1. International Conference on Human Rights and Biomedicine Rotterdam, The Netherlands, 10-12 December 2008 Clinical Trials Different types of medical research – appropriate regulations Prof. Elmar Doppelfeld MD Chairman of the Permanent Working Party of Research Ethics Committees in Germany Chair (2005 – 2007) of the „Steering Committee on Bioethics (CDBI)“ of the Council of Europe

2. E. Doppelfeld, Rotterdam, 10-12 December 2008 2 Motivation for Medical Research All men by their nature aim at knowledge All men by their nature aim at knowledge (Aristotle,metaphysics) “….The physician must take care that curable diseases do not become incurable. He must know how to prevent incurability of diseases. He must be experienced in incurable diseases to avoid any useless treatment”. (Hippocrates, de articulis reponendis 58) “Today’s research is tomorrow’s healthcare”  Medical research is stimulated by the wish to enhance knowledge -“curiosité”- and by the aim to improve healthcare - “salus aegroti”

3. E. Doppelfeld, Rotterdam, 10-12 December 2008 3 Experimentation - Clinical Research Experimentation involving human beings - Intention: improvement of knowledge - Benefit: science? better healthcare? Clinical research Clinical research - Intention: treatment and improvement of knowledge - Benefit: patient? science?

4. E. Doppelfeld, Rotterdam, 10-12 December 2008 4 Dilemma of Research on Man Medical research involving human beings is necessary to gain proven clinical experience Medical research involving human beings entails risks for the patient/healthy participant Unproven treatment entails risks for the patient

5. E. Doppelfeld, Rotterdam, 10-12 December 2008 5 Ethical Dilemma of Research on Man “The ethical aporia: it is unethical to use a treatment with unproven safety and efficacy; it is unethical as well to expose human beings to unknown risks for proving the efficacy of treatment” ( Richard Toellner ) “The ethical aporia: it is unethical to use a treatment with unproven safety and efficacy; it is unethical as well to expose human beings to unknown risks for proving the efficacy of treatment” ( Richard Toellner )

6. E. Doppelfeld, Rotterdam, 10-12 December 2008 6 Definition of Medical Research Definition of Medical Research „ to obtain, independently from an individual case, “ „Research on man is every activity involving a risk for the somatic or psychological integrity of the participant, which is undertaken with the aim to obtain, independently from an individual case, general knowledge in the fields of prevention, diagnosis, treatment or pathophysiology “ (Permanent Working Party of Research Ethics Committees in Germany) (Permanent Working Party of Research Ethics Committees in Germany)

7. E. Doppelfeld, Rotterdam, 10-12 December 2008 7 Medical Research Basic research - e.g. anatomy, biochemistry, physiology Observational research - e.g. medical epidemiology Interventional research - with physical interventions: e.g. surgery, internal medicine - without physical interventions: e.g. preventive trials to change „life style“ of a population or group of population Research on biological materials of human origin and related data

8. E. Doppelfeld, Rotterdam, 10-12 December 2008 8 „Clinical Trial“ Classifying trials by their purpose. * - - Prevention trials - - Screening trials - - Diagnostic trials - - Treatment trials - - Quality of life trials - - (Compassionate use trials) *(National Institute of Health) *(National Institute of Health)

9. E. Doppelfeld, Rotterdam, 10-12 December 2008 9 Variety of Regulations

10. E. Doppelfeld, Rotterdam, 10-12 December 2008 10 Council of Europe Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine Oviedo, 4.IV.1997, ETS No. 164 Additional Protocol to the Convention on Human Rights and Biomedicine concerning Biomedical Research Strasbourg, 25.I.2005, CETS No. 195 Recommendation Rec(2006)4 of the Committee of Ministers to member states on research on biological materials of human origin (Adopted by the Committee of Ministers on 15 March 2006 at the 958th meeting of the Ministers' Deputies)

11. E. Doppelfeld, Rotterdam, 10-12 December 2008 11 Qualification and Quality Qualification of researcher „duly qualified“ „duly qualified“ - physician – specialized or not or to what extent specialized? reaction to contingencies or adverse events? duty of care? - other researchers: e.g. psychology, biochemistry, biophysics Quality of the research project - scientific quality - accordance with national law - ethical acceptability  Which body decides? - Research Ethics Committee? Authority? Both of them?

12. E. Doppelfeld, Rotterdam, 10-12 December 2008 12 Relationship Researcher/Participant Caring physician as researcher – patient - duty of care, improvement of treatment - interest on results of the research project - personal relationship as factor of influence? Physician as researcher – participant - interest on results of the research project - little or no relationship to the participant Non-medical researcher: mainly results!  participant involved as “object”

13. E. Doppelfeld, Rotterdam, 10-12 December 2008 13 Research Participant „free informed consent“ - „ free“: no undue influence, no vulnerability - „informed“: all relevant information before starting a project including information on foreseen or foreseeable further use of the results - consent to a specific project or to projects in the future  Participant able to consent  Participant not able to consent: authorization by a legal representative; assent of the represented person

14. E. Doppelfeld, Rotterdam, 10-12 December 2008 14 Specific or open Consent Specific consent - Physical intervention, e.g. surgical research, drug research, catherization, removal of tissue - Without physical intervention: e.g. research using questionnaires Open consent - On the base of appropriate information: further use of stored biological material, with or without a specific scope, new contact or not, safeguarding provisions for further scientific use by independent examination (REC) and/or approval (competent body) - Anonymization of tissue related data, restrictions?

15. E. Doppelfeld, Rotterdam, 10-12 December 2008 15 Risk and Benefit Medical Care - Risk and benefit are known by statistical analyses of treatment results using a specific method - In individual cases deviations from the statistical values! Medical Research - Risk and benefit are not known - Potential direct benefit or or - No benefit for the participant - Risk may be assessed on the experience with the research methods obtained in similar or other applications

16. E. Doppelfeld, Rotterdam, 10-12 December 2008 16 Proportion of Risk and Benefit Minimising of risk and burden for research participants! The lower the probability of benefit, the lower the acceptable risk! No potential direct benefit (healthy volunteers) - only acceptable risk and acceptable burden for the participant Potential direct benefit - risk and burden must not be disproportinate to the potential direct benefit for the involved person

17. E. Doppelfeld, Rotterdam, 10-12 December 2008 17 Research on Persons not able to consent All conditions for research must be fulfilled! In addition: - Justification for research on this specific group, „no alternative of comparable effectiveness“ - Authorization by the legal representative - Information and participation in the authorization procedure of the represented person to the extent of his or her understanding - Research for the potential direct benefit - Exceptionally research without potential direct benefit: protective provisions prescribed by law, only minimal risk and minimal burden! Research on biological material - Authorization by the legal representative

18. E. Doppelfeld, Rotterdam, 10-12 December 2008 18 Specific Situations (I) Research during pregnancy and breastfeeding - Benefit for other women in relation to reproduction, for other embryos, foetuses or children - Avoiding any adverse impact on the health of a breast fed child Research on persons deprived of liberty - Permission by law - Benefit to persons deprived of liberty  Conditions for both situations - Justification for research on this specific group, „no alternative of comparable effectiveness“ - Minimal risk and minimal burden

19. E. Doppelfeld, Rotterdam, 10-12 December 2008 19 Specific Situations (II) Research on persons in emergency clinical situations - Legal regulation - Person concerned not able to consent - Because of urgency of the situation authorization not possible - Research of comparable effectiveness cannot be carried out on persons in non-emergency situations - Approval of the project specifically for emergency research by the competent body - No potential direct benefit for the person concerned: minimal risk and minimal burden - Information of the person concerned or of the legal representative as soon as possible - Free informed consent or authorization as soon as possible

20. E. Doppelfeld, Rotterdam, 10-12 December 2008 20 Examination and Approval Every research project shall be submitted for independent examination of its ethical acceptability to an ethics committee Research may only be undertaken if the research project has been approved by the competent body after independent examination of its scientific merit, including assessment of the importance of the aim of research, and multidisciplinary review of its ethical acceptability Research may only be undertaken if the research project has been approved by the competent body after independent examination of its scientific merit, including assessment of the importance of the aim of research, and multidisciplinary review of its ethical acceptability  Ethical examination before approval!