Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Ethics should be considered when planning
your next research activity
Professor, PhD Lisbeth E. Knudsen
Department of Environmental Health,
Institute of Public Health,
University of Copenhagen
Denmark
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
My background
Professor in toxicology at Institute of
Public Health, Copenhagen
Partner in several EU programs/projects
with human samples:
NANOTEST, COPHES/DEMOCOPHES,
ESBIO, NEWGENERIS,
CANCERRISKBIOMARKERS, BIOMODEM
Coordinator of Childrengenonetwork
President of ECOPA (European Consensus
Platform for 3R Alternatives to Animal
Experimentation)
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Learn from history
Thalidomide
Gene therapy
Clinical testing of human-like
biomolecules
Avoid negative neighbours
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Gene therapy
Jesse Gelsinger , an 18 year old Arizona man, suffered from an inherited
disorder called deficiency of ornithine transcarbamylase (OTC). OTC
deficiency is a genetic error, which effects urea metabolism and effects one
out of every 30,000 children. OTC is the second enzyme in the urea cycle
and catalyzes the conversion of ornithine and carbamoyl phosphate to
citrullinne.
The E1-deleted, E2A-temperature-sensitive adenovirus vector expressing the
human OTC enzyme was infused directly into the hepatic vein over two
hours. Jesse was the 18th patient enrolled in the study and was one of two
patients that received the highest dose in the study. The maximum dose
was three hundred times the amount given to the initial patients. The other
patient received the maximum dose just before with no adverse side effects.
Researchers unexpectedly found significant amounts of the adenovirus vector in
the lymph nodes, spleen, and bone marrow. They also found Jesse's bone
marrow to be stem cell depleted. This has led some scientists to believe that
an existing condition might have been responsible for the rapid and extreme
immune reaction. Other scientists believe that administering the vector into
the hepatic artery is the culprit.
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Elephant man
After a drug is confirmed as safe and efficacious in
preclinical studies, it is tested in healthy human
volunteers for first in man trials.
In 2006, a phase I clinical study was conducted for a
CD28 superagonist antibody TGN1412 in six
human volunteers.
After very first infusion of a dose 500 times smaller
than that found safe in animal studies, all six
human volunteers faced life-threatening conditions
involving multiorgan failure for which they were
moved to intensive care unit.
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Elephant man
The victims of the catastrophic 'Elephant Man' clinical trial were given the test
drug at a 'reckless' rate, according to experts.
The drug TGN 1412, designed to fight leukaemia, rheumatoid arthritis and
multiple sclerosis, was injected 15 times more quickly than when given to
monkeys in animal studies, confidential documents have revealed.
Leading scientists believe this 'reckless' mistake could explain the horrendous
reaction to the drug which left volunteers fighting for their lives.
The six young men - all fit and healthy before signing up for the March trial at
Northwick Park Hospital in North-West London - suffered a host of sideeffects, including pain, vomiting and organ failure.
Bar manager Mohamed 'Nino' Abdelhady, 28, was described as 'the Elephant
Man' by his partner Myfanwy Marshall after his head swelled up.
Trainee plumber Ryan Wilson, 20, suffered heart, kidney and liver failure,
pneumonia and blood poisoning and was in a coma for three weeks.
While in the coma, he suffered a frostbite-like reaction and has since lost parts
of his fingers and had his toes amputated.
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Nanoparticles
Size range 1-100 nm
Naturally occuring
Volcanoes
Forest fires
Virusses
Ferritin
Materials
Metal oxides
Liposomes
Polymers
Carbon
Nanotechnology
Electronics
Fabrics
Coatings
Paintings
Man made
Combustion engine
Power plants
Shapes
Spheres Airplane jets
Metal fumes
Fibers
Tubes
Nanomedicine
Medical imaging
Drug delivery
Cancer therapy
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Human placenta ex vivo perfusions
Placenta collected immediately after birth and informed consent
Intact tissue mimics physiological in vivo conditions
Placental transfer, accumulation, metabolism, acute toxicity etc.
Figure from (Mathiesen et al. 2010) Photos from Tina Mose
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Placental transport of Silica Nanoparticles (25nm)
Ex vivo placental perfusion and in vitro BeWo cell
transport models show no transport of Silica
Nanoparticles
.
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Biomarkers in environmental/food health research
Environmental/food
concentration
(external dose)
internal
dose
dose-response
relationship
biologically
significant
dose
biomarkers of
exposure
early
biological
effects
toxic effects
alterations
in structure/
function
biomarkers of risk
biomarkers of individual susceptibility (genetic or acquired)
Biomarkers of exposure (internal dose or biologically significant dose)
Biomarkers of risk (early biological effects or alterations in structure and
function of cellular macromolecules)
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Ethical issues
Human participation
Who, where how
Informed consent and data privacy, bio banking
Animal experiments
3Rs Replacment, refinement reduction
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Ethics check list
Informed Consent
Does the proposal involve
Does the proposal involve
Does the proposal involve
Does the proposal involve
Does the proposal involve
Does the proposal involve
children?
patients or persons not able to give consent?
adult healthy volunteers?
Human Genetic Material?
Human biological samples?
Human data collection?
Research on Human embryos/foetus
Does the proposal involve Human Embryos?
Does the proposal involve Human Foetal Tissue/Cells?
Does the proposal involve Human Embryonic Stem Cells?
Privacy
Does the proposal involve processing of genetic information or personal
data (eg. health, sexual lifestyle, ethnicity, political opinion, religious
or philosophical convinction)?
Does the proposal involve tracking the location or observation of people?
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Research on Animals
Does the proposal involve research on animals?
Are those animals transgenic small laboratory animals?
Are those animals transgenic farm animals?
Are those animals cloning farm animals?
Are those animals non-human primates?
Research Involving Developing Countries
Use of local resources (genetic, animal, plant, etc.)?
Benefit to local community (capacity building ie access to healthcare,
education, etc. )
Dual Use
Resarch having potential military/terrorist application
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
http://cordis.europa.eu/fp7/ethics_en.html#ethics_cl
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
An informed consent form is required in the following
cases:
When the research involves:
Patients
Children
Incompetent/Incapacitated persons
Healthy volunteers
Immigrants
Others (i.e.prisoners)
When the research uses/collects:
Human Genetic Material
Biological samples
Personal data
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
A statement that the study involves research subjects and an
explanation of the purposes of the research.
The expected duration of the subject's participation.
A description of the procedures to be followed/ of the
medicine that is going to be tested, and an identification of
any procedures which are experimental.
A statement that participation is voluntary.
Information about who is organising and funding the research.
A description of any reasonably foreseeable risk, discomfort
or disadvantages.
A description of any benefits to the subject or to others
which may reasonably be expected from the research
avoiding inappropriate expectations.
A disclosure of appropriate alternative procedures for
treatment/diagnosis if any, that might be advantageous to
the subject.
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
A statement describing the procedures adopted for ensuring data
protection/confidentiality/privacy including duration of
storage of personal data.
A description of how incidental findings are handled.
A description of any planned genetic tests.
For research involving more than minimal risk, an explanation as to
whether there are any treatments or compensation if injury
occurs and, if so, what they consist of, or where further
information may be obtained. Insurance coverage should be
mentioned.
A reference to whom to contact for answers to pertinent
questions about the research and research subjects' rights, and
whom to contact in the event of a research-related injury to the
subject.
A statement offering the subject the opportunity to ask questions
and to withdraw at any time from the research without
consequences.
An explanation of what will happen with the data or samples at the
end of the research period and if the data/ samples are
retained or sent/sold to a third party for
further research.
Information about what will happen to the results of the research.
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
What is ethics?
•An academic discipline. Ethics is the critical study of the norms
that guide our actions.
•Practical skills. Ethics is the practical art of knowing how to
apply moral principles in concrete situations
•Value systems. Ethics deals with the core valuesthat guide a
person or an organisation on the way to its sharedvision
•
Ethics is the result of our pursuit to systematically reflect on,
analyse, and question the norms and values that guide human
action.
Göran Hermerén, President of the European Group on Ethics
(EGE)
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Principles of European research ethics
•The
•The
•The
•The
principle
principle
principle
principle
of
of
of
of
respect for human dignity
utility
precaution
justice
A moral principle is a general guide of action that provides a
standard of relevance or ”reasonableness”
A moral principle is applied prima facie, i. e. it must be
observed unless it comes in conflict with any other, equally
pertinent, consideration.
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
How do you strengthen the ethical perspective?
Conditions:
•The initiative must include all partners and all individual
researchers participating in research
•Ethical questions that arise must be addressed with
transparency
•The initiative must reflectthe genuine desire to foster best
ethical practices (no windowdressing)
•Recourse to independent expert advice in ethics maybe
necessary
•Need for periodical review within the management structure of
how ethical issues are dealt with
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Before submission of proposal
•Identification by all partners of actual and potential ethical
issues in the research program
•Preliminary reflection on how these will be addressed in the
proposal
•Formulation of a policy outlining how ethical issues will be
dealt with overall and within each individual workpackages
During funding period
•Implementation of the ethical policy
•Continual feedback from parties about ethical issues
•Periodic review of ethical strategy in view of feedback
•Formulation of updated ethical policy as need be
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
The European Consensus Platform for 3R Alternatives
to Animal Experimentation, ecopa, is a non-profit
association that was formally created in 2002
according to the Belgian law. It is an umbrella
organization which presently includes 13 National
Consensus Platforms (NCPs), one of which is
DACOPA.
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
The concept of consensus between the parties
concerned, i.e. animal welfare, industry, academia
and governmental institutions has been accepted in
various countries as an efficient way to stimulate
research into alternatives to animal experiments and
enforce the acceptance of alternatives in
experimental practice.
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Implementaton of the new EU Directive 2010/63/EU
On the protection of animals used for scientific purposes:
Opportunities for the 3Rs
Berlin. January 31-February 2, 2011
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
National consensus platforms composing ecopa are
defined as platforms comprising the four concerned
parties in the field of alternative methods (3-R-methods)
to animal experiments, i.e. academia, animal welfare,
industry and government.
ecopa will organise conferences, seminars, publish
documents, collect and circulate information, support
scientific and educational initiatives, and promote the
implementation of co-operative action in the fulfilment
of its purposes.
ecopa may participate or become a Member of other
institutions, organisations or European or International
Networks whose aims are in accordance with Article 4 of
these Statutes.
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
http://www.eu-hbm.info/cophes
FP7 funded by the
DEMOCOPHES
European Commission
Provides framework
Provides guidance
Analyses results on a
EU level
Recommendations &
Conclusions
Life+, funded by
European Commission
and Member States
children and their
mothers
at least 3600 study
subjects
cadmium, phthalates,
cotinine in urine
mercury in hair
(bisphenol A in urine)
Harmonised approach for HBM in Europe
30
Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen
Acknowledgements
University of Copenhagen
Jeanette KS Nielsen
Marie S. Poulsen
Line Mathiesen
Janne Fangel Jensen
Thit Aarøe Mørck
Marie Pedersen (CREAL, Barcelona)
Marie Frederiksen (Hørsholm)
NewGeneris
Jos Kleinjans et al
Mischeline Kirch-Volders et
al
Kirsi Vähänkangas et al
Päivi Myllynen et al
Harrie Besselink et al
Margareta Törnquist et al
NanoTEST
Maria Dusinska et al
Margaret Saunders et
al
Danish National Environmental Insti
Katrin Vorkamp
Marianne Thomsen
Århus University
Herman Autrup et al
Evas Bonefeld Jørgensen
University Hospital Copenhagen
Morten Hedegård
Morten Dziengiel
Leif Kofoed
Lisa Maroun
Lise Grupe