How best to interpret the minimal risk threshold in the EU Regulation on Clinical Trials?
Article Sidebar
Main Article Content
Abstract
Biomedical research involving minors or other persons incapable of giving consent raise many complex ethical issues, particularly when the research offers no prospect of direct therapeutic benefit to the participants. To protect such individuals from exploitation and undue risks that compromise their dignity, integrity, rights, and well-being, most ethical and regulatory standards prohibit the enrollment of incompetent subjects in studies that have no therapeutic potential, unless participation involves only minimal risk and burden. This well-established standard has also been adopted by Regulation (EU) No 536/2014 on Clinical Trials on Medicinal Products for Human Use, and Repealing Directive 2001/20/EC, which recently entered into force. However, the provisions of the Regulation defining the minimal risk threshold are so ambiguous and confusing that they can easily be interpreted in ways that are unethical and inconsistent with the overall goals of the legislation. This paper critically analyzes the minimal risk requirement of the Clinical Trials Regulation and offers an ethically and legally sound interpretation of the threshold in “non-therapeutic” clinical trials involving selected categories of vulnerable subjects.
Article Details
This work is licensed under a Creative Commons Attribution 4.0 International License.
By submitting his/her work to the Editorial Board, the author accepts, upon having his/her text recommended for publication, that Diametros applies the Attribution 4.0 International (CC BY 4.0) license to the works we publish. Under this license, authors agree to make articles legally available for reuse, without permission or fees. Anyone may read, download, copy, print, distribute or reuse these articles without asking prior permission from the publisher or the author, as long as the author and original source are properly cited. The author holds the copyright without any other restrictions. Full information about CC-BY: https://creativecommons.org/licenses/by/4.0/legalcode.
How to Cite
References
Abou-El-Enein M., Schneider C.K. (2016), “Deciphering the EU clinical trials regulation,” Nature Biotechnology 34 (3): 231–233.
Ackerman T.F. (1980), “Moral duties of parents and nontherapeutic clinical research procedures involving children,” Bioethics Quarterly 2 (2): 94–111.
Alexander D. (2002), “Regulation of research with children: The evolution from exclusion to inclusion,” Journal of Health Care Law & Policy 6 (1): 1–13.
Altavilla A. (2008), “Clinical research with children: the European legal framework and its implementation in French and Italian law,” European Journal of Health Law 15 (2): 109–125.
Andorno R. (2010), “Regulatory discrepancies between the Council of Europe and the EU regarding biomedical research,” [in:] Human Rights and Biomedicine, A. den Exter (ed.), Maklu Press, Antwerp: 117–133.
Barnbaum D. (2002), “Making more sense of ‘minimal risk’,” IRB: Ethics & Human Research 24 (3): 10–13.
Bartholome W.G. (1976), “Parents, children, and the moral benefits of research,” The Hastings Center Report 6 (6): 44–45.
Binik A. (2014), “On the minimal risk threshold in research with children,” The American Journal of Bioethics 14 (9): 3–12.
Binik A. (2017), “A defense of the-risks-of-daily-life,” Kennedy Institute of Ethics Journal 27 (3): 413–442.
Binik A. (2018), “Does benefit justify research with children?,” Bioethics 32 (1): 27–35.
Binik A., Weijer C. (2014), “Why the debate over minimal risk needs to be reconsidered,” Journal of Medicine and Philosophy 39 (4): 387–405.
Binik A., Weijer C., Sheehan M. (2011), “Minimal risk remains an open question,” The American Journal of Bioethics 11 (6): 25–27.
Broström L., Johansson M. (2014), “Involving children in nontherapeutic research: On the development argument,” Medicine, Health Care and Philosophy 17 (1): 53–60.
Brannon V. C. (2018), Statutory Interpretation: theories, tools, and trends, Congressional Research Service Report R45153, URL = https://crsreports.congress.gov/product/pdf/R/R45153 [Accessed 12.06.2024].
Buchner B., Hart D. (2008), “Research with minors in Germany,” European Journal of Health Law 15 (2): 127–134.
Canellopoulou-Bottis M. (2008), “Research with minors in Greece and the EU Directive on clinical trials,” European Journal of Health Law 15 (2): 163–168.
CIOMS (Council for International Organizations of Medical Sciences) (2016), International Ethical Guidelines for Health-Related Research Involving Humans, Geneva, URL = https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf [Accessed 12.06.2024].
Common Rule (1991/2018), the US Code of Federal Regulations, Title 45, Part 46 Protection of Human Subjects, URL = https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-A/part-46?toc=1 [Accessed 12.06.2024].
Council of Europe (1997a), 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, ETS 164, URL = https://rm.coe.int/168007cf98 [Accessed 12.06.2024].
Council of Europe (1997b), Explanatory Report to the 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, URL = https://rm.coe.int/16800ccde5 [Accessed 12.06.2024].
Council of Europe (2005a), Additional Protocol to the Convention on Human Rights and Biomedicine concerning Biomedical Research, CETS 195, URL = https://rm.coe.int/168008371a [Accessed 12.06.2024].
Council of Europe (2005b), Explanatory Report to the Additional Protocol to the Convention on Human Rights and Biomedicine concerning Biomedical Research, URL = https://rm.coe.int/16800d3810 [Accessed 12.06.2024].
DeGrazia D., Groman M., Lee L.M. (2017), “Defining the boundaries of a right to adequate protection: A new lens on pediatric research ethics,” Journal of Medicine and Philosophy 42 (2): 132–153.
DuBois J.M., Beskow L., Campbell J., Dugosh K., Festinger D., Hartz S., James R., Lidz C. (2012), “Restoring balance: A consensus statement on the protection of vulnerable research participants,” The American Journal of Public Health 102 (12): 2220–2225.
EMA (European Medicine Agency) (2023), Clinical Trials Regulation, URL = https://www.ema.europa.eu/en/human-regulatory/research-development/clinical-trials/clinical-trials-regulation [Accessed 12.06.2024].
European Commission (2008), Ethical Considerations for Clinical Trials on Medicinal Products Conducted with the Paediatric Population. Recommendations of Ad Hoc Group for the Development of Implementing Guidelines for Directive 2001/20/EC relating to Good Clinical Practice in the Conduct of Clinical Trials on Medicinal Products for Human Use, URL = https://ec.europa.eu/health//sites/health/files/files/eudralex/vol-10/ethical_considerations_en.pdf [Accessed 12.06.2024].
European Commission (2017a), Ethical Considerations for Clinical Trials on Medicinal Products Conducted with Minors. Recommendations of the Expert Group on Clinical Trials for the Implementation of Regulation (EU) No 536/2014 on Clinical Trials on Medicinal Products for Human Use, URL = https://health.ec.europa.eu/document/download/d721d6cb-687a-477f-b40f-8c7922e9ec9a_en [Accessed 12.06.2024].
European Commission (2017b), Risk Proportionate Approaches in Clinical Trials. Recommendations of the Expert Group on Clinical Trials for the Implementation of Regulation (EU) No 536/2014 on Clinical Trials on Medicinal Products for Human Use, URL = https://health.ec.europa.eu/system/files/2017-08/2017_04_25_risk_proportionate_approaches_in_ct_0.pdf [Accessed 12.06.2024].
European Union (2001), 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 Use, Official Journal of the European Union L 121 (44): 34–44 with further amendments. Consolidated text: URL = https://eur-lex.europa.eu/eli/dir/2001/20/2022-01-01 [Accessed 12.06.2024].
European Union (2006), Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on Medicinal Products for Paediatric Use and Amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004, Official Journal of the European Union L 378 (1): 1–19, URL = https://eur-lex.europa.eu/eli/reg/2006/1901/oj [Accessed 12.06.2024].
European Union (2014), Regulation (EU) 536/2014 on 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, Official Journal of the European Union L 158 (57): 1–76 with further amendments. Consolidated text: URL = https://eur-lex.europa.eu/eli/reg/2014/536/2022-12-05 [Accessed 12.06.2024].
FDA (Food and Drug Administration) (2022), Ethical Considerations for Clinical Investigations of Medical Products Involving Children; Draft Guidance for Industry, Sponsors, and Institutional Review Boards, URL = https://www.fda.gov/media/161740/download [Accessed 18.12.2024].
Flear M.L. (2016), “The EU Clinical Trials Regulation: key priorities, purposes and aims and the implications for public health,” Journal of Medical Ethics 42 (3): 192–198.
Freedman B., Fuks A., Weijer C. (1993), “In loco parentis: minimal risk as an ethical threshold for research upon children,” Hastings Center Report 23 (2): 13–19.
Gambos K. (2014), “EU Law viewed through the eyes of a national judge,” The European Commission’s Legal Service Seminar Paper, URL = https://web.archive.org/web/20211123102230/https://ec.europa.eu/dgs/legal_service/seminars/20140703_gombos_speech_en.pdf [Accessed 12.06.2024].
Gefenas E., Cekanauskaite A., Lekstutiene J., Lukaseviciene V. (2017), “Application challenges of the new EU Clinical Trials Regulation,” European Journal of Clinical Pharmacology 73: 795–798.
Gennet É., Altavilla A. (2016), “Paediatric research under the new EU Regulation on clinical trials: Old issues new challenges,” European Journal of Health Law 23: 325–349.
Giannuzzi V., Altavilla A., Ruggieri L., Cecci A. (2016), “Clinical trial application in Europe: what will change with the new regulation?,” Science and Engineering Ethics 22 (2): 451–466.
Gill D. (2004), “Ethical principles and operational guidelines for good clinical practice in paediatric research. Recommendations of the Ethics Working Group of the Confederation of European Specialists in Paediatrics (CESP),” European Journal of Pediatrics 163: 53–57.
Glantz L.H. (1998), “Research with children,” American Journal of Law & Medicine 24 (2–3): 213–244.
Helmchen H., Hoppu K., Stock G., Thiele F., Vitiello B., Weimann A. (2014), From exclusion to inclusion: Improving clinical research in vulnerable populations. Memorandum, Berlin-Brandenburg Academy of Sciences and Humanities, URL = https://edoc.bbaw.de/opus4-bbaw/frontdoor/index/index/docId/2290 [Accessed 12.06.2024].
ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) (2016), ICH Harmonised Guideline Integrated Addendum to ICH E6 (R1): Guideline For Good Clinical Practice E6 (R2), URL = https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf [Accessed 12.06.2024].
Iltis A. (2007), “Pediatric research posing a minor increase over minimal risk and no prospect of direct benefit: challenging 45 CFR 46.406,” Accountability in Research 14 (1): 19–34.
IOM (Institute of Medicine of the National Academies, Committee on Clinical Research Involving Children, Board on Health Sciences Policy) (2004), Ethical Conduct of Clinical Research Involving Children, M. J. Field, R.E. Behrman (eds.), The National Academy Press, Washington D.C., URL= https://nap.nationalacademies.org/catalog/10958/ethical-conduct-of-clinical-research-involving-children [Accessed 12.06.2024].
Johansson M., Broström L. (2012), “Does peer benefit justify research on incompetent individuals? The same-population condition in codes of research ethics,” Medicine, Health Care and Philosophy 15: 287–294.
Jonsen A.R. (2006), “Nontherapeutic research with children: The Ramsey versus McCormick debate,” The Journal of Pediatrics 149 (1): S12–S14.
Junod V. (2008), “The Swiss regulatory framework for paediatric health research,” European Journal of Health Law 15 (2): 183–195.
Kim D., Hasford J. (2020), “Redundant trials can be prevented, if the EU clinical trial regulation is applied duly,“ BMC Medical Ethics 21: 1–19.
Knaapen M., Ploem M.C., Kruijt M., Oudijk M.A., van der Graff R., Bet P.M., Bakx P., van Heurn L.W.E., Gorter R.R., van der Lee J.H. (2020), “Low-risk trials for children and pregnant women threatened by unnecessary strict regulations. Does the coming EU Clinical Trial Regulation offer a solution?,” European Journal of Pediatrics 179: 1205–1211.
Kopelman L.M. (2000), “Moral problems in assessing research risk,” IRB: Ethics & Human Research 22: 3–7.
Kopelman L.M. (2004a), “What conditions justify risky nontherapeutic or “no benefit” pediatric studies: A sliding scale analysis,” Journal of Law, Medicine & Ethics 32 (4): 749–758.
Kopelman L.M. (2004b), “Minimal risk as an international standard in research,” Journal of Medicine and Philosophy 29 (3): 351–738.
Kopelman L.M. (2012), “On justifying pediatric research without the prospect of clinical benefit,” The American Journal of Bioethics 12 (1): 32–34.
Kwek A. (2024), “The ‘risks of routine tests’ and analogical reasoning in assessments of minimal risk,” The Journal of Medicine and Philosophy 49 (1): 102–111.
Labson M.S. (2002), “Pediatric priorities: legislative and regulatory initiatives to expand research on the use of medicines in pediatric patients,” Journal of Health Care Law & Policy 6 (1): 34–71.
Lenaerts K., Gutiérrez-Fons J.A. (2013), “To say what the law of the EU is: Methods of interpretation and the European Court of Justice,” European University Institute-Academy of European Law: EUI Working Paper AEL 2013/9, URL = https://cadmus.eui.eu/bitstream/handle/1814/28339/AEL_2013_09_DL.pdf?sequence=1&isAllowed=y [Accessed 12.06.2024].
Lenk C., Radenbach K., Dahl K.M., Wiesemann C. (2004), “Non-therapeutic research with minors: how do chairpersons of German research ethics committees decide?,” Journal of Medical Ethics 30: 85–87.
Litton P. (2008), “Non-beneficial pediatric research and the best interests standard: A legal and ethical reconciliation,” Yale Journal of Health Policy, Law & Ethics 8 (2): 359–420.
Litton P. (2012), “A more persuasive justification for pediatric research,” The American Journal of Bioethics, 12 (1): 44–46.
Lötjönen S. (2008), “Medical research on minors in Finland,” European Journal of Health Law 15 (2): 135–144.
Lukaseviciene V., Hasford J., Lanzerath D., Gefenas E. (2021), “Implementation of the EU Clinical Trial Regulation transforms the ethics committee systems and endangers ethical standards,” Journal of Medical Ethics 47 (12): e82–e82.
Lurie P., Wolfe S. (1997), “Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries,” NEJM 337: 853–856.
Macklin R. (2004), Double Standards in Medical Research in Developing Countries, Cambridge University Press, Cambridge.
Macklin R., Natanson C. (2020), “Misrepresenting ‘usual care’ in research: an ethical and scientific error,” The American Journal of Bioethics 20 (1): 31–39.
Mastroianni A., Kahn J. (2001), “Swinging on the pendulum: shifting views of justice in human subjects research,” Hastings Center Report 31 (3): 21–28.
McCormick R.A. (1974), “Proxy consent in the experimentation situation,” Perspectives in Biology and Medicine 18 (1): 2–23.
McCormick R.A. (1976), “Experimentation in children: sharing in sociality,” Hastings Center Report 6 (6):41–46.
Mittica G., Pfisterer J. (2015), “The hurdles of conducting clinical trials across different countries: focus on new European regulations,” Cancer Breaking News 3 (2): 44–46.
National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research (1977), Research Involving Children. Report and Recommendations, U.S. Govern- ment Printing Office, Washington, D.C., URL = https://videocast.nih.gov/pdf/ohrp_research_involving_children.pdf [Accessed 12.06.2024].
NHRPAC (National Human Research Protections Advisory Committee) (2002), Clarifying Specific Portion of 45 CFR 46 Subpart D That Governs Children’s Research, URL = https://wayback.archive-it.org/4657/20150930183548/http://www.hhs.gov/ohrp/archive/nhrpac/documents/nhrpac16.pdf [Accessed 18.12.2024].
Nuremberg Military Tribunal (1947), The Nuremberg Code (United States vs. Karl Brandt, et al. Nov. 21, 1946 - Aug. 20, 1947), [in:] Trials of War Criminals Before the Nuernberg Military Tribunals under Control Council Law no. 10, U.S. Government Printing Office, Washington, D.C. 1946-1949, vol. II: 181–182, URL = https://collections.nlm.nih.gov/catalog/nlm:nlmuid-01130400RX2-mvpart [Accessed 12.06.2024].
Nys H., Dierickx K., Pinxten W. (2008), “The implementation of Directive 2001/20/EC into Belgian law and the specific provisions on pediatric research,” European Journal of Health Law 15 (2): 153–161.
Piasecki J., Waligóra M., Dranseika V. (2015), “Non-beneficial pediatric research: individual and social interests,” Medicine, Health Care and Philosophy 18 (1): 103–112.
Pinxten W., Dierickx K., Nys H. (2011), “Diversified harmony: Supranational and domestic regulation of pediatric clinical trials in the European Union,” Journal of Cystic Fibrosis 10: S183–S198.
Ramsey P. (1970), The Patient as Person, Yale University Press, New Haven.
Ramsey P. (1976), “The enforcement of morals: Non-therapeutic research on children,” Hastings Center Report 6 (4): 21–30.
Ramsey P. (1977), “Children as research subjects: A reply,” Hastings Center Report 7 (2): 40–41.
Redmon R.B. (1986), “How minors can be respected as ends yet still be used as subjects in non-therapeutic research,” Journal of Medical Ethics 12 (2): 77–82.
Resnik D.B. (1998), “The ethics of HIV research in developing nations,” Bioethics 12: 286–306.
Resnik D.B. (2005), “Eliminating the daily life risks standard from the definition of minimal risk,” Journal of Medical Ethics 31 (1): 35–38.
Resnik D.B. (2014), “Making sense of the undue burden interpretation of minimal risk,” The American Journal of Bioethics 14 (9): 1–2.
Rid A. (2012), “Risk and risk-benefit evaluations in biomedical research,” [in:] Handbook of Risk Theory. Epistemology, Decision Theory, Ethics, and Social Implications of Risk, S. Roeser, R. Hillerbrand, P. Sandin, M. Peterson (eds.), Springer, Dordrecht: 179–211.
Rid A. (2014), “Setting risk thresholds in biomedical research: lessons from the debate about minimal risk,” Monash Bioethics Review 32: 63–85.
Rid A., Emanuel E.J., Wendler D. (2010), “Evaluating the risks of clinical research,” JAMA 304 (13): 1472–1479.
Rid A., Wendler D. (2010), “Risk-benefit assessment in medical research – critical review and open questions,” Law, Probability and Risk 9: 151–177.
Rid A., Wendler D. (2011a), “A framework for risk-benefit evaluations in biomedical research,” Kennedy Institute of Ethics Journal 21 (2): 141–179.
Rid A., Wendler D. (2011b), “A proposal and prototype for a research risk repository to improve the protection of research participants,” Clinical Trials 8 (6): 705–715.
Rose K. (2014), “Pediatric pharmaceutical legislation in the USA and EU and their impact on adult and pediatric drug development,” [in:] Pediatric Formulations, D. Bar-Shalom, K. Rose (eds.), Springer, New York: 405–419.
Ross L.F. (2004), “Children in medical research. Balancing protection and access: Has the pendulum swung too far?,” Perspectives in Biology and Medicine 47 (4): 519–536.
Ross, L.F. (2006), Children in Medical Research: Access versus Protection, Oxford University Press, New York.
Ross L.F., Coffey M.J. (2002), “(Women and) children first: applicable to lifeboats applicable to human experimentation,” Journal of Health Care Law & Policy 6 (1): 14–33.
Ross L.F., Nelson R.M. (2006), “Pediatric research and the federal minimal risk standard,” JAMA 295 (7): 759–760.
Rossi J., Nelson R.M. (2017), “Minimal risk in pediatric research: a philosophical review and reconsideration,” Accountability in Research 24 (7): 407–432.
Różyńska J. (2022), “The principle of the primacy of the human subject and minimal risk in non-beneficial paediatric research,” Journal of Bioethical Inquiry 19 (2): 273–286.
Różyńska J. (2023), “How risky can biomedical research be? On setting an upper limit of risk in non-beneficial research involving volunteers,” [in:] Medical Research Ethics: 21st Century Challenges, D.N. Weisstub, T. Zima (eds.), Springer, Cham: 265–286.
SACHRP (The Secretary’s Advisory Committee on Human Research Protections) (2005), Appendix B: Recommendations Regarding Risk in Research Involving Children, URL = https://www.hhs.gov/ohrp/sachrp-committee/recommendations/2005-july-28-letter-appendix-b/index.html [Accessed 18.12.2024].
SACHRP (The Secretary’s Advisory Committee on Human Research Protections) (2008), Recommendations Related to Waiver of Informed Consent and Interpretation of “Minimal Risk”, URL = https://www.hhs.gov/ohrp/sachrp-committee/recommendations/2008-january-31-letter/index.html [Accessed 12.06.2024].
Saint Raymond A., Brasseur D. (2005), “Development of medicines for children in Europe: ethical implications,” Paediatric Respiratory Reviews 6 (1): 45–51.
Scavone C., di Mauro G., Pietropaolo M., Alfano R., Berrino L., Rossi F., Tomino C., Capluano L. (2019), “The European Clinical Trials Regulation (No 536/2014): changes and challenges,” Expert Review of Clinical Pharmacology 12 (11): 1027–1032.
Schüklenk U. (1998), “Unethical perinatal HIV transmission trials establish bad precedent,” Bioethics 12: 312–319.
Shah S. (2013), “Does research with children violate the best interests standard? An empirical and conceptual analysis,” Northwestern Journal of Law and Social Policy 8: 121–173.
Shah S., Whittle A., Wilfond B., Gensler G., Wendler D. (2004), “How do institutional review boards apply the federal risk and benefit standards for pediatric research?,” JAMA 291: 476–482.
Sheikh A. (2008), “Ireland and medical research with minors: some medico-legal aspects,” European Journal of Health Law 15 (2): 169–181.
Shirkey H. (1968), “Therapeutic orphans,” The Journal of Pediatrics 72: 119–120.
Simonsen S. (2012), Acceptable Risk in Biomedical Research. European Perspective, Springer, Dordrecht, Heidelberg, London, New York.
Snyder J., Miller C.L., Gray G. (2011), “Relative versus absolute standards for everyday risk in adolescent HIV prevention trials: Expanding the debate,” The American Journal of Bioethics 11 (6): 5–13.
Spriggs M. (2012), “Justifying pediatric research not expected to benefit child subjects,” The American Journal of Bioethics 12 (1): 42–44.
Tenti E., Simonetti G., Bochicchio M.T., Martinelli G. (2018), “Main changes in European Clinical Trials Regulation (No 536/2014),” Contemporary Clinical Trials Communications 11: 99–101.
UNESCO (United Nations Educational, Scientific and Cultural Organization) (2005), Universal Declaration on Bioethics and Human Rights, URL = https:// www.unesco.org/en/legal-affairs/universal-declaration-bioethics-and-human-rights [Accessed 12.06.2024].
Van Luijn H.R.M., Aaronson N.K., Keus R.B., Musschenga A.W. (2006), “The evaluation of the risks and benefits of phase II cancer clinical trials by institutional review board (IRB) members: a case study,” Journal of Medical Ethics 32: 170–176.
Wade K. (2017), “Defining the threshold of permissible risk for non-therapeutic clinical trials with children in Europe,” European Journal of Health Law 24: 414−431.
Weijer C. (1999), “Thinking clearly about research risk: implications of the work of Benjamin Freedman,” IRB: Ethics & Human Research 21 (6): 1−5.
Weijer C. (2000), “The ethical analysis of risk,” The Journal of Law, Medicine & Ethics 28 (4): 344−361.
Weijer C., Miller P.B. (2004), “When are research risks reasonable in relation to anticipated benefits?,” Nature Medicine 10 (6): 570−573.
Weijer C., Miller P.B. (2007), “Refuting the net risks test: a response to Wendler and Miller’s ‘Assessing research risks systematically’,” Journal of Medical Ethics 33 (8): 487−490.
Wendler D. (2005), “Protecting subjects who cannot give consent: toward a better standard for ‘minimal’ risks,” Hastings Center Report 35 (5): 37–43.
Wendler D. (2010), The Ethics of Pediatric Research, Oxford University Press, New York.
Wendler D. (2012), “A new justification for pediatric research without the potential for clinical benefit,” The American Journal of Bioethics 12 (1): 23–31.
Wendler D. (2013), “Do US regulations allow more than minor increase over minimal risk pediatric research? Should they?,” IRB: Ethics & Human Research 35 (6): 1–8.
Wendler D., Belsky L., Thompson K.M., Emanuel E.J. (2005), “Quantifying the federal minimal risk standard: implications for pediatric research without a prospect of direct benefit,” JAMA 294 (7): 826–832.
Wendler D., Emanuel E.J. (2005), “What is a ‘minor’ increase over minimal risk?,” The Journal of Pediatrics 147 (5): 575–578.
Wendler D., Glantz L. (2007), “A standard for assessing the risks of pediatric research: pro and con,” The Journal of Pediatrics 150 (6): 579–582.
Wendler D., Miller F.G. (2007), “Assessing research risks systematically: the net risks test,” Journal of Medical Ethics 33 (8): 481–486.
Westra A.E. (2016), “Ambiguous articles in new EU Regulation may lead to exploitation of vulnerable research subjects,” Journal of Medical Ethics 42: 189−191.
Westra A.E., Bos W., Cohen A.F. (2014), “New EU Clinical Trials Regulation,” BMJ 348 (48): g3710.
Westra A.E., Engberts D.P., Sukhai R.N., Wit M., de Beaufort I.D. (2010), “Drug development for children: how adequate is the current European ethical guidance?,” Archives of Disease in Childhood 95 (1): 3–6.
Westra A.E., Wit J.M., Sukhai R.N., de Beaufort I.D. (2011), “How best to define the concept of minimal risk,” The Journal of Pediatrics 159 (3): 496–500.
WHO (World Health Organization) (2018), Safety of medicines – adverse drug reactions, URL = https://www.who.int/docs/default-source/medicines/safety-of-medicines--adverse-drug-reactions-jun18.pdf?sfvrsn=4fcaf40_2 [Accessed 12.06.2024].
WMA (World Medical Association) (1964), Declaration of Helsinki. Recommendations Guiding Doctors in Clinical Research, Helsinki, Finland, URL = https:// www.wma.net/wp-content/uploads/2018/07/DoH-Jun1964.pdf [Accessed 12.06.2024].
WMA (World Medical Association) (1975), Declaration of Helsinki. Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects, Tokyo, Japan, URL = https://www.wma.net/wp-content/uploads/2018/07/DoH-Oct1975.pdf [Accessed 12.06.2024].
WMA (World Medical Association) (1983), Declaration of Helsinki. Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects, Venice, Italy, URL = https://www.wma.net/wp-content/uploads/2018/07/DoH-Oct1983.pdf [Accessed 12.06.2024].
WMA (World Medical Association) (1989), Declaration of Helsinki. Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects, Hong Kong, URL = https://www.wma.net/wp-content/uploads/2018/07/DoH-Sept1989.pdf [Accessed 12.06.2024].
WMA (World Medical Association) (1996), Declaration of Helsinki. Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects, Somerset West, Republic of South Africa, URL = https://www.wma.net/wp-content/uploads/2018/07/DoH-Oct1996.pdf [Accessed 12.06.2024].
WMA (World Medical Association) (2000), Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects, Edinburgh, Scotland, URL = https://www.wma.net/wp-content/uploads/2018/07/DoH-Oct2000.pdf [Accessed 12.06.2024].
WMA (World Medical Association) (2008). Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects, Seoul, Korea, URL = https://www.wma.net/wp-content/uploads/2018/07/DoH-Oct2008.pdf [Accessed 12.06.2024].
WMA (World Medical Association) (2013), Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects, Fortaleza, Brazil, URL = https://www.wma.net/wp-content/uploads/2024/10/DoH-Oct2013.pdf [Accessed 18.12.2024].
WMA (World Medical Association) (2024), WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Participants, Helsinki, Finland, URL= https://www.wma.net/policies-post/wma-declaration-of-helsinki/ [Accessed 18.12.2024].