- Email: [email protected]
Ethical aspects of drug development
Microchemical Journal 136 (2018) 244–246
Contents lists available at ScienceDirect
Microchemical Journal journal homepage: www.elsevier.com/locate/microc
Ethical aspects of drug development Péter Arányi Ethics Committee for Clinical Pharmacology, Medical Research Council, 6-8 AranyJános u., H-1051 Budapest, Hungary
a r t i c l e
i n f o
Article history: Received 8 September 2016 Received in revised form 22 November 2016 Accepted 23 November 2016 Available online 24 November 2016 Keywords: Ethics Clinical Drug Development
a b s t r a c t In order for an active substance to get registration as a drug, preclinical development should be followed by three phases of clinical trials. Clinical phase I recruits healthy volunteers or patients in certain conditions, whereas later phases recruit well defined patient populations. All clinical studies have to be authorized by the competent authority and evaluated by an independent ethics committee. No clinical trial can be initiated in the absence of a supportive opinion from the responsible ethics committee of the country where the study will be conducted. The ‘ethics committee’ is an independent body in a EU member state, consisting of healthcare professionals and non-medical members, whose responsibility it is to protect the rights, safety and wellbeing of human subjects involved in a trial. Each and every protocol should be individually evaluated. All that evaluation is based on the Good Clinical Practice (GCP) and on the World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects. The Declaration is reduced to practical approach by EU regulation and national laws. The Hungarian experience of the Ethics Committee for Clinical Pharmacology, Medical Research Council, is highlighted. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Drug development means getting through a series of phases from preclinical to registration via clinical development, where each step enriches the knowledge of the developer on the properties of the future drug (Fig. 1). Planning and performing those phases and steps represent not only scientific but also ethical problems and issues to avoid. Nonclinical development requires in vitro and in vivo experiments in pharmacokinetics, pharmacodynamics and toxicology, clinical development phases involve human patients and healthy volunteers, sometimes vulnerable subjects. Ethical issues may also arise when the product is already on the market, associated with side effects not recognized during development or with pricing and marketing policy. Understandably, ethical issues related to animal experiments fundamentally differ from those concerning human subjects. This paper describes and discusses ethical questions of clinical development. Specific examples are given from the experience in Hungary.
2. Background and legal framework Directive 2001/20/EC on the conduct of clinical trials on medicinal products for human use [1], which has been implemented in the legal system of the European Member states, set the rules that are applied 15 years later. Its accepted basis is founded in the protection of human rights and the dignity of the human being with regard to the application E-mail address: [email protected].
http://dx.doi.org/10.1016/j.microc.2016.11.015 0026-265X/© 2016 Elsevier B.V. All rights reserved.
of biology and medicine, as reflected in the Helsinki Declaration [2] and corresponds to the principles of ICH GCP [3]. Directive 2001/20/EC is replaced by Regulation No 536/2014 [4] of the European Parliament and of the Council, already in force but it is not applied until the EU portal and the EU database have achieved full functionality. According to the Directive as well as the Regulation authorization of a trial is subject to a favorable opinion given by the Ethics Committee concerned. In Hungary, Law XCV/2005, Decrees 235/2009 and 35/2005 [5–7] determine the legal background of conducting clinical trials. 3. Working principles of ethics committees The Ethics Committee (EC) is an independent body in an EU Member State, consisting of healthcare professionals and non-medical members, whose responsibility is to protect the rights, safety and wellbeing of human subjects involved in a trial. In case of multicenter trials, a single opinion should be given for each member state [1]. ECs are entirely independent of research sponsors, funders and investigators. They work according to the laws of the EU member states. Conflict of interest of the EC members should be declared. Strict rules of confidentiality also apply to them. 3.1. Patient protection The clinical trial subject's protection is safeguarded through risk assessment considering toxicological experiments prior to any clinical
P. Arányi / Microchemical Journal 136 (2018) 244–246
245
Fig. 1. Value chain of drug development. Drug development projects are initiated in the hope of meeting an unmet medical need. That approach ensures the benefit to the society as well as the financial reward for the developer. The development process is organized logically, corresponding also to the requirements of the authorities. The product of the discovery phase is the active principle to develop. Discovery and preclinical development raise questions of animal ethics. The three phases of clinical development requires human ethics considerations all along the value chain. This part is discussed in the paper in detail. Ethical issues may emerge later on, too, when the drug product is already on the market. However those aspects will not be addressed here.
trial, results of previous clinical trials, screening by ethics committees and competent authorities and rules on the protection of personal data. The Ethics Committee should consider the relevance of the clinical trial and the trial design; whether the evaluation of the anticipated benefits and risks is satisfactory, suitability of the investigator and supporting staff, quality of the facilities, adequacy and completeness of the written information to be given to participants. Analyzing the protocol, attention should be paid to the indication, inclusion/exclusion criteria, endpoints (i.e. outcome of the treatment), reference treatment. Recruitment and post-trial treatment options of the patients should also be considered. 3.2. Involvement of vulnerable population Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Children and adolescent persons, incapacitated persons, persons suffering from mental illnesses, pregnant or breastfeeding women, members of the army and prisoners are generally considered as vulnerable people. Medical research with a vulnerable group is only justified if the research is responsive to the health needs or priorities of this group and the research cannot be carried out in a nonvulnerable group. In addition, this group should stand to benefit from the knowledge, practices or interventions that result from the research. 4. Hungarian practice Ethical principles governing the activities of KFEB are collected and described in [8] in Hungarian. Details related to our everyday practice and adviceto applicants are available on our homepage [9]. 4.1. Single (central) ethics committee for clinical pharmacology All clinical trials related to drug development should be authorized by the Competent Authority (OGYÉI in Hungary) and should get a favorable opinion from the Ethics Committee for Clinical Pharmacology, Medical Research Council (KFEB), which is the single ethics committee in Hungary entitled to evaluate those protocols. 384 applications were submitted to KFEB in 2015. Those clinical trials were multinational multicenter studies in most cases. Majority of the sponsors have their
headquarters in different European countries and in the USA. Sponsors with decision center in Hungary represent a rather small minority. KFEB has 30 experts and lay members to review those submissions. At least two members give their detailed opinion on each protocol and discuss those with the plenum of the Committee. The Committee's opinion is taken by vote after discussion. Decision is only reached if two thirds of the participants vote the same way. Otherwise the Committee reevaluates the protocol after the sponsor clarified the issues in their response to the deficiency letter. Final decision can be favorable or unfavorable. In our experience unfavorable ethical opinion is given to less than 5% of the submissions. Conclusion is forwarded to OGYÉI. I recall that the competent authority may only authorize a trial if EC opinion is favorable. 4.2. Evaluation of the protocols KFEB determines their opinion on the basis of professional-ethical evaluation of the trial within the legal frame. Protocol should be based on scientifically acceptable assumptions. Suitability of the principal investigators and their team is also evaluated concerning both their medical specialty and knowledge of the principles of GCP. The trial site should be also properly equipped according to the protocol requirements. Special attention is given to the adequacy and completeness of the written information to be given to participants. All patient material should be presented in native language i.e. in Hungarian or in case of a patient whose mother tongue is not the official language of the country, the documents should be translated to a language that is properly understood by the patient. Also, the text should correspond to local requirements, laws, decrees of the country and the requirements generally put forward by the Committee. A patient can only be included in a trial is he/she has signed the informed consent form. Ethical evaluation may go beyond and above the legal requirements. In addition, the members of KFEB believe that they should also consider and foster advancement of medical sciences. 4.3. Cancer trials Cancer trials have been representing the largest fraction of clinical trials since several years. 26% of all trials initiated in Hungary in 2015 had some type of cancer or haematopoetic and lymphoid malignances as indication. Due to the severity of disease, more serious side effects
246
P. Arányi / Microchemical Journal 136 (2018) 244–246
of treatment are acceptable in cancer than in other indications. However healthy volunteers cannot be subjected to such kind of treatment, even for short duration or even to a single dose. Therefore Phase I subjects are in general cancer patients who, in case of apparent improvement of health status, may continue treatment in Phase II later on and benefit from it. Protocols in Phase II or Phase III should be designed in such a way, that both the investigational product and the placebo have to be given “add on” to the standard basic therapy. In case when effective medical therapy for the selected indication is not available, the patients randomized to the placebo arm should receive best supportive care. Hard endpoints such as overall survival or progression free survival should be used by preference in these phases. Some protocols permit inclusion of end stage disease patients with the slogan that participation holds some hope for them. This is not acceptable considering that treatment side effects are usually severe and render the last part of their life full of distress and unnecessary suffering. Our ethics committee claims that one should not “experiment” on end stage disease patients! 4.4. Pediatric trials Several diseases afflict children and adolescent patients. Clinical trials with participation of that age group of patients are therefore warranted. It is only acceptable in case the clinical trial either relates directly to a medical condition from which the minor concerned suffers or is of such a nature that it can only be carried out on minors. This is the case also when a drug or treatment is already approved for adults but not for children or adolescent patients and extension of indication to minors is aimed at. Participation should produce direct benefit for the minor concerned outweighing the risks and burdens involved. The patient's parents or guardians are properly informed and should sign the informed consent form in such cases. The wish of a minor who is capable of forming an opinion or to refuse participation in, or to withdraw from, the clinical trial should be respected. Therefore they should also be informed in a way that is comprehensible for them and their assent should be obtained. The information sheet for minors usually differs in different age groups. No incentives or financial inducements may be given to the minor subject as a compensation for participation. 5. Future perspectives When Regulation No 536/2014 has to be applied, in about a year's time, the rules will substantially change. Evaluation of the protocols is going to take place in two parts: Part I giving detailed information on the investigational product and on the trial arrangements will not be necessarily evaluated by ECs. Each member state decides if it wants their EC to participate in this work. It appears that Hungary will opt
for KFEB participation. Part II, (dealing with recruitment arrangements, subject information, informed consent form and procedure, suitability of the investigator, suitability of the trial site, proof of insurance coverage or indemnification, financial and other arrangements, proof of payment of fee, proof that data will be processed in compliance with union law on data protection) will obligatorily require an opinion from the national EC in order for the competent authority to authorize the trial [4]. Deadlines of decisions are also regulated in detail and, in fact short deadlines require prompt reactions on the submitted documentation from the authorities and ECs as well. This change represents a significant challenge in Hungary as well as in many other member states of EU.
Declaration of interest The author has no conflict of interest to declare.
Acknowledgements The author is grateful for the in depth discussions on many of the points addressed here and for the intellectual encouragement by professors Zsuzsanna Fürst and Ernő Bácsy. References [1] Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 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 useOJ L 121, 1.5.2001 [2] WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI. Ethical Principles for Medical Research Involving Human Subjects, Adopted June 1964, as amended, See http://www.wma.net/en/30publications/10policies/b3/17c.pdf (Last visited 6 September 2016) [3] The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline on Good Clinical Practice, See http://www. ich.org/products/guidelines/efficacy/efficacy-single/article/good-clinical-practice. html (Last visited 6 September 2016) [4] Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC Text with EEA relevanceOJ L 158, 27.5.2014, p. 1–76 [5] 2005 évi XCV. törvényazemberialkalmazásrakerülőgyógyszerekrőlésegyéb, a gyógyszerpiacotszabályozótörvényekmódosításáról. http://mkogy.jogtar.hu/?page= show&docid=a0500095.TV [6] 235/2009. (X.20.)Korm. rendelet az emberen végzett orvostudományi kutatások, az emberi felhasználásra kerülő vizsgálati készítmények klinikaivizsgálata, valamint az emberen történő alkalmazásra szolgáló, klinikai vizsgálatra szánt orvostechnikai eszközök klinikai vizsgálata engedélyezési eljárásának szabályairól. http://net.jogtar. hu/jr/gen/hjegy_doc.cgi?docid=A0900235.KOR [7] 35/2005. (VIII. 26.) EüM rendelet az emberi felhasználásra kerülő vizsgálati készítmények klinikai vizsgálatáról és a helyes klinikai gyakorlat alkalmazásáról http://njt.hu/cgi_bin/njt_doc.cgi?docid=93895.292588 [8] Bioetikaikódex Az orvosbiológiai/klinikaikutatások elveiről és gyakorlatáról, Mandl József, CsalaMiklós eds. (Semmelweiskiadó, Budapest, 2016) [9] http://www.ett.hu/kfeb.htm.
Contents lists available at ScienceDirect
Microchemical Journal journal homepage: www.elsevier.com/locate/microc
Ethical aspects of drug development Péter Arányi Ethics Committee for Clinical Pharmacology, Medical Research Council, 6-8 AranyJános u., H-1051 Budapest, Hungary
a r t i c l e
i n f o
Article history: Received 8 September 2016 Received in revised form 22 November 2016 Accepted 23 November 2016 Available online 24 November 2016 Keywords: Ethics Clinical Drug Development
a b s t r a c t In order for an active substance to get registration as a drug, preclinical development should be followed by three phases of clinical trials. Clinical phase I recruits healthy volunteers or patients in certain conditions, whereas later phases recruit well defined patient populations. All clinical studies have to be authorized by the competent authority and evaluated by an independent ethics committee. No clinical trial can be initiated in the absence of a supportive opinion from the responsible ethics committee of the country where the study will be conducted. The ‘ethics committee’ is an independent body in a EU member state, consisting of healthcare professionals and non-medical members, whose responsibility it is to protect the rights, safety and wellbeing of human subjects involved in a trial. Each and every protocol should be individually evaluated. All that evaluation is based on the Good Clinical Practice (GCP) and on the World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects. The Declaration is reduced to practical approach by EU regulation and national laws. The Hungarian experience of the Ethics Committee for Clinical Pharmacology, Medical Research Council, is highlighted. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Drug development means getting through a series of phases from preclinical to registration via clinical development, where each step enriches the knowledge of the developer on the properties of the future drug (Fig. 1). Planning and performing those phases and steps represent not only scientific but also ethical problems and issues to avoid. Nonclinical development requires in vitro and in vivo experiments in pharmacokinetics, pharmacodynamics and toxicology, clinical development phases involve human patients and healthy volunteers, sometimes vulnerable subjects. Ethical issues may also arise when the product is already on the market, associated with side effects not recognized during development or with pricing and marketing policy. Understandably, ethical issues related to animal experiments fundamentally differ from those concerning human subjects. This paper describes and discusses ethical questions of clinical development. Specific examples are given from the experience in Hungary.
2. Background and legal framework Directive 2001/20/EC on the conduct of clinical trials on medicinal products for human use [1], which has been implemented in the legal system of the European Member states, set the rules that are applied 15 years later. Its accepted basis is founded in the protection of human rights and the dignity of the human being with regard to the application E-mail address: [email protected].
http://dx.doi.org/10.1016/j.microc.2016.11.015 0026-265X/© 2016 Elsevier B.V. All rights reserved.
of biology and medicine, as reflected in the Helsinki Declaration [2] and corresponds to the principles of ICH GCP [3]. Directive 2001/20/EC is replaced by Regulation No 536/2014 [4] of the European Parliament and of the Council, already in force but it is not applied until the EU portal and the EU database have achieved full functionality. According to the Directive as well as the Regulation authorization of a trial is subject to a favorable opinion given by the Ethics Committee concerned. In Hungary, Law XCV/2005, Decrees 235/2009 and 35/2005 [5–7] determine the legal background of conducting clinical trials. 3. Working principles of ethics committees The Ethics Committee (EC) is an independent body in an EU Member State, consisting of healthcare professionals and non-medical members, whose responsibility is to protect the rights, safety and wellbeing of human subjects involved in a trial. In case of multicenter trials, a single opinion should be given for each member state [1]. ECs are entirely independent of research sponsors, funders and investigators. They work according to the laws of the EU member states. Conflict of interest of the EC members should be declared. Strict rules of confidentiality also apply to them. 3.1. Patient protection The clinical trial subject's protection is safeguarded through risk assessment considering toxicological experiments prior to any clinical
P. Arányi / Microchemical Journal 136 (2018) 244–246
245
Fig. 1. Value chain of drug development. Drug development projects are initiated in the hope of meeting an unmet medical need. That approach ensures the benefit to the society as well as the financial reward for the developer. The development process is organized logically, corresponding also to the requirements of the authorities. The product of the discovery phase is the active principle to develop. Discovery and preclinical development raise questions of animal ethics. The three phases of clinical development requires human ethics considerations all along the value chain. This part is discussed in the paper in detail. Ethical issues may emerge later on, too, when the drug product is already on the market. However those aspects will not be addressed here.
trial, results of previous clinical trials, screening by ethics committees and competent authorities and rules on the protection of personal data. The Ethics Committee should consider the relevance of the clinical trial and the trial design; whether the evaluation of the anticipated benefits and risks is satisfactory, suitability of the investigator and supporting staff, quality of the facilities, adequacy and completeness of the written information to be given to participants. Analyzing the protocol, attention should be paid to the indication, inclusion/exclusion criteria, endpoints (i.e. outcome of the treatment), reference treatment. Recruitment and post-trial treatment options of the patients should also be considered. 3.2. Involvement of vulnerable population Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Children and adolescent persons, incapacitated persons, persons suffering from mental illnesses, pregnant or breastfeeding women, members of the army and prisoners are generally considered as vulnerable people. Medical research with a vulnerable group is only justified if the research is responsive to the health needs or priorities of this group and the research cannot be carried out in a nonvulnerable group. In addition, this group should stand to benefit from the knowledge, practices or interventions that result from the research. 4. Hungarian practice Ethical principles governing the activities of KFEB are collected and described in [8] in Hungarian. Details related to our everyday practice and adviceto applicants are available on our homepage [9]. 4.1. Single (central) ethics committee for clinical pharmacology All clinical trials related to drug development should be authorized by the Competent Authority (OGYÉI in Hungary) and should get a favorable opinion from the Ethics Committee for Clinical Pharmacology, Medical Research Council (KFEB), which is the single ethics committee in Hungary entitled to evaluate those protocols. 384 applications were submitted to KFEB in 2015. Those clinical trials were multinational multicenter studies in most cases. Majority of the sponsors have their
headquarters in different European countries and in the USA. Sponsors with decision center in Hungary represent a rather small minority. KFEB has 30 experts and lay members to review those submissions. At least two members give their detailed opinion on each protocol and discuss those with the plenum of the Committee. The Committee's opinion is taken by vote after discussion. Decision is only reached if two thirds of the participants vote the same way. Otherwise the Committee reevaluates the protocol after the sponsor clarified the issues in their response to the deficiency letter. Final decision can be favorable or unfavorable. In our experience unfavorable ethical opinion is given to less than 5% of the submissions. Conclusion is forwarded to OGYÉI. I recall that the competent authority may only authorize a trial if EC opinion is favorable. 4.2. Evaluation of the protocols KFEB determines their opinion on the basis of professional-ethical evaluation of the trial within the legal frame. Protocol should be based on scientifically acceptable assumptions. Suitability of the principal investigators and their team is also evaluated concerning both their medical specialty and knowledge of the principles of GCP. The trial site should be also properly equipped according to the protocol requirements. Special attention is given to the adequacy and completeness of the written information to be given to participants. All patient material should be presented in native language i.e. in Hungarian or in case of a patient whose mother tongue is not the official language of the country, the documents should be translated to a language that is properly understood by the patient. Also, the text should correspond to local requirements, laws, decrees of the country and the requirements generally put forward by the Committee. A patient can only be included in a trial is he/she has signed the informed consent form. Ethical evaluation may go beyond and above the legal requirements. In addition, the members of KFEB believe that they should also consider and foster advancement of medical sciences. 4.3. Cancer trials Cancer trials have been representing the largest fraction of clinical trials since several years. 26% of all trials initiated in Hungary in 2015 had some type of cancer or haematopoetic and lymphoid malignances as indication. Due to the severity of disease, more serious side effects
246
P. Arányi / Microchemical Journal 136 (2018) 244–246
of treatment are acceptable in cancer than in other indications. However healthy volunteers cannot be subjected to such kind of treatment, even for short duration or even to a single dose. Therefore Phase I subjects are in general cancer patients who, in case of apparent improvement of health status, may continue treatment in Phase II later on and benefit from it. Protocols in Phase II or Phase III should be designed in such a way, that both the investigational product and the placebo have to be given “add on” to the standard basic therapy. In case when effective medical therapy for the selected indication is not available, the patients randomized to the placebo arm should receive best supportive care. Hard endpoints such as overall survival or progression free survival should be used by preference in these phases. Some protocols permit inclusion of end stage disease patients with the slogan that participation holds some hope for them. This is not acceptable considering that treatment side effects are usually severe and render the last part of their life full of distress and unnecessary suffering. Our ethics committee claims that one should not “experiment” on end stage disease patients! 4.4. Pediatric trials Several diseases afflict children and adolescent patients. Clinical trials with participation of that age group of patients are therefore warranted. It is only acceptable in case the clinical trial either relates directly to a medical condition from which the minor concerned suffers or is of such a nature that it can only be carried out on minors. This is the case also when a drug or treatment is already approved for adults but not for children or adolescent patients and extension of indication to minors is aimed at. Participation should produce direct benefit for the minor concerned outweighing the risks and burdens involved. The patient's parents or guardians are properly informed and should sign the informed consent form in such cases. The wish of a minor who is capable of forming an opinion or to refuse participation in, or to withdraw from, the clinical trial should be respected. Therefore they should also be informed in a way that is comprehensible for them and their assent should be obtained. The information sheet for minors usually differs in different age groups. No incentives or financial inducements may be given to the minor subject as a compensation for participation. 5. Future perspectives When Regulation No 536/2014 has to be applied, in about a year's time, the rules will substantially change. Evaluation of the protocols is going to take place in two parts: Part I giving detailed information on the investigational product and on the trial arrangements will not be necessarily evaluated by ECs. Each member state decides if it wants their EC to participate in this work. It appears that Hungary will opt
for KFEB participation. Part II, (dealing with recruitment arrangements, subject information, informed consent form and procedure, suitability of the investigator, suitability of the trial site, proof of insurance coverage or indemnification, financial and other arrangements, proof of payment of fee, proof that data will be processed in compliance with union law on data protection) will obligatorily require an opinion from the national EC in order for the competent authority to authorize the trial [4]. Deadlines of decisions are also regulated in detail and, in fact short deadlines require prompt reactions on the submitted documentation from the authorities and ECs as well. This change represents a significant challenge in Hungary as well as in many other member states of EU.
Declaration of interest The author has no conflict of interest to declare.
Acknowledgements The author is grateful for the in depth discussions on many of the points addressed here and for the intellectual encouragement by professors Zsuzsanna Fürst and Ernő Bácsy. References [1] Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 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 useOJ L 121, 1.5.2001 [2] WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI. Ethical Principles for Medical Research Involving Human Subjects, Adopted June 1964, as amended, See http://www.wma.net/en/30publications/10policies/b3/17c.pdf (Last visited 6 September 2016) [3] The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline on Good Clinical Practice, See http://www. ich.org/products/guidelines/efficacy/efficacy-single/article/good-clinical-practice. html (Last visited 6 September 2016) [4] Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC Text with EEA relevanceOJ L 158, 27.5.2014, p. 1–76 [5] 2005 évi XCV. törvényazemberialkalmazásrakerülőgyógyszerekrőlésegyéb, a gyógyszerpiacotszabályozótörvényekmódosításáról. http://mkogy.jogtar.hu/?page= show&docid=a0500095.TV [6] 235/2009. (X.20.)Korm. rendelet az emberen végzett orvostudományi kutatások, az emberi felhasználásra kerülő vizsgálati készítmények klinikaivizsgálata, valamint az emberen történő alkalmazásra szolgáló, klinikai vizsgálatra szánt orvostechnikai eszközök klinikai vizsgálata engedélyezési eljárásának szabályairól. http://net.jogtar. hu/jr/gen/hjegy_doc.cgi?docid=A0900235.KOR [7] 35/2005. (VIII. 26.) EüM rendelet az emberi felhasználásra kerülő vizsgálati készítmények klinikai vizsgálatáról és a helyes klinikai gyakorlat alkalmazásáról http://njt.hu/cgi_bin/njt_doc.cgi?docid=93895.292588 [8] Bioetikaikódex Az orvosbiológiai/klinikaikutatások elveiről és gyakorlatáról, Mandl József, CsalaMiklós eds. (Semmelweiskiadó, Budapest, 2016) [9] http://www.ett.hu/kfeb.htm.