Ethics should be considered when planning your next research activity

1. 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

2. 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)

3. 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

4. Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen

5. 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.

6. 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.

7. 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 side-effects, 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.

8. Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen

9. Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen

10. Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen

11. Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen Nanoparticles Size range 1-100 nm Man made Combustion engines Power plants Airplane jets Metal fumes Shapes Naturally occuring Spheres Fibers Tubes Materials Volcanoes Forest fires Virusses Ferritin Metal oxides Liposomes Polymers Carbon Nanomedicine Nanotechnology Medical imaging Drug delivery Cancer therapy Electronics Fabrics Coatings Paintings

12. 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

13. 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.

14. Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen biomarkers of risk Biomarkers in environmental/food healthresearch Environmental/food concentration (external dose) dose-response relationship toxic effects early biological effects internal dose biologically significant dose alterations in structure/ function biomarkers of exposure 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)

15. 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

16. Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen • Ethics check list • Informed Consent • Does the proposal involve children? • Does the proposal involve patients or persons not able to give consent? • Does the proposal involve adult healthy volunteers? • Does the proposal involve Human Genetic Material? • Does the proposal involve Human biological samples? • Does the proposal involve 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?

17. 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

18. Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen • http://cordis.europa.eu/fp7/ethics_en.html#ethics_cl

19. 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

20. 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.

21. 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.

22. 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)

23. Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen Principles of European research ethics • •The principle of respect for human dignity • •The principle of utility • •The principle of precaution • •The principle of 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.

24. 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

25. 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

26. 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.

27. 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.

28. 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

29. 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.

30. Industrial technologies Århus Ethics 19 June 2012 Lisbeth E. Knudsen http://www.eu-hbm.info/cophes • 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) • FP7 funded by the • European Commission • Provides framework • Provides guidance • Analyses results on a EU level • Recommendations & Conclusions DEMOCOPHES Harmonised approach for HBM in Europe 30

31. 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) Danish National Environmental Institute Katrin Vorkamp Marianne Thomsen Århus University Herman Autrup et al Evas Bonefeld Jørgensen 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 University Hospital Copenhagen Morten Hedegård Morten Dziengiel Leif Kofoed Lisa Maroun Lise Grupe NanoTEST Maria Dusinska et al Margaret Saunders et al