Medical research and clinical trials

1. Medical research and clinical trials Lukáš Prudil Masaryk University Brno, Czech Republic

2. Medical research milestones • 1750: Voltaire states: "The art of medicine consists of amusing the patient while nature cures the disease." • 1759: Francis Home of Scotland tests measles “vaccine” (blood from a measles patient) in 12 children. • 1767: English court rules in Slater v. Baker & Stapleton that informed consent is required prior to experimental medical treatment. Baker and Stapleton set and then rebroke Slater’s fractured but healing leg to test a new device. • 1767: Prior to inoculating all the children at the Foundling Hospital in London, England for smallpox, Dr. William Watson conducts a vaccination trial with three groups of 10 children each. Two of the groups receive pre-and post-treatments; one does not. • 1784: Under appointment by Louis XVI of France, a commission led by Benjamin Franklin conducts placebo-controlled and single-blinded (literally, by blindfolding the subjects) studies of the use of magnetism to treat various ailments. • 1796: Edward Jenner of England demonstrates that cowpox vaccination protects against smallpox by vaccinating and then exposing 12-year-old James Phipps to someone with smallpox.

3. 1800: Benjamin Waterhouse, one of three full-time professors at Harvard Medical School, successfully tests Edward Jenner’s cowpox vaccine on his son, then on six members of his household, and then on 19 children in a Boston hospital. He then creates a commercial monopoly on the vaccine in the United States. Partially as a result, he is expelled from the Harvard faculty in 1812. • 1803: Thomas Percival of England publishes “Code of Ethics”, advising physicians to consult with colleagues before trying new remedies and treatments. Percival separately advises physicians not to inform the patient if the information would adversely affect the patient, the patient’s family, or the community. • 1809: Scottish physician Alexander Lesassier Hamilton and two other army physicians conduct a clinical trial in which 366 sequentially-admitted sick soldiers are assigned in rotation to three physicians. One physician uses bloodletting; the other two do not. Mortality rate is 29% with bloodletting and 2% without. • 1830: English physician J.W. Willcock writes: “When an experiment is performed with the consent of the party subjected to it after he has been informed that it is an experiment, the practitioner is answerable neither in damages nor on an original proceeding. But if the practitioner performs his experiment without giving such information and obtaining consent he is liable to compensate in damages any injury.”

4. 1831: Physician Herrmann compared homeopathic, allopathic and placebo treatments in three wards in the Regional Military Hospital in St.Petersburg, Russia, finding that the placebo ward yielded the best results. • 1832: "Placebo" takes on its current meaning of a treatment that has no medical value except psychologically. • 1833: Physician William Beaumont publishes research ethical guidelines, including voluntary consent and right to withdraw. • 1847: American Medical Association adopts a code of ethics, including the “sacred duty” to avoid disclosures that would discourage or depress the patient. • 1865: In “An Introduction to the Study of Human Experimentation”French physiologist Claude Bernard states "Never perform an experiment that might be harmful to the patient even though highly advantageous to science or the health of others.” • 1871: Court rules in Carpenter v. Blake that the physician must fully inform the patient before departing from standard medical practice.

5. 1877: American Humane Association is founded to protect animals and, later, children. • 1880: German physician Gerhard Armauer Hansen, co-discoverer of the leprosy bacillus, loses his license to practice medicine after deliberately infecting the eye of a patient with leprosy bacilli. • 1884: Possibly after successful experiments with dogs, Louis Pasteur first tests an antidote to rabies on an infected child, Joseph Meister, but only after pleadings from the child’s mother and consultations with two medical colleagues, who advise him that the child’s death is inevitable without treatment. Meister later becomes a guard at the Institut Pasteur in Paris, and is shot defending Pasteur’s laboratory in World War II. • 1900: “Instructions of the Prussian Minister of Culture to the Directors of Clinics, Polyclinics, and Other Health Care Institutions” Prussia prohibits medical interventions for other than therapeutic purposes without informing the subject of potential adverse consequences and obtaining consent.

6. 1900: Walter Reed uses written consent form (in English and Spanish) in a study of yellow fever transmission at Camp Lazear in Cuba; stipend is $100 plus an additional $100 if the subject is infected by the experiment. • 1902: Albert Moll’s book, “Medical Ethics”, recommends that advisory boards of physicians, lawyers and other learned men consider the ethical aspects of planned human experiments. • 1906: Richard Pearson Strong, head of the Philippine Biological Laboratory, inoculates 24 inmates of Manila's Bilibid Prison with an experimental cholera vaccine contaminated with plague bacilli, resulting in 13 deaths. • 1914: Mary Schloendorff, a patient at New York Hospital, consents to an examination under ether of a fibroid tumor, but prohibits the doctor from performing an operation. Once the patient is unconscious from the ether, the doctor removes the tumor, and the patient later develops gangrene, requiring the amputation of several fingers. In the case of Schloendorff v. Society of New York Hospital, future Supreme Court Justice Benjamin Cardozo writes “Every human being of adult years and sound mind has a right to determine what shall be done with his own body; and a surgeon who performs an operation without his patient's consent commits an assault, for which he is liable in damages.”

7. 1930: Pharmacologist ToraldSollman writes, "Apparent results must be checked by the 'blind test,' i.e., another remedy or a placebo, without the knowledge of the observer, if possible." • 1931: “Circular of the Minister of the Interior of the German Reich Concerning Guidelines for Innovative Therapy and Human Experimentation” differentiates between therapeutic research, primarily intended to benefit the patient, and non-therapeutic research, primarily intended to advance knowledge. • 1931: After 72 of 251 infants vaccinated in 1929-1930 in Lubeck, Germany for tuberculosis die because the vaccine was accidently prepared with virulent bacteria, the German government enacts “Regulation on New Therapy and Experimentation”, requiring human experiments to be preceded by animal experiments. • 1931: Great Britain’s Medical Research Council establishes Therapeutic Trials Committee “to consider applications by commercial firms for the examination of new products, submitted with the available experimental evidence of their value, and appropriate clinical trials will be arranged in suitable cases.”

8. 1946: American Medical Association adopts code of ethics for research on human subjects that requires informed consent. • 1946: Nuremberg Code, the first internationally-recognized code of ethics for human research, requires voluntary and informed consent, minimizing risks to subjects, and results that are valuable to society. • 1948: United Nations General Assembly adopts Universal Declaration of Human Rights, including the right to “security of person.” • 1948: World Medical Association updates and clarifies Hippocratic Oath in Declaration of Geneva. • 1964: World Medical Association’s “Declaration of Helsinki” requires informed consent. In contrast to the legal form of the Nuremburg Code, it takes the form of ethical guidelines. • http://firstclinical.com/milestones/?page=10&date=All&anchor=word

9. A survey conducted for the European Commission by Eurobarometer confirms that there is a strong interest in most European countries, particularly in the old EU member states, in health research as well as in science and technology. The interest is even higher than in international news and economic and social affairs. Europeans are especially paying attention to the added value that health and medical research can bring to their daily lives. The survey indicates also that citizens trust the scientific and medical professions above all others when it comes to information on science or health research, and that international institutions – including the European Union itself – are significantly more trusted than regional or national governmental sources. • For additional information on the survey and to access the report: http://ec.europa.eu/public_opinion/index_en.htm

10. Legal framework • World Medical Association • Declaration of Helsinki (revised) • Council of Europe • Convention on Human Rights and Biomedicine • Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research • European Union • Directive 2001/20/EC of the European Parliament and of the Council on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use

11. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects • The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical principles for medical research involving human subjects, includingresearch on identifiable human material and data. • Although the Declaration is addressed primarily to physicians, the WMA encourages other participants in medical research involving human subjects to adopt these principles. • E.g. other health care professionals, work experiments, academic research

12. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects • In medical research involving human subjects, the well-being of the individual research subject must take precedence over all other interests. •  Medical research is subject to ethical standards that promote respect for all human subjects and protect their health and rights. Some research populations are particularly vulnerable and need special protection. These include those who cannot give or refuse consent for themselves and those who may be vulnerable to coercion or undue influence.

13. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects - PRINCIPLES FOR ALL MEDICAL RESEARCH • It is the duty of physicians who participate in medical research to protect the life, health, dignity, integrity, right to self-determination, privacy, and confidentiality of personal information of research subjects. • Moral damages claims – breaching dignity, privacy and/or confidentiality(broad variety – not properly informed, breaching of confidentiality, broader scope of research etc.) • Bodily harm claims • E.g. behavioral experiments, sociological, psychological experiments

14. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects - PRINCIPLES FOR ALL MEDICAL RESEARCH • Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for research must be respected.

16. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects - PRINCIPLES FOR ALL MEDICAL RESEARCH • The design and performance of each research study involving human subjects must be clearly described in a research protocol. The protocol should contain a statement of the ethical considerations involved and should indicate how the principles in this Declaration have been addressed. The protocol should include information regarding funding, sponsors, institutional affiliations, other potential conflicts of interest, incentives for subjects and provisions for treating and/or compensating subjects who are harmed as a consequence of participation in the research study. The protocol should describe arrangements for post-study access by study subjects to interventions identified as beneficial in the study or access to other appropriate care or benefits. • Conflicts of interests – studies sponsored by pharmaceutical companies

17. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects - PRINCIPLES FOR ALL MEDICAL RESEARCH • The research protocol must be submitted for consideration, comment, guidance and approval to a research ethics committee before the study begins. This committee must be independent of the researcher, the sponsor and any other undue influence. It must take into consideration the laws and regulations of the country or countries in which the research is to be performed as well as applicable international norms and standards but these must not be allowed to reduce or eliminate any of the protections for research subjects set forth in this Declaration. The committee must have the right to monitor ongoing studies. The researcher must provide monitoring information to the committee, especially information about any serious adverse events. No change to the protocol may be made without consideration and approval by the committee. • Independence of the committees - often established by research institution, their independence is thus disputable • Knowledge of members of ethics committees • Real monitoring of ongoing studies – sometimes only formal

18. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects - PRINCIPLES FOR ALL MEDICAL RESEARCH • The responsibility for the protection of research subjects must always rest with the physician or other health care professional and never the research subjects, even though they have given consent.

19. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects - PRINCIPLES FOR ALL MEDICAL RESEARCH • Medical research involving a disadvantaged or vulnerable population or community is only justified if the research is responsive to the health needs and priorities of this population or community and if there is a reasonable likelihood that this population or community stands to benefit from the results of the research.

20. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects - PRINCIPLES FOR ALL MEDICAL RESEARCH • Every medical research study involving human subjects must be preceded by careful assessment of predictable risks and burdens to the individuals and communities involved in the research in comparison with foreseeable benefits to them and to other individuals or communities affected by the condition under investigation. • „Experiment for experiment“ – no foreseeable benefit to anyone, except researcher • Physicians may not participate in a research study involving human subjects unless they are confident that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians must immediately stop a study when the risks are found to outweigh the potential benefits or when there is conclusive proof of positive and beneficial results.

21. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects - PRINCIPLES FOR ALL MEDICAL RESEARCH • Participation by competent individuals as subjects in medical research must be voluntary. Although it may be appropriate to consult family members or community leaders, no competent individual may be enrolled in a research study unless he or she freely agrees. • No coercion (physical or psychological (e.g. gratitude)) • In medical research involving competent human subjects, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail, and any other relevant aspects of the study. The potential subject must be informed of the right to refuse to participate in the study or to withdraw consent to participate at any time without reprisal. Special attention should be given to the specific information needs of individual potential subjects as well as to the methods used to deliver the information. After ensuring that the potential subject has understood the information, the physician or another appropriately qualified individual must then seek the potential subject's freely-given informed consent, preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be formally documented and witnessed. • Information must be given in understandable way • Not only formal procedure, but real information must be given in appropriate way

22. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects - PRINCIPLES FOR ALL MEDICAL RESEARCH • When seeking informed consent for participation in a research study the physician should be particularly cautious if the potential subject is in a dependent relationship with the physician or may consent under duress. In such situations the informed consent should be sought by an appropriately qualified individual who is completely independent of this relationship. • For a potential research subject who is incompetent, the physician must seek informed consent from the legally authorized representative. These individuals must not be included in a research study that has no likelihood of benefit for them unless it is intended to promote the health of the population represented by the potential subject, the research cannot instead be performed with competent persons, and the research entails only minimal risk and minimal burden. • Conflict of interests of legally authorized representative.

23. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects - PRINCIPLES FOR ALL MEDICAL RESEARCH • When a potential research subject who is deemed incompetent is able to give assent to decisions about participation in research, the physician must seek that assent in addition to the consent of the legally authorized representative. The potential subject's dissent should be respected. • Research involving subjects who are physically or mentally incapable of giving consent, for example, unconscious patients, may be done only if the physical or mental condition that prevents giving informed consent is a necessary characteristic of the research population. In such circumstances the physician should seek informed consent from the legally authorized representative. If no such representative is available and if the research cannot be delayed, the study may proceed without informed consent provided that the specific reasons for involving subjects with a condition that renders them unable to give informed consent have been stated in the research protocol and the study has been approved by a research ethics committee. Consent to remain in the research should be obtained as soon as possible from the subject or a legally authorized representative.

25. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects - PRINCIPLES FOR ALL MEDICAL RESEARCH • Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their personal information and to minimize the impact of the study on their physical, mental and social integrity. • Databases • Public disclosure • Disclosure to insurance companies • Disclosure to employers • Disclosure to family members

26. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects - PRINCIPLES FOR ALL MEDICAL RESEARCH • For medical research using identifiable human material or data, physicians must normally seek consent for the collection, analysis, storage and/or reuse. There may be situations where consent would be impossible or impractical to obtain for such research or would pose a threat to the validity of the research. In such situations the research may be done only after consideration and approval of a research ethics committee.

27. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects - PRINCIPLES FOR ALL MEDICAL RESEARCH • Authors, editors and publishers all have ethical obligations with regard to the publication of the results of research. Authors have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports. They should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results should be published or otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of interest should be declared in the publication. Reports of research not in accordance with the principles of this Declaration should not be accepted for publication.

28. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects - ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE • The physician may combine medical research with medical care only to the extent that the research is justified by its potential preventive, diagnostic or therapeutic value and if the physician has good reason to believe that participation in the research study will not adversely affect the health of the patients who serve as research subjects. • The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention, except in the following circumstances: • The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists; or • Where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm. Extreme care must be taken to avoid abuse of this option. • E.g. psychiatric studies

29. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects - ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE • At the conclusion of the study, patients entered into the study are entitled to be informed about the outcome of the study and to share any benefits that result from it, for example, access to interventions identified as beneficial in the study or to other appropriate care or benefits. • Access to new pharmaceuticals (experiment in one country but pharmaceuticals are distributed in different countries)

30. Oviedo Convention • The interests and welfare of the human being shall prevail over the sole interest of society or science. • Any intervention in the health field, including research, must be carried out in accordance with relevant professional obligations and standards. • Standards may vary from country to country; especially in the EU it cannot be easily said that standard of one EU country is not applicable in other EU country.

31. Oviedo Convention • An intervention in the health field may only be carried out after the person concerned has given free and informed consent to it. • This person shall beforehand be given appropriate information as to the purpose and nature of the intervention as well as on its consequences and risks. • The person concerned may freely withdraw consent at any time.

32. Oviedo Convention • Scientific research in the field of biology and medicine shall be carried out freely, subject to the provisions of this Convention and the other legal provisions ensuring the protection of the human being.

33. Oviedo Convention • Protection of persons undergoing research • Research on a person may only be undertaken if all the following conditions are met: • 1) there is no alternative of comparable effectiveness to research on humans; • 2) the risks which may be incurred by that person are not disproportionate to the potential benefits of the research; • 3) 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 the research, and multidisciplinary review of its ethical acceptability, • 4) the persons undergoing research have been informed of their rights and the safeguards prescribed by law for their protection; • 5) the necessary consent as provided for under Article 5 has been given expressly, specifically and is documented. Such consent may be freely withdrawn at any time. • Informing not only about the purpose of the research, but also about rights and safeguards.

34. Case of Hristozov and others v. Bulgaria (app. 47039/11 and 358/12) • The applicants complained under Article 2 § 1 of the Conventionthat under Bulgarian law individuals who were terminally ill and who hadunsuccessfully exhausted all conventional methods of treatment could notexceptionally be allowed to use unauthorised medicinal products. Theyfurther complained that the authorities’ response to their requests to obtainsuch permission had been both incoherent and slow, arguing that this hadbeen due to the lack of clear rules in that domain. • The applicants also complained under Article 3 of the Conventionthat by denying them access to the experimental medicinal product that theywished to use the authorities had subjected them to inhuman and degradingtreatment. • Lastly, they complained under Article 8 of the Convention that theauthorities’ refusal to allow them to use the product had been an unjustifiedinterference with their right to respect for their private and family life.

35. Case of Hristozov and others v. Bulgaria (app. 47039/11 and 358/12) • TheCourt is therefore not called upon in the presentcase to pass judgment on the system of rules governing access tounauthorised medicinal products in Bulgaria, or to decide whether refusal ofaccess to medicinal products is in principle compatible with the Convention.Moreover, the Court is not competent to express an opinion as to thesuitability of a particular medical treatment. Lastly, the Court does not haveto establish whether the product that the applicants wished to use met therequirements of European Union law.

36. Case of Hristozov and others v. Bulgaria (app. 47039/11 and 358/12) • The applicants rather claim that the refusal by the authorities toallow them access to an experimental product which, according to them,was potentially life-saving, amounted to inhuman and degrading treatmentfor which the State was responsible, as it thereby failed to protect them fromthe suffering resulting from the final stages of their illness. However, as inPretty (cited above, § 54), the Court considers that this claim puts anextended construction on the concept of inhuman or degrading treatmentthat it cannot accept. It cannot be said that by refusing the applicants accessto a product – even if potentially life-saving – whose safety and efficacy arestill in doubt, the authorities directly added to the applicants’ physicalsuffering.

37. The countervailing public interest in regulating the access ofterminally ill patients such as the applicants to experimental productsappears to be based on three premises. Firstly, to protect them, in view oftheir vulnerable state and the lack of clear data on the potential risks andbenefits of experimental treatments, against a course of action which mayprove harmful to their own health and life, their terminal conditionnotwithstanding (see, mutatis mutandis, Haas, cited above, § 54). The Courtnotes in this connection that it has emphasised, albeit in a different context,the importance of informed consent to medical procedures (see V.C.v. Slovakia, no. 18968/07, §§ 107-17 and 152, ECHR 2011-... (extracts),and N.B. v. Slovakia, no. 29518/10, §§ 76-78 and 96, 12 June 2012).Secondly, to ensure that the prohibition laid down in section 7(1) of theMedicinal Products in Human Medicine Act 2007 (see paragraph 22 above)against the production, importation, trade in, advertisement, or use formedical treatment, prophylaxis or diagnostics of products which have notbeen granted authorisation under the appropriate regulatory channels is notdiluted or circumvented. Thirdly, to ensure that the development of newmedicinal products is not compromised by, for instance, diminished patientparticipation in clinical trials.

38. Oviedo Convention • Protection of persons not able to consent to research • Research on a person without the capacity to consent as stipulated in Article 5 may be undertaken only if all the following conditions are met: • 1) the conditions laid down in Article 16, sub-paragraphs i to iv, are fulfilled; • 2) the results of the research have the potential to produce real and direct benefit to his or her health; • 3) research of comparable effectiveness cannot be carried out on individuals capable of giving consent; • 4) the necessary authorisation provided for under Article 6 has been given specifically and in writing; and • 5) the person concerned does not object. • How can the person object?

39. Oviedo Convention • Protection of persons not able to consent to research • Exceptionally and under the protective conditions prescribed by law, where the research has not the potential to produce results of direct benefit to the health of the person concerned, such research may be authorised subject to the conditions laid down in paragraph 1, sub-paragraphs i, iii, iv and v above, and to the following additional conditions: • 1) the research has the aim of contributing, through significant improvement in the scientific understanding of the individual's condition, disease or disorder, to the ultimate attainment of results capable of conferring benefit to the person concerned or to other persons in the same age category or afflicted with the same disease or disorder or having the same condition; • 2) the research entails only minimal risk and minimal burden for the individual concerned.

40. Oviedo Convention • Research on embryos in vitro • Where the law allows research on embryos in vitro, it shall ensure adequate protection of the embryo. • The creation of human embryos for research purposes is prohibited. • Legal status of embryos. • It is left on domestic legal regulation. • Usage and production of so-called spare embryos.

41. Additional Protocol to the Oviedo Convention • Scope • 1This Protocol covers the full range of research activities in the health field involving interventions on human beings. • 2This Protocol does not apply to research on embryos in vitro. It does apply to research on foetuses and embryos in vivo. • 3For the purposes of this Protocol, the term “intervention” includes: ia physical intervention, and iiany other intervention in so far as it involves a risk to the psychological health of the person concerned.

42. Additional Protocol to the Oviedo Convention • General conditions • Primacy of the human being • Free research ensuring the protection of human being • Absence of alternatives • Risks and benefits • Research shall not involve risks and burdens to the human being disproportionate to its potential benefits. • In addition, where the research does not have the potential to produce results of direct benefit to the health of the research participant, such research may only be undertaken if the research entails no more than acceptable risk and acceptable burden for the research participant. This shall be without prejudice to the provision contained in Article 15 paragraph 2, sub-paragraph ii for the protection of persons not able to consent to research. • Approval • 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. • Scientific quality • Any research must be scientifically justified, meet generally accepted criteria of scientific quality and be carried out in accordance with relevant professional obligations and standards under the supervision of an appropriately qualified researcher.

43. Additional Protocol to the Oviedo Convention • Ethics committee • Independent examination by an ethics committee • Every research project shall be submitted for independent examination of its ethical acceptability to an ethics committee. Such projects shall be submitted to independent examination in each State in which any research activity is to take place. • The purpose of the multidisciplinary examination of the ethical acceptability of the research project shall be to protect the dignity, rights, safety and well-being of research participants. The assessment of the ethical acceptability shall draw on an appropriate range of expertise and experience adequately reflecting professional and lay views. • The ethics committee shall produce an opinion containing reasons for its conclusion.

44. Additional Protocol to the Oviedo Convention • Independence of the ethics committee • Parties to this Protocol shall take measures to assure the independence of the ethics committee. That body shall not be subject to undue external influences. • Members of the ethics committee shall declare all circumstances that might lead to a conflict of interest. Should such conflicts arise, those involved shall not participate in that review.

45. Additional Protocol to the Oviedo Convention • Information for the ethics committee • All information which is necessary for the ethical assessment of the research project shall be given in written form to the ethics committee. • In particular, information on items contained in the appendix to this Protocol shall be provided, in so far as it is relevant for the research project. • Description of the project • Participants, consent and information • Other information – payments, rewards, insurance

46. Additional Protocol to the Oviedo Convention • Undue influence • The ethics committee must be satisfied that no undue influence, including that of a financial nature, will be exerted on persons to participate in research. In this respect, particular attention must be given to vulnerable or dependent persons.

47. Additional Protocol to the Oviedo Convention • Information for research participants • The persons being asked to participate in a research project shall be given adequate information in a comprehensible form. This information shall be documented. • The information shall cover the purpose, the overall plan and the possible risks and benefits of the research project, and include the opinion of the ethics committee. Before being asked to consent to participate in a research project, the persons concerned shall be specifically informed, according to the nature and purpose of the research: • of the nature, extent and duration of the procedures involved, in particular, details of any burden imposed by the research project; • of available preventive, diagnostic and therapeutic procedures; • of the arrangements for responding to adverse events or the concerns of research participants;of arrangements to ensure respect for private life and ensure the confidentiality of personal data; • of arrangements for access to information relevant to the participant arising from the research and to its overall results; • of the arrangements for fair compensation in the case of damage; • of any foreseen potential further uses, including commercial uses, of the research results, data or biological materials; • of the source of funding of the research project. • In addition, the persons being asked to participate in a research project shall be informed of the rights and safeguards prescribed by law for their protection, and specifically of their right to refuse consent or to withdraw consent at any time without being subject to any form of discrimination, in particular regarding the right to medical care.

48. Additional Protocol to the Oviedo Convention • Research with minimal risk and minimal burden • For the purposes of this Protocol it is deemed that the research bears a minimal risk if, having regard to the nature and scale of the intervention, it is to be expected that it will result, at the most, in a very slight and temporary negative impact on the health of the person concerned. • It is deemed that it bears a minimal burden if it is to be expected that the discomfort will be, at the most, temporary and very slight for the person concerned. In assessing the burden for an individual, a person enjoying the special confidence of the person concerned shall assess the burden where appropriate.

49. Additional Protocol to the Oviedo Convention • Research during pregnancy or breastfeeding • Research on a pregnant woman which does not have the potential to produce results of direct benefit to her health, or to that of her embryo, foetus or child after birth, may only be undertaken if the following additional conditions are met: • the research has the aim of contributing to the ultimate attainment of results capable of conferring benefit to other women in relation to reproduction or to other embryos, foetuses or children; • research of comparable effectiveness cannot be carried out on women who are not pregnant; • the research entails only minimal risk and minimal burden. • Where research is undertaken on a breastfeeding woman, particular care shall be taken to avoid any adverse impact on the health of the child.

50. Additional Protocol to the Oviedo Convention • Research on persons in emergency clinical situations • The law shall determine whether, and under which protective additional conditions, research in emergency situations may take place when: • a person is not in a state to give consent, and • because of the urgency of the situation, it is impossible to obtain in a sufficiently timely manner, authorisation from his or her representative or an authority or a person or body which would in the absence of an emergency situation be called upon to give authorisation. • The law shall include the following specific conditions: • research of comparable effectiveness cannot be carried out on persons in non-emergency situations; • the research project may only be undertaken if it has been approved specifically for emergency situations by the competent body; • any relevant previously expressed objections of the person known to the researcher shall be respected; • where the research has not the potential to produce results of direct benefit to the health of the person concerned, it has the aim of contributing, through significant improvement in the scientific understanding of the individual's condition, disease or disorder, to the ultimate attainment of results capable of conferring benefit to the person concerned or to other persons in the same category or afflicted with the same disease or disorder or having the same condition, and entails only minimal risk and minimal burden. • Persons participating in the emergency research project or, if applicable, their representatives shall be provided with all the relevant information concerning their participation in the research project as soon as possible. Consent or authorisation for continued participation shall be requested as soon as reasonably possible.