and
Business (2006) on line source available at http://heinonline.org
Sustein C.R., “Laws of Fear: Beyond the Precautionary Principle” Cambridge, University Press
2005.
Turner R.S., “Of Milk and Mandarins RBST, Mandated Science and the Canadian Regulatory
Style”(2001) 36 J. Can. Stud.107.
Warheit D.B. et al., "Comparative Pulmonary Toxicity Assessment of Single-Wall Carbon
Nanotubes in Rats, “ (2004) 77 Toxicological Science.
44
Wilson. R.F., “Nanotechnology: The Challenge of Regulating Known Unknown Risks”(2006)
Vol.4, Issue n.34 Journal of Law, Medicine & Ethics.
OTHER MATERIALS:
FDA, Overview of the Office of Combination Products, FDA.GOV, online source available at
http://www.fda.gov/oc/combination/overview.html
Gillert J. and Knight L., ”On the borderline between drugs and medical devices”(2009) Europe
Pharmaceutical & Healthcare Newsletter online source available at http://bakerxchange.com/last
Guidance for Identification and Naming of Substances in REACH at 28 online source available at
guidance. echa. europa.eu/guidance_en.htm.
Hansen, S.F. “Regulation and Risk-Assessment of Nanomaterials -Too little Too late?” (2009)
Technical University of Denmark, at p. 19. source available at www.env.dtu.dk.
Health Canada, on line source available at www.hc-sc.gc.ca.
Health Canada, online source available at http://www.hc-.gc.ca7english.protection.precaution.html
Miller G., “Who’s afraid of the Precautionary Principle?”online source available at
http://nano.foe.org.au/
Ostiguy et al. Best Practices Guide to Synthetic Risk Nanoparticles Management (2009) at 56
online source available at www.safenano.org l
Renn O., “Precaution and Analyses: Two Sides of the Same Coin? Introduction to Talking Point on
the Precautionary Principle”(2007) 8 EMBO Reports at 303-304 on line source avaialabel at
<http:www.nature.comembor/journal/v8/n4/full/7400950.html>.
Stirling A., “Risk, Precaution and Science: Towards a More Constructive Policy Debate. Talking
point on the Precautionary Principle. 2007) EMBO Reports at 303-304 online source available at
<http:www.nature.comembor/journal/v8/n4/full/7400950.html>.