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Drug regulators and ethics: which GCP issues are also ethical issues?
Accepted Manuscript Title: Drug regulators and ethics: which GCP issues are also ethical issues? Author: Rosemarie D.L.C. Bernabe Ghislaine J.M.W. van Thiel Nancy S. Breekveldt ohannes J.M. van Delden PII: DOI: Reference:
S1359-6446(15)00425-0 http://dx.doi.org/doi:10.1016/j.drudis.2015.11.006 DRUDIS 1712
To appear in: Received date: Revised date: Accepted date:
2-6-2015 2-11-2015 10-11-2015
Please cite this article as: Bernabe, R.D.L.C., van Thiel, G.J.M.W., Breekveldt, N.S., van Delden, J.M.,Drug regulators and ethics: which GCP issues are also ethical issues?, Drug Discovery Today (2015), http://dx.doi.org/10.1016/j.drudis.2015.11.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Research highlights for Drug regulators and ethics: which GCP issues are also ethical issues?
1. Of the 384 imperatives of the ethics framework for biomedical research involving human participants, GCP covers 21.88%.
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2. The ethics mandate of drug regulators falls within the following sections of the ethics framework: principles; favorable benefit-risk ratio; scientific validity; publication registration, and regulatory sanctions; (independent review); IC; respect for participants; and special populations.
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3. There were GCP articles that though would fall within the sections of the ethics framework but were not directly pairable to any imperative.
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4. At the same time, there were regulations that were stricter than the ethical imperatives.
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Drug regulators and ethics: which GCP issues are also ethical issues?
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Rosemarie D.L.C. Bernabe1, Ghislaine J.M.W. van Thiel1, Nancy S. Breekveldt2, and Johannes J.M. van Delden1 1
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Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands 2 Dutch Medicines Evaluation Board, Graadt van Roggenweg 500, 3531 AH Utrecht, the Netherlands Corresponding author: Bernabe, R.D.L.C. ([email protected]) Keywords: GCP; ethics; regulation; EU; guidelines. Teaser: The mandate of drug regulators is not only scientific, but also ethical.
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Within the European Union (EU), good clinical practice (GCP) provides an ethical mandate to regulators; however, it is unclear what the content of that mandate is. By looking at the correspondence between GCP and ethical imperatives, we identify that the mandate is within the following: principles; benefit:risk ratio; scientific validity; results publication; informed consent; respect for participants; and special populations. There are also cases when regulations were ethical but were not pairable to an imperative, and when the former were stricter than latter. Hence, we suggest closer cooperation between ethics committees and regulators to ensure that future versions of ethics guidelines cover the ethically relevant regulations that were not directly pairable to any imperative, and cooperation between GCP legislative bodies and ethics guideline-making bodies to resolve the discordant areas.
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Introduction
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Regulators in the pharmaceutical environment execute not only a scientific, but also an ethical mandate: they assess and inspect using GCP as a framework, with GCP defined as ‘an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects’ [1]. For example, a 2012 European Medicines Agency (EMA) document [2] expects regulators to have the skillset to identify and act upon ethical issues. However, given that this document is meant for clinical trials conducted outside the EU/European Economic Area (EEA), it would be logical to think that regulators are expected to utilize the same ethics skillset for clinical trials conducted within the EU/EEA. It would be unreasonable to expect regulators to cover all ethical aspects present in the various international ethics guidelines. The ethical mandate of regulators is clearly limited by what is within GCP. However, the problem is that it is still unclear what the contents of this ethical mandate are. Here, we specify which ethical issues we can expect regulators to identify and act upon by looking at the concordance between regulation (i.e., GCP) and ethics. We define the current field of ethics that is relevant to regulators. By regulators, we refer to those involved in marketing authorization applications (MAAs) for medicines, which include clinical assessors and GCP inspectors. As the regulators immediately responsible for the evaluation of clinical trial data within a MAA, it is reasonable to think that, at the very least, they share the responsibility for identifying and addressing the ethical issues mentioned above. Given that they evaluate clinical trial data after the fact[LM1], these regulators would ideally identify and then address ethical issues retrospectively through means such as sanctions and warnings, among others. To understand which ethical issues we can reasonably expect to be within the mandate of regulators, it was necessary to pair an ethics framework with GCP documents because GCP is the framework for clinical trial regulation. Before identifying and extracting the articles from the directives and/or guidelines that relate to ethics, we created a robust ethics framework on which the extraction would be based. We did this by putting together the Nuremberg Code ( imperatives from five international ethics guidelines: http://www.hhs.gov/ohrp/archive/nurcode.html), Declaration of Helsinki [3], Belmont Report [4], Council of Europe’s Additional Protocol [5], and CIOMS International Ethical Guidelines for Biomedical Research [6] (as detailed in the supplementary material online)*. Using this framework, we identified and extracted the ethically relevant articles from the three EU documents on harmonized GCP [7]†: ICH-GCP E6 [1], Directive 2005/28/EC [8], and EU 536/2014 [9]. The first document was created by the International Conference on Harmonization (ICH) to ‘provide a unified standard for the EU, Japan and the United States’ [1]. Within the EU, two directives were introduced to harmonize the conduct of clinical trials: 2001/20/EC and 2005/28/EC [7]. In place of the repealed 2001/20/EC, we looked at 536/2014. After extracting the relevant GCP articles (henceforth termed ‘regulation’) from the documents, these were explicitly paired with the corresponding ethics imperative (henceforth termed ‘imperative’) from the ethics framework (the pairing is henceforth termed ‘correspondence’). Correspondences were based on complete (i.e., a
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regulation and an imperative are identical) to at least mild similitude (i.e., a regulation is similar but not identical to an imperative). When a correspondence was based on identity, no distinction between imperative and regulation was made (e.g., we simply say ‘…the interests and the welfare of the research participants prevail over the sole interest of science and society’). However, when a correspondence was based on mild similitude, both the imperative and the regulation are provided [e.g., we say, ‘the imperative that informed consent (IC) must be secured in writing…corresponds with the regulation that IC must be dated and signed by the person performing the interview and the participant…’]. Correspondences and the lack thereof between imperatives and regulations
Correspondences between regulations and our ethics framework
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Principles
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Corresponding to the major themes of the ethical requirements in human research, the ethics framework we created has the following 11 sections: principles; collaborative partnerships; social value; scientific validity; fair participant selection; favorable benefit:risk ratio; independent review; IC; respect for participants; publication, registration, and regulatory sanctions; and special populations (see the supplementary material online). Of the 11 sections in the ethics framework, eight had correspondences (Box 1). The following three sections did not have correspondences: collaborative partnerships, social value, and fair participant selection. This means, for example, that of the seven imperatives within ‘collaborative partnerships’, no matching articles were found. Of the sections with correspondences, most correspondences were found in special populations (40.4%), respect for participants (36.1%), and independent review (22.5%). Table 1 presents the percentages of the correspondences per section. Here, we first elaborate on the contents of the correspondences within the eight sections. We then look at regulations that are ethical in nature but are not pairable with any of the imperatives.
Of the ten imperatives in this section, one correspondence was found. Specifically, there was correspondence that the interests and the welfare of the research participants prevail over the sole interest of science and society. Scientific validity
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Of the 37 imperatives in this section, five correspondences were found specifically on the themes of scientific design, protocol compliance, and the qualifications of the research staff. The scientific design and statistical methods of research must be sound. This means that, among others, there must be sufficient basis for the study and the study design in current knowledge and previous efficacy and safety data from nonclinical and/or clinical studies. In terms of the protocol, a detailed protocol that contains the justification of the design and performance of the study is a necessity. This protocol, once approved by the research ethics committee (REC) and other relevant authorities, must always be complied with. The investigator and the clinical trial staff must be scientifically qualified individuals; that is, they are qualified in terms of education, training, and experience to perform their tasks. Also, they are required to always perform their tasks with the highest degree of skill and care. Related to this is the area of correspondence that says that the medical care and supervision of the participants must be entrusted to a competent and qualified physician (or dentist). Favorable benefit:risk ratio
Of the 25 imperatives in this section, three correspondences were found. First is the necessity of minimizing pain, discomfort, fear, and other risks and inconveniences as much as possible in a study; second is the necessity of constantly monitoring the degree of distress and the risk threshold; third is the necessity of ensuring that risks are justified; that is, that the anticipated benefits to individuals and public health justify the risks and inconveniences to the participants. Independent review
Of the 80 imperatives in this section, 18 correspondences were found within the themes of REC composition/requirements, REC rights and responsibilities, and the responsibilities of the investigator and/or sponsor. In terms of REC requirements, REC members must be independent from the sponsor and the investigators; they should not have financial or personal interests that could affect their impartiality as assessors; and they should regularly declare any possible conflicts of interest. With regard to REC composition, the imperative that a REC must be multidisciplinary corresponds with the regulation that assessment must be done by a sufficient number of people who, as a group, have the needed qualifications and experience to make the assessment. There is also correspondence with the necessity of the inclusion of a layperson in the REC. As for REC rights and responsibilities, the imperative that a REC should provide reasons for its decisions corresponds with the regulation that the REC should document its views in writing. There is also correspondence between the imperative that the REC must examine several aspects of a study (such as risks and benefits, IC procedures, selection of participants, among others) and the regulations that RECs should safeguard the rights, safety, and wellbeing of all the participants, and that RECs should pay special attention to studies that include vulnerable participants. Lastly, RECs are tasked to ensure that monetary and in-kind recompense do not constitute undue inducement. Concerning the responsibilities of the investigator and/or sponsor, there is correspondence that every interventional study shall be submitted to a REC for review and approval. The information and/or documents that
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the investigator and/or sponsor must submit to the REC for assessment and approval are as follows: information about the principal researcher through a curriculum vitae or other documentation of the investigator; nature and degree of foreseeable risks through available safety information; recruitment procedures, written information provided to the participants, and the IC forms or IC form updates; details of payments and compensation; trial protocol or protocol amendments; any other document that the REC deems necessary for assessment. Protocol amendment by the investigator and/or sponsor is not possible without the approval of the REC. Regarding the imperative that unexpected or unforeseen adverse reactions must be reported by the investigator and/or sponsor to the REC for prompt review, the corresponding regulation states that the REC, together with the regulators, must be involved in the assessment of suspected unexpected serious adverse reactions and annual reports. Informed consent
Respect for participants
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Of the 98 imperatives in this section, 22 correspondences were found within themes of securing consent, information given to the participants, comprehension and voluntariness of the participants, and the use of data outside the protocol. The imperative that securing IC must be in writing and, if that is not possible, securing of consent must be formally documented and witnessed, corresponds with the regulation that IC must be dated and signed by the person performing the interview and the participant, or in the case of incapacity, the participant’s legal representative. The person securing consent must be appropriately qualified, knowledgeable about the research, and capable of answering questions from the prospective participants. After consent is secured, the participant or the participant’s representative should be given a copy of the IC document. In terms of the information given to the participants, it must be comprehensive, accurate, relevant, but not overwhelming; that is, it must be understandable to a layperson. Specifically, the potential participants must be informed of the following: anticipated benefits, right to refuse and to withdraw without reprisal and without the need for a justification; objectives of the study; methods and procedures; risks and inconveniences; current alternative interventions, if any; damage compensation system in place; expected duration of the participants’ participation in the study; and the possibility of early termination of participation and follow-up measures. In the process of providing information, the comprehension of the participants must be ensured and verified. This means that, according to another correspondence, attention should be paid to the means and methods used to provide the information and that the informational needs of specific populations should always be taken into account. Aside from comprehension, the voluntariness of the participants during the IC process must also be ensured. This closely relates to the following correspondences: the participant’s right to refuse and withdraw without reprisal must also be ensured; that adequate time is provided for the participants to decide; that the participants must not be exposed to undue influence in the decision-making process; and that fees and other incentives do not constitute undue inducement. Lastly, the use of data outside the protocol for scientific purposes also needs IC.
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Of the 36 imperatives in this section, 13 correspondences were found within the themes of participant safety, privacy/confidentiality, dissemination of results, compensation, and the responsibilities of researching physicians to the research participants. All reasonable means should be taken to ensure participant safety. Four other correspondences specify what this means: first, the imperative that monitoring of the health of the participants to minimize harm, particularly through the task of the Data and Safety Monitoring Board to protect participants from previously unknown adverse reactions and unnecessary prolonged exposure to inferior therapy, which corresponds with the regulation that one of the purposes of monitoring is the verification that the rights and wellbeing of the participants are protected. Second, adequate healthcare facilities for the safe conduct of the research must be provided. Third, there must be adequate criteria for changing dose or procedures for stopping the study for the sake of the health of the participants. Fourth, research is not enough justification to alter the treatment of patients in a detrimental manner. Aside from participant safety, the confidentiality of the participants’ data must also be kept. Concerning dissemination of results, imperatives state that everyone is entitled to know about the information collected about one’s health and that sufficient attention must be placed on the manner of disseminating the results to the participants and the community. These correspond with regulations that the participant must be informed of the summary results of a study and that a summary understandable to a layperson shall be made available in the EU database. Regarding compensation, there must be appropriate compensation for participants who were harmed as a result of research. By contrast, for participants who withdraw because of research-related or health-related reasons, an imperative states that they must be paid in full, while those who withdraw for any other reason should be paid in proportion to their participation. This imperative corresponds with a regulation that states that payments to participants must be prorated and not wholly dependent on completion of trial participation. In terms of the responsibility of researching physicians to the participants, the imperative that the clinical professional supervising the participants must be easily accessible and ready to respond to the health concerns of the participants corresponds with the regulation that participants must be provided with the contact details of the
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entity or person from whom information may be received in case of need. Also, the imperative that states that the physician involved in research must protect the life, health, dignity, integrity, right to self-determination, privacy, and confidentiality of the participants corresponds with the regulation that medical care and the medical decisions made on behalf of the participants must be the responsibility of a qualified physician. Publication, registration, and regulatory sanctions
Of the six imperatives in this section, there was a correspondence on the theme of study registration. The imperative that every study involving human participants must be registered in a publicly available database corresponds with the regulation that sponsors should notify concerned Member States about the start of a trial through the EU Portal and that summaries in lay language should be made available in the EU database.
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Special populations
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Of the 52 imperatives in this section, 21 correspondences were found on themes of vulnerable populations in general, persons not able to consent, emergency research, and pregnant or breastfeeding women. For the vulnerable populations in general, the imperative that REC review of a study involving vulnerable individuals should invite representatives or advocates corresponds with the regulation that for the assessment of the clinical trial application, experts in the relevant condition and representatives from the population concerned must be invited. For persons not able to consent, including minors, research on individuals unable to consent may be acceptable if data of comparable validity cannot be obtained from individuals able to consent and that the condition (either the illness or the condition of being a minor) is a necessary characteristic of the research group. The research must also have the potential to produce direct benefits to the participants that outweigh the risks and the burdens. In the event that the research has no potential to produce direct benefits (i.e., nontherapeutic research), such research might be acceptable if the risks and burdens are minimal (in comparison with standard therapy for the condition) and if there are scientific grounds to expect some benefits to the population represented by the incapacitated participant. In terms of the inclusion of persons not able to consent in a study, the IC of a legal representative is necessary. This legal representative, according to another correspondence, shall receive no recompense other than refund for travel and related expenses. In the event that the person unable to consent is capable of forming an opinion and assessing information, their assent or dissent shall be respected; that is, the participant must be involved in the IC procedure as much as possible. In the case of minors, their opinion is increasingly a determining factor in proportion to their age and level of maturity. There might be situations when a participant is initially unable to consent but gains the competence to consent within the duration of the study. In such cases, the consent of the participant must be secured for their continued participation. There could also be situations when the inclusion of persons unable to consent is necessary and the protocol indicates that prior IC of the legal representative is not possible. In such cases, the inclusion of persons unable to consent might still be allowable with the approval of the REC. In such cases, IC must be secured as soon as possible. In emergency research, when the IC of the participant or legal representative cannot be reasonably secured because of the urgency of the situation, inclusion is possible with the approval of the REC. The participant’s or the legal representative’s IC must be secured for continued participation as soon as possible. Such a study is justifiable only when research of comparable effectiveness cannot be achieved with persons in nonemergency situations. Also, risks and burdens must be minimal in comparison with standard treatment. Regarding pregnant or breastfeeding women, the inclusion of pregnant women in therapeutic studies is ethically acceptable when the study is relevant to the health needs of the pregnant woman or her fetus; and the trial has the potential to produce direct benefits for the pregnant or breastfeeding woman, fetus, embryo, or children. Undue inducement must be prevented. Nontherapeutic studies might be acceptable if they aim to contribute to attaining results that are capable of benefitting other pregnant or breastfeeding women, or to fetuses, embryos, or children; research of comparable effectiveness cannot be carried out on women who are not pregnant or who are not breastfeeding; and risks to the pregnant or breastfeeding woman, and to her fetus, embryo, or child, are minimal. When research is undertaken on breastfeeding women, utmost care must be in place to avoid any adverse effect on the health of the child. Regulations that are ethically relevant but are not pairable to any imperative from the ethics framework
In the process of identifying correspondences between imperatives and regulations, we noted that there were also regulations that are more specific than the imperatives. Table 2 contains regulations from EU 536/2014 and 2005/28/EC that might fall within the larger sections of the ethics framework but are not directly pairable to any imperative. GCP articles that are stricter than ethical imperatives
Lastly, there were also GCP requirements from EU/536/2014 that were stricter than the ethics imperatives. For one, Article 33.d states that no incentives or financial inducements must be given to the participants in a clinical trial on and about pregnant or breastfeeding women. By contrast, an ethics imperative states that there should be special safeguards to prevent undue inducement, but it does not explicitly say that incentives or inducements must be banned from such trials. Also, Article 35.1.b states that clinical trials in emergency situations must have the
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potential to produce direct benefits to the participants (i.e., these studies must be therapeutic in nature). By contrast, an ethics imperative accepts nontherapeutic emergency studies within conditions. The latter specifically says that nontherapeutic clinical trials in emergency situations might be acceptable when such a study aims to significantly contribute to the scientific understanding of the patients’ condition, disease, or disorder; and risks are minimal. Recommendations
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We stated in the introduction that GCP is the framework for clinical trials regulation. It is the frame of reference of the regulators, not to mention everyone else involved in a clinical trial. To understand which ethical issues we can reasonably expect to be within the mandate of regulators, it was necessary to pair our ethics framework with the three GCP documents. Our results provide the areas of correspondence (with the exception of the correspondences in ‘independent review’, because the latter apply specifically to RECs and not to clinical assessors or inspectors). Thus, as a response to the question on which ethical issues we can expect regulators to identify and act upon, regulators are mandated to be engaged in the ethical issues specifically within the following sections: principles; favorable benefit:risk ratio; scientific validity; publication registration, and regulatory sanctions; (independent review); IC; respect for participants; and special populations. Within these sections, of the 384 imperatives in the ethics framework, 84 (21.88%) are covered by GCP; hence, only this percentage of this ethics framework is within the mandate of the regulators. Within these areas of correspondence, further studies are needed to specify the ethical responsibilities of clinical assessors and GCP inspectors. Table 1 shows that, at best, GCP articles cover 40.4% of the imperatives in a given section. Given this gap, the question of who should be enforcing these must be raised. Some areas will be covered by RECs, but it would be unfair to say that the uncovered areas are, by default, to be enforced by the REC. We have two options: the mandate of the regulators can be expanded to include the areas within the gap or the cooperation between regulators and RECs must be further developed and expanded for the specific purpose of covering these gap areas. Intuitively, the latter seems more reasonable. Further studies are needed to explore the current state of affairs in terms of REC–regulator cooperation, how this cooperation may be improved to cover the gap areas, and how the gap areas must be delegated to either the RECs or the regulators, among others. Apart from identifying areas in the ethics framework that are not covered by GCP, we noted that there are also regulations that are not directly pairable to any imperative (Table 2). As stated above, these regulations fall well within the sections of informed consent, independent review, and special populations. As such, these sections are undeniably not only regulatory mandates, but also imperatives. Given their ethical relevance, it might be best to consider the inclusion of such specifications in future versions of international ethics guidelines for human research. Lastly, in the Recommendations section above, we showed that some regulations are in fact stricter than the imperatives (i.e., that in a few sections, there are discordances between regulations and imperatives). The persistence of this discordance might cause unwanted divergence between regulators and RECs, for example, on the issue of what constitutes undue inducement on trials with pregnant women. This discordance must be addressed through the cooperation of regulatory and ethics-guideline bodies. Hence, further studies on how to address the discordant areas are also needed. Box 2 presents a summary of the recommendations. This study is limited by the fact that we concentrated on European Commission documents on harmonized GCP. There are other regulatory guidelines on the use of placebo, for example, that we did not consult. However, because we are working at the level of mandates, principles, and imperatives, we thought it sufficient to limit ourselves to GCP regulations and to not include study-type specific guidelines. Also, we excluded the appendices of the ethics guidelines (and the CIOMS appendix contained the list of necessary contents of a protocol) in our analysis, and hence Annex 1 in EU 536/2014 and Section 6 of Directive 75/318/EEC that enumerated the required contents of a protocol were also excluded. Concluding remarks
Ethics imperatives and GCP regulation corresponded, at least in some aspects, within the following areas: upholding the basic principles; favorable benefit:risk ratio; scientific validity; publication registration, and regulatory sanctions; IC; respect for participants; and special populations. This means that, at most, the ethics mandate of regulators lies within these areas. Further studies are needed to specify the responsibilities of assessors and GCP inspectors within these areas. Next, because the ethics mandate of the regulators, even within these areas, is understandably limited by GCP, closer cooperation between RECs and regulators must be developed specifically to cover the gaps. We also saw that there were GCP requirements that were more specific than the imperatives. We recommend these specificities to be covered in future versions of ethics guidelines. Lastly, there were discordant areas (i.e., areas where the ethics imperatives and GCP regulations conflict). We recommend the cooperation of GCP legislative bodies and ethics-guideline making bodies specifically to resolve these discordant areas. Conflicts of interest R.D.L.C.B. and G.J.M.W.vT. received funding for this research from the Dutch Medicines Evaluation Board. N.S.B. works as a clinical assessor in the Dutch Medicines Evaluation Board. Acknowledgement This project was funded by the Dutch Medicines Evaluation Board. The views expressed by the authors are their personal views and may not be understood or quoted as being made on behalf of or reflecting the position of the Dutch Medicines Evaluation Board.
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References 1 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (1996) Guideline for Good Clinical Practice E6(R1), ICH 2 EMA, (2012) Reflection Paper on Ethical and GCP Aspects of Clinical Trials of Medicinal Products for Human Use Conducted Outside of the EU/EEA and Submitted in Marketing Authorization Applications to the EU Regulatory Authorities, EMA 3 World Medical Association, (2013) Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects, WMA / 4 US National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1979) The Belmont Report, Department of Health, Education, and Welfare 5 Council of Europe (2005) Additional Protocol to the Convention on Human Rights and Biomedicine, Concerning Biomedical Research, COE 6 Council for International Organizations of Medical Sciences (2002) International Ethical Guidelines for Biomedical Research Involving Human Subjects, CIOMS 7 Tobin, J.J. and Walsh G. (2008) Medical Product Regulatory Affairs: Pharmaceuticals, Diagnostics, Medical Devices, Wiley-VCH 8 Commission of the European Communities (2005) Commission Directive 2005/28/EC Laying Down Principles and Detailed Guidelines for Good Clinical Practice as Regards Investigational Medicinal Products for Human Use, as well as the Requirements for Authorisation of the Manufacturing or Importation of such Products, CEC 9 European Parliament and the Council of the European Union (2014) Regulation (EU) No 536/2014 on Clinical Trials on Medicinal Products for Human Use, and Repealing Directive 2001/20/EC, EUR-Lex
Box 1. Correspondences between ethical imperatives and GCP guidelines and/or regulations I Comparison of the basic principles (preambles)
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1. The interests and welfare of the human being participating in research shall prevail over the sole interest of society or science (2005/28/EC Art. 2; EU/536/2014 Art 3.a).
IV Scientific validity Scientific design research (ICH E6 Art 2.5; 2005/28/EC Art. 2.3.; EU/536.2016 Art. 3.b).
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1. Scientific design and statistical methods satisfy generally accepted standards and achieve research objectives before approval and throughout 2. Study justified by previous studies and current knowledge (ICH E6 Art. 2.4; 5.12.1; 2005/28/EC Art. 3).
Protocol
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9. Design and performance of study must be justified in the protocol (ICH E6 Art 2.5; 5.23.1; 4.5.1; 4.5.3). Professionalism
11. Research conducted only by scientifically qualified persons. Highest degree of skill and care required through all stages (ICH E6 Art 2.8; 2005/28/EC Art. 2.2.; EU/526/2014 Art. 49; 73).
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12. Physicians who supervise patients must be competent and qualified (EU/536/2014 Art. 28.1.f).
VI Favorable benefit/risk ratio
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1. Risks and burdens minimized (EU/536/2014 Art. 28.1.e).
4. Risks monitored, assessed, and documented (ICH E6 Art. 5.18.1.a-c; EU/536/2014 Art. 28.1.a,e; Art. 48).
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12. Risk justified: risk does not outweigh potential benefits (risk to subjects outweighed by anticipated benefit to subject + anticipated benefit to society (ICH E6 Art. 2.2; EU/536/2014 Art. 28.1. a).
VII Independent review
REC Composition/requirements
1. Independent and competent (EU/536/2014 Art. 9.1.-2). 2. REC provides reasons for decision (ICH E6 Art. 3.1.2). 3. REC members should declare possible COI (EU/536/2014 Art. 9.1). 4. REC member with interest on a proposal should not take part in assessment (EU/536/2014 Art. 9.1). 5. REC must be multidisciplinary (EU/536/2014 Art. 9.2). 10. Financial assistance should not be provided directly to the REC to avoid conflict of interest and to safeguard the independence of their review. Instead, funds should be made available to appropriate authorities or to the host research institute (EU/536/2014 Art. 9.1). 11. Participation of laypersons important; the layperson should not be a healthcare professional nor have experience in carrying out biomedical research (EU/536/2014 Art. 9.3). 13. An REC must examine the following: (ICH E6 Art. 3.1.1). 13.3. If monetary and in-kind recompense constitute undue inducement (ICH E6 Art. 3.1.8).
For the investigator/sponsor 17. Every interventional study should be submitted to an REC for independent examination and approval (ICH E6 Art. 2.6.; EU/536/2014 Art. 4). 21. The following shall be provided to the REC: 21.1. Info about principal researcher (ICH E6 Art. 3.1.2-3). 21.9. Nature and degree of foreseeable risks (ICH E6 Art. 3.1.2). 21.12. Timing and details of info and the means proposed for the provision of info (ICH E6 Art. 3.1.2). 21.13. Documentation for IC/authorization for participation (ICH E6 Art. 3.1.2). 21.16. Details of all payments/rewards (ICH E6 Art. 3.1.2.; 3.1.8).
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22. REC may request for additional necessary information (ICH E6 Art. 3.1.2.; 3.1.5). 23. No protocol amendment w/o REC approval (ICH E6 Art. 3.1.2). 24. Unexpected or unforeseen adverse reactions must be reported to the REC for prompt review as they occur (EU/536/2014 Art. 41.1-4; 42.1.a.c.; 44.3.3.; 53.1).
VIII Informed consent Securing consent 4. Consent preferably in writing; if not, must be formally documented and witnessed (EU/536/2014 Art. 29.1.; 29. 3.; 29.7).
Information
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7. Potential participants must be informed of the following: 7.1. Anticipated benefits (EU/536/2014 Art. 29.2.a.i). 7.2. Right to withdraw without reprisal (EU/536/2014 Art. 28.2.-3; 29.2.a.iii). 7.3. Aims (EU/536/2014 Art. 29.2.a.i).
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7.4. Methods/procedures (EU/536/2014 Art. 29.2.a.iii). 7.6. Institutional affiliations of researchers (EU/536/2014 Art. 28.1.g).
7.7. All risks and discomforts that a reasonable person would consider material (EU/536/2014 Art. 29.2.a.i). 7.11. Rights to refuse to participate (EU/536/2014 Art. 29.2.a.ii).
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7.8. Any current alternative interventions (EU/536/2014 Art. 29.2.a.iv). 7.20. Compensation, if any, in case of damage, disability or death (EU/536/2014 Art. 29.2.d).
7.37. Duration of participation (including number and duration of visits (EU/536/2014 Art. 29.2.a.iii). 7.38. Possibility of early termination of trial or of participation (EU/536/2014 Art. 29.2.a.iv).
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8. Information complete, accurate, and not overwhelming (EU/536/2014 Art. 29.2.b).
Comprehension
15. Participants’ comprehension of information must be ensured (EU/536/2014 Art. 29.5).
17. Means must be used to ensure potential participant’s understanding of procedure (EU/536/2014 Art. 29.2.c;29.4).
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Voluntariness
20. IC must be voluntarily obtained for all biomedical research involving humans (ICH E6 Art. 2.9). 21. Participants must be actually free to refuse or to withdraw (EU/536/2014 Art. 28.2.-3). 22. Potential participant must be given enough time to decide (EU/536/2014 Art. 29.1). 23. Prospective subject must not be exposed to undue influence (e.g., asking spouse or community leader to influence decision) (EU/536/2014
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Person obtaining consent
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24. Payments/services should not lead to undue inducement to participate (EU/536/2014 Art.28.1.h).
35. Person obtaining informed consent must be knowledgeable about the research and is capable of answering questions (EU/536/2014 Art. 29.2.c).
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37. IC necessary for research using identifiable human material or data; when consent is impossible or impracticable, permission from REC still necessary (EU/536/2014 Art. 28.2).
IX Respect for participants Participant safety
2. Criteria for changing dose or procedures for stopping the study for the health of the participants must be adequate (EU/536/2014 Art. 54.1). 3. All reasonable means should be taken to ensure safety (that death or disabling injury will not occur) (EU/536/2014 Art. 3.a). 4. To protect participants from injury, disability or death: 4.1. Adequate healthcare facilities provided and incorporated in study for the safe conduct of research (EU/536/2014 Art. 50). 7. Research shall not delay nor deprive participants of medically necessary preventative, diagnostic, or therapeutic procedures. Treatment of patient should not be altered in a detrimental manner to facilitate research (EU/536/2014 Art. 54.1).
Dissemination of research results to participants/community 13. Everyone is entitled to know the information collected about one’s health; however, one’s wishes to not be informed shall be respected (EU/536/2014 Art. 29.6). 17. There must be sufficient care on the manner of disseminating research results to the participants and the community (EU/536/2014 Art. 29.6).
Privacy/confidentiality 18. Confidentiality procedures must be effectively implemented (EU/536/2014 Art. 56.2). 19. The confidentiality of the subject’s research data must be protected (ICH E6 Art. 2.11.; EU/536/2014 Art. 28.1.d.; 56.1.-2).
Compensation 23. There must be appropriate compensation for subjects harmed due to research participation; in case of death, compensation goes to dependents (EU/536/2014 Art. 29.2.d.; 76.1.; 76.3). 25. A subject who withdraws due to research related reasons (such as unacceptable side-effects). or due to health grounds should be paid in full (ICH E6 Art. 3.1.8).
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26. A subject who withdraws for any other reason other than research or health related should be paid in proportion to the amount of participation (ICH E6 Art. 3.1.8).
Physicians and participants 30. Clinical professional who supervises the research should always be accessible to the participants and ready to respond to their health concerns (EU/536/2014 Art. 28.1.g).
XI Special populations Vulnerable population in general 5. RECs reviewing proposals directed at specific diseases or impairments or involving vulnerable people should invite representatives or
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advocates (EU/536/2014 Art. 10.2.; 10.4).
Persons not able to consent (including minors). 9. Research on a person without the capacity to consent may be undertaken only if all are met:
9.2. Assent is secured and dissent respected (EU/536/2014 Art. 29.8.; 31.1.c.; 32.1.c).
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9.1. Necessary authorization given specifically in writing by the legal representative, taking into account the individual’s previously expressed wishes and objections (EU/536/2014 Art. 31.1.a; 32.1.a).
9.3. Research of comparable effectiveness cannot be carried out on individuals capable of consent (i.e., condition necessary characteristic of
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the research group). (EU/536/2014 Art. 31.1.e., f.; 32.1.e.,f).
9.4. Results of the research must have the potential to produce real and direct benefit (EU/536/2014 Art. 31.1.g.,i.; 32.1.g.,i). 9.6. An adult not able to consent shall as far as possible take part in the authorization procedure. The opinion of a minor shall be taken into consideration as an increasingly determining factor in proportion to age and degree of maturity (EU/536/2014 Art. 29.8; 31.1.b.; 31.3.; 32.1.b.;32.2).
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10. Non-therapeutic research may be authorized subject to the following: (ICH E6 3.1.6).
10.1. Minimal (low). risk and minimal (low). burden (i.e., medical test standard).; any consideration of additional potential benefits of the research shall not be used to justify an increased level of risk or burden (EU/536/2014 Art.31.1.g.ii.; 32.1.g.ii). 10.2. Research aims to contribute through significant improvement in scientific understanding of the individual’s condition, disease or disorder (EU/536/2014 Art. 31.1.g.ii.; 32.1.g.ii).
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13. When subjects initially unable to consent become capable of consenting, their consent for continued participation must be secured (EU/536/2014 Art. 32.3).
18. The guardian asked to give permission should be offered no recompense other than a refund of travel and related expenses (EU/536/2014 Art. 31.1.d.; 32.1.d).
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19. For individuals physically or mentally unable to consent, and consent from a legal rep cannot be obtained, study may proceed provided that reasons stated in protocol and REC approved. Consent must be secured a.s.a.p. (ICH E6 Art. 3.1.7). 21. In emergency research where prior research is not possible, participants, or their representatives if relevant, should be given all relevant
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information as soon as they are in the state to receive it, and their consent to continued participation should be obtained as soon as is reasonably possible (EU/536/2014 Art. 35.1.a.,c.; 35.2.a.-b).
24. Research of comparable effectiveness cannot be carried out in persons in nonemergency situations (EU/536/2014 Art. 35.1.e).
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30. Nontherapeutic emergency research may be justifiable given the following, 30.2. Minimal risk and minimal burden (EU/536/2014 Art. 35.1.f).
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33. Research in this population should be performed only if 33.1. it is relevant to the particular health needs of a pregnant woman or her fetus, or to the health needs of pregnant women in general (broadly understood). (EU/536/2014 33.a).
33.3. Special safeguards should be established to prevent undue inducement to pregnant women to participate in research in which interventions hold out the prospect of direct benefit to the fetus (EU/536/2014 Art. 33.d). 34. Research on a pregnant woman that does not have the potential to produce results of direct benefit to her health, or to that of her embryo, fetus or child after birth, may only be undertaken if the following additional conditions are met: 34.1. 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, fetuses or children, broadly understood; (EU/536/2014 Art. 33.b.ii). 34.2. Research of comparable effectiveness cannot be carried out on women who are not pregnant; (EU/536/2014 Art. 33.b.i). 34.3. The research entails only minimal risk and minimal burden (EU/536/2014 Art. 33.b.iii). 35. Where research is undertaken on a breastfeeding woman, particular care shall be taken to avoid any adverse impact on the health of the child (EU/536/2014 Art. 33.c).
Box 2. Recommendations based on the correspondences (and lack thereof) between ethical imperatives and GCP regulations Within areas with correspondences between imperatives and GCP regulations, there is the need to further specify what exactly the ethical responsibilities are of clinical assessors and GCP inspectors. The cooperation between regulators and research ethics committees must be further developed and expanded for the specific purpose of covering the gap areas (i.e., areas covered by ethical imperatives but not by GCP regulations). The inclusion of the GCP regulations that are not directly pairable to any imperative, but are nevertheless ethical in nature, must be considered in future versions of international ethics guidelines for human research.
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The discordant areas between ethical imperatives and GCP regulations must be addressed through the cooperation of regulatory and ethicsguideline bodies.
Percentage correspondence between GCP articles and framework imperatives (no. of GCP articles/number of framework imperatives)
Principles (10) Collaborative partnerships (7) Social value (25) Scientific validity (37) Fair participant selection (8) Favorable benefit:risk ratio (25) Independent review (80) Informed consent (98) Respect for participants (36) Publication, registration, and regulatory sanctions (6) Special populations (52)
10% (1/10) None (0/7) None (0/25) 13.5% (5/37) None (0/8) 12% (3/25) 22.5% (18/80) 22.4% (22/98) 36.1% (13/36) 16.7% (1/6)
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Ethical framework sections (no. of imperatives per section)
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Table 2. Percentage of the pairing of GCP articles with ethics imperatives
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40.4% (21/52)
Table 3. GCP guidelines/regulations that are ethically relevant but are not directly pairable to any ethical imperative Regulations that are ethically relevant but are not pairable to any imperative
Informed consent
EU/536/2014, Art. 30. 1-4: discusses the requirements for informed consent in cluster randomized trials; specifically, it provides the requirements for the acceptability of simplified informed consent in such trials EU/536/2014, Art. 31.1.d. For clinical trials on incapacitated subjects, it states that no incentives or financial inducements must be given to the subjects (and not only to the legal representatives) EU/536/2014, Art. 35.1.d. For clinical trials in emergency situations, it states that, before the inclusion of participants without IC, the investigator must certify that they are not aware of previously expressed objections to participation in clinical trials by the participant EU/536/2014, Art. 35.3. For clinical trials in emergency situations, it states that, once IC is sought and the participant or the legal representative denied consent, the participant or legal representative shall be informed of the right to object to the use of data obtained from the study 2005/28/EC, Art. 6.2: states that RECs should retain essential documents of a clinical trial for at least 3 years 2005/28/EC, Art. 6.3: states that efficient and appropriate communication of information between RECs and competent authorities should be maintained 2005/28/EC, Art. 8.3: states that the sponsor should validate and update the investigator’s brochure yearly
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Sections from the ethics framework
*Note that, although we included the explanatory reports from these guidelines in our ethics framework, the appendices were excluded. †As stated in footnote*, the appendices of the ethics guidelines were not included in the framework. Given that the CIOMS appendices include the list of the sections that ought to be present in a protocol, Annex 1 in EU 536/2014 and Section 6 of Directive 75/318/EEC that enumerate the required contents of a protocol were also not included in our analysis.
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S1359-6446(15)00425-0 http://dx.doi.org/doi:10.1016/j.drudis.2015.11.006 DRUDIS 1712
To appear in: Received date: Revised date: Accepted date:
2-6-2015 2-11-2015 10-11-2015
Please cite this article as: Bernabe, R.D.L.C., van Thiel, G.J.M.W., Breekveldt, N.S., van Delden, J.M.,Drug regulators and ethics: which GCP issues are also ethical issues?, Drug Discovery Today (2015), http://dx.doi.org/10.1016/j.drudis.2015.11.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Research highlights for Drug regulators and ethics: which GCP issues are also ethical issues?
1. Of the 384 imperatives of the ethics framework for biomedical research involving human participants, GCP covers 21.88%.
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2. The ethics mandate of drug regulators falls within the following sections of the ethics framework: principles; favorable benefit-risk ratio; scientific validity; publication registration, and regulatory sanctions; (independent review); IC; respect for participants; and special populations.
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3. There were GCP articles that though would fall within the sections of the ethics framework but were not directly pairable to any imperative.
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4. At the same time, there were regulations that were stricter than the ethical imperatives.
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Drug regulators and ethics: which GCP issues are also ethical issues?
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Rosemarie D.L.C. Bernabe1, Ghislaine J.M.W. van Thiel1, Nancy S. Breekveldt2, and Johannes J.M. van Delden1 1
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Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands 2 Dutch Medicines Evaluation Board, Graadt van Roggenweg 500, 3531 AH Utrecht, the Netherlands Corresponding author: Bernabe, R.D.L.C. ([email protected]) Keywords: GCP; ethics; regulation; EU; guidelines. Teaser: The mandate of drug regulators is not only scientific, but also ethical.
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Within the European Union (EU), good clinical practice (GCP) provides an ethical mandate to regulators; however, it is unclear what the content of that mandate is. By looking at the correspondence between GCP and ethical imperatives, we identify that the mandate is within the following: principles; benefit:risk ratio; scientific validity; results publication; informed consent; respect for participants; and special populations. There are also cases when regulations were ethical but were not pairable to an imperative, and when the former were stricter than latter. Hence, we suggest closer cooperation between ethics committees and regulators to ensure that future versions of ethics guidelines cover the ethically relevant regulations that were not directly pairable to any imperative, and cooperation between GCP legislative bodies and ethics guideline-making bodies to resolve the discordant areas.
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Introduction
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Regulators in the pharmaceutical environment execute not only a scientific, but also an ethical mandate: they assess and inspect using GCP as a framework, with GCP defined as ‘an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects’ [1]. For example, a 2012 European Medicines Agency (EMA) document [2] expects regulators to have the skillset to identify and act upon ethical issues. However, given that this document is meant for clinical trials conducted outside the EU/European Economic Area (EEA), it would be logical to think that regulators are expected to utilize the same ethics skillset for clinical trials conducted within the EU/EEA. It would be unreasonable to expect regulators to cover all ethical aspects present in the various international ethics guidelines. The ethical mandate of regulators is clearly limited by what is within GCP. However, the problem is that it is still unclear what the contents of this ethical mandate are. Here, we specify which ethical issues we can expect regulators to identify and act upon by looking at the concordance between regulation (i.e., GCP) and ethics. We define the current field of ethics that is relevant to regulators. By regulators, we refer to those involved in marketing authorization applications (MAAs) for medicines, which include clinical assessors and GCP inspectors. As the regulators immediately responsible for the evaluation of clinical trial data within a MAA, it is reasonable to think that, at the very least, they share the responsibility for identifying and addressing the ethical issues mentioned above. Given that they evaluate clinical trial data after the fact[LM1], these regulators would ideally identify and then address ethical issues retrospectively through means such as sanctions and warnings, among others. To understand which ethical issues we can reasonably expect to be within the mandate of regulators, it was necessary to pair an ethics framework with GCP documents because GCP is the framework for clinical trial regulation. Before identifying and extracting the articles from the directives and/or guidelines that relate to ethics, we created a robust ethics framework on which the extraction would be based. We did this by putting together the Nuremberg Code ( imperatives from five international ethics guidelines: http://www.hhs.gov/ohrp/archive/nurcode.html), Declaration of Helsinki [3], Belmont Report [4], Council of Europe’s Additional Protocol [5], and CIOMS International Ethical Guidelines for Biomedical Research [6] (as detailed in the supplementary material online)*. Using this framework, we identified and extracted the ethically relevant articles from the three EU documents on harmonized GCP [7]†: ICH-GCP E6 [1], Directive 2005/28/EC [8], and EU 536/2014 [9]. The first document was created by the International Conference on Harmonization (ICH) to ‘provide a unified standard for the EU, Japan and the United States’ [1]. Within the EU, two directives were introduced to harmonize the conduct of clinical trials: 2001/20/EC and 2005/28/EC [7]. In place of the repealed 2001/20/EC, we looked at 536/2014. After extracting the relevant GCP articles (henceforth termed ‘regulation’) from the documents, these were explicitly paired with the corresponding ethics imperative (henceforth termed ‘imperative’) from the ethics framework (the pairing is henceforth termed ‘correspondence’). Correspondences were based on complete (i.e., a
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regulation and an imperative are identical) to at least mild similitude (i.e., a regulation is similar but not identical to an imperative). When a correspondence was based on identity, no distinction between imperative and regulation was made (e.g., we simply say ‘…the interests and the welfare of the research participants prevail over the sole interest of science and society’). However, when a correspondence was based on mild similitude, both the imperative and the regulation are provided [e.g., we say, ‘the imperative that informed consent (IC) must be secured in writing…corresponds with the regulation that IC must be dated and signed by the person performing the interview and the participant…’]. Correspondences and the lack thereof between imperatives and regulations
Correspondences between regulations and our ethics framework
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Principles
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Corresponding to the major themes of the ethical requirements in human research, the ethics framework we created has the following 11 sections: principles; collaborative partnerships; social value; scientific validity; fair participant selection; favorable benefit:risk ratio; independent review; IC; respect for participants; publication, registration, and regulatory sanctions; and special populations (see the supplementary material online). Of the 11 sections in the ethics framework, eight had correspondences (Box 1). The following three sections did not have correspondences: collaborative partnerships, social value, and fair participant selection. This means, for example, that of the seven imperatives within ‘collaborative partnerships’, no matching articles were found. Of the sections with correspondences, most correspondences were found in special populations (40.4%), respect for participants (36.1%), and independent review (22.5%). Table 1 presents the percentages of the correspondences per section. Here, we first elaborate on the contents of the correspondences within the eight sections. We then look at regulations that are ethical in nature but are not pairable with any of the imperatives.
Of the ten imperatives in this section, one correspondence was found. Specifically, there was correspondence that the interests and the welfare of the research participants prevail over the sole interest of science and society. Scientific validity
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Of the 37 imperatives in this section, five correspondences were found specifically on the themes of scientific design, protocol compliance, and the qualifications of the research staff. The scientific design and statistical methods of research must be sound. This means that, among others, there must be sufficient basis for the study and the study design in current knowledge and previous efficacy and safety data from nonclinical and/or clinical studies. In terms of the protocol, a detailed protocol that contains the justification of the design and performance of the study is a necessity. This protocol, once approved by the research ethics committee (REC) and other relevant authorities, must always be complied with. The investigator and the clinical trial staff must be scientifically qualified individuals; that is, they are qualified in terms of education, training, and experience to perform their tasks. Also, they are required to always perform their tasks with the highest degree of skill and care. Related to this is the area of correspondence that says that the medical care and supervision of the participants must be entrusted to a competent and qualified physician (or dentist). Favorable benefit:risk ratio
Of the 25 imperatives in this section, three correspondences were found. First is the necessity of minimizing pain, discomfort, fear, and other risks and inconveniences as much as possible in a study; second is the necessity of constantly monitoring the degree of distress and the risk threshold; third is the necessity of ensuring that risks are justified; that is, that the anticipated benefits to individuals and public health justify the risks and inconveniences to the participants. Independent review
Of the 80 imperatives in this section, 18 correspondences were found within the themes of REC composition/requirements, REC rights and responsibilities, and the responsibilities of the investigator and/or sponsor. In terms of REC requirements, REC members must be independent from the sponsor and the investigators; they should not have financial or personal interests that could affect their impartiality as assessors; and they should regularly declare any possible conflicts of interest. With regard to REC composition, the imperative that a REC must be multidisciplinary corresponds with the regulation that assessment must be done by a sufficient number of people who, as a group, have the needed qualifications and experience to make the assessment. There is also correspondence with the necessity of the inclusion of a layperson in the REC. As for REC rights and responsibilities, the imperative that a REC should provide reasons for its decisions corresponds with the regulation that the REC should document its views in writing. There is also correspondence between the imperative that the REC must examine several aspects of a study (such as risks and benefits, IC procedures, selection of participants, among others) and the regulations that RECs should safeguard the rights, safety, and wellbeing of all the participants, and that RECs should pay special attention to studies that include vulnerable participants. Lastly, RECs are tasked to ensure that monetary and in-kind recompense do not constitute undue inducement. Concerning the responsibilities of the investigator and/or sponsor, there is correspondence that every interventional study shall be submitted to a REC for review and approval. The information and/or documents that
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the investigator and/or sponsor must submit to the REC for assessment and approval are as follows: information about the principal researcher through a curriculum vitae or other documentation of the investigator; nature and degree of foreseeable risks through available safety information; recruitment procedures, written information provided to the participants, and the IC forms or IC form updates; details of payments and compensation; trial protocol or protocol amendments; any other document that the REC deems necessary for assessment. Protocol amendment by the investigator and/or sponsor is not possible without the approval of the REC. Regarding the imperative that unexpected or unforeseen adverse reactions must be reported by the investigator and/or sponsor to the REC for prompt review, the corresponding regulation states that the REC, together with the regulators, must be involved in the assessment of suspected unexpected serious adverse reactions and annual reports. Informed consent
Respect for participants
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Of the 98 imperatives in this section, 22 correspondences were found within themes of securing consent, information given to the participants, comprehension and voluntariness of the participants, and the use of data outside the protocol. The imperative that securing IC must be in writing and, if that is not possible, securing of consent must be formally documented and witnessed, corresponds with the regulation that IC must be dated and signed by the person performing the interview and the participant, or in the case of incapacity, the participant’s legal representative. The person securing consent must be appropriately qualified, knowledgeable about the research, and capable of answering questions from the prospective participants. After consent is secured, the participant or the participant’s representative should be given a copy of the IC document. In terms of the information given to the participants, it must be comprehensive, accurate, relevant, but not overwhelming; that is, it must be understandable to a layperson. Specifically, the potential participants must be informed of the following: anticipated benefits, right to refuse and to withdraw without reprisal and without the need for a justification; objectives of the study; methods and procedures; risks and inconveniences; current alternative interventions, if any; damage compensation system in place; expected duration of the participants’ participation in the study; and the possibility of early termination of participation and follow-up measures. In the process of providing information, the comprehension of the participants must be ensured and verified. This means that, according to another correspondence, attention should be paid to the means and methods used to provide the information and that the informational needs of specific populations should always be taken into account. Aside from comprehension, the voluntariness of the participants during the IC process must also be ensured. This closely relates to the following correspondences: the participant’s right to refuse and withdraw without reprisal must also be ensured; that adequate time is provided for the participants to decide; that the participants must not be exposed to undue influence in the decision-making process; and that fees and other incentives do not constitute undue inducement. Lastly, the use of data outside the protocol for scientific purposes also needs IC.
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Of the 36 imperatives in this section, 13 correspondences were found within the themes of participant safety, privacy/confidentiality, dissemination of results, compensation, and the responsibilities of researching physicians to the research participants. All reasonable means should be taken to ensure participant safety. Four other correspondences specify what this means: first, the imperative that monitoring of the health of the participants to minimize harm, particularly through the task of the Data and Safety Monitoring Board to protect participants from previously unknown adverse reactions and unnecessary prolonged exposure to inferior therapy, which corresponds with the regulation that one of the purposes of monitoring is the verification that the rights and wellbeing of the participants are protected. Second, adequate healthcare facilities for the safe conduct of the research must be provided. Third, there must be adequate criteria for changing dose or procedures for stopping the study for the sake of the health of the participants. Fourth, research is not enough justification to alter the treatment of patients in a detrimental manner. Aside from participant safety, the confidentiality of the participants’ data must also be kept. Concerning dissemination of results, imperatives state that everyone is entitled to know about the information collected about one’s health and that sufficient attention must be placed on the manner of disseminating the results to the participants and the community. These correspond with regulations that the participant must be informed of the summary results of a study and that a summary understandable to a layperson shall be made available in the EU database. Regarding compensation, there must be appropriate compensation for participants who were harmed as a result of research. By contrast, for participants who withdraw because of research-related or health-related reasons, an imperative states that they must be paid in full, while those who withdraw for any other reason should be paid in proportion to their participation. This imperative corresponds with a regulation that states that payments to participants must be prorated and not wholly dependent on completion of trial participation. In terms of the responsibility of researching physicians to the participants, the imperative that the clinical professional supervising the participants must be easily accessible and ready to respond to the health concerns of the participants corresponds with the regulation that participants must be provided with the contact details of the
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entity or person from whom information may be received in case of need. Also, the imperative that states that the physician involved in research must protect the life, health, dignity, integrity, right to self-determination, privacy, and confidentiality of the participants corresponds with the regulation that medical care and the medical decisions made on behalf of the participants must be the responsibility of a qualified physician. Publication, registration, and regulatory sanctions
Of the six imperatives in this section, there was a correspondence on the theme of study registration. The imperative that every study involving human participants must be registered in a publicly available database corresponds with the regulation that sponsors should notify concerned Member States about the start of a trial through the EU Portal and that summaries in lay language should be made available in the EU database.
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Special populations
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Of the 52 imperatives in this section, 21 correspondences were found on themes of vulnerable populations in general, persons not able to consent, emergency research, and pregnant or breastfeeding women. For the vulnerable populations in general, the imperative that REC review of a study involving vulnerable individuals should invite representatives or advocates corresponds with the regulation that for the assessment of the clinical trial application, experts in the relevant condition and representatives from the population concerned must be invited. For persons not able to consent, including minors, research on individuals unable to consent may be acceptable if data of comparable validity cannot be obtained from individuals able to consent and that the condition (either the illness or the condition of being a minor) is a necessary characteristic of the research group. The research must also have the potential to produce direct benefits to the participants that outweigh the risks and the burdens. In the event that the research has no potential to produce direct benefits (i.e., nontherapeutic research), such research might be acceptable if the risks and burdens are minimal (in comparison with standard therapy for the condition) and if there are scientific grounds to expect some benefits to the population represented by the incapacitated participant. In terms of the inclusion of persons not able to consent in a study, the IC of a legal representative is necessary. This legal representative, according to another correspondence, shall receive no recompense other than refund for travel and related expenses. In the event that the person unable to consent is capable of forming an opinion and assessing information, their assent or dissent shall be respected; that is, the participant must be involved in the IC procedure as much as possible. In the case of minors, their opinion is increasingly a determining factor in proportion to their age and level of maturity. There might be situations when a participant is initially unable to consent but gains the competence to consent within the duration of the study. In such cases, the consent of the participant must be secured for their continued participation. There could also be situations when the inclusion of persons unable to consent is necessary and the protocol indicates that prior IC of the legal representative is not possible. In such cases, the inclusion of persons unable to consent might still be allowable with the approval of the REC. In such cases, IC must be secured as soon as possible. In emergency research, when the IC of the participant or legal representative cannot be reasonably secured because of the urgency of the situation, inclusion is possible with the approval of the REC. The participant’s or the legal representative’s IC must be secured for continued participation as soon as possible. Such a study is justifiable only when research of comparable effectiveness cannot be achieved with persons in nonemergency situations. Also, risks and burdens must be minimal in comparison with standard treatment. Regarding pregnant or breastfeeding women, the inclusion of pregnant women in therapeutic studies is ethically acceptable when the study is relevant to the health needs of the pregnant woman or her fetus; and the trial has the potential to produce direct benefits for the pregnant or breastfeeding woman, fetus, embryo, or children. Undue inducement must be prevented. Nontherapeutic studies might be acceptable if they aim to contribute to attaining results that are capable of benefitting other pregnant or breastfeeding women, or to fetuses, embryos, or children; research of comparable effectiveness cannot be carried out on women who are not pregnant or who are not breastfeeding; and risks to the pregnant or breastfeeding woman, and to her fetus, embryo, or child, are minimal. When research is undertaken on breastfeeding women, utmost care must be in place to avoid any adverse effect on the health of the child. Regulations that are ethically relevant but are not pairable to any imperative from the ethics framework
In the process of identifying correspondences between imperatives and regulations, we noted that there were also regulations that are more specific than the imperatives. Table 2 contains regulations from EU 536/2014 and 2005/28/EC that might fall within the larger sections of the ethics framework but are not directly pairable to any imperative. GCP articles that are stricter than ethical imperatives
Lastly, there were also GCP requirements from EU/536/2014 that were stricter than the ethics imperatives. For one, Article 33.d states that no incentives or financial inducements must be given to the participants in a clinical trial on and about pregnant or breastfeeding women. By contrast, an ethics imperative states that there should be special safeguards to prevent undue inducement, but it does not explicitly say that incentives or inducements must be banned from such trials. Also, Article 35.1.b states that clinical trials in emergency situations must have the
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potential to produce direct benefits to the participants (i.e., these studies must be therapeutic in nature). By contrast, an ethics imperative accepts nontherapeutic emergency studies within conditions. The latter specifically says that nontherapeutic clinical trials in emergency situations might be acceptable when such a study aims to significantly contribute to the scientific understanding of the patients’ condition, disease, or disorder; and risks are minimal. Recommendations
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We stated in the introduction that GCP is the framework for clinical trials regulation. It is the frame of reference of the regulators, not to mention everyone else involved in a clinical trial. To understand which ethical issues we can reasonably expect to be within the mandate of regulators, it was necessary to pair our ethics framework with the three GCP documents. Our results provide the areas of correspondence (with the exception of the correspondences in ‘independent review’, because the latter apply specifically to RECs and not to clinical assessors or inspectors). Thus, as a response to the question on which ethical issues we can expect regulators to identify and act upon, regulators are mandated to be engaged in the ethical issues specifically within the following sections: principles; favorable benefit:risk ratio; scientific validity; publication registration, and regulatory sanctions; (independent review); IC; respect for participants; and special populations. Within these sections, of the 384 imperatives in the ethics framework, 84 (21.88%) are covered by GCP; hence, only this percentage of this ethics framework is within the mandate of the regulators. Within these areas of correspondence, further studies are needed to specify the ethical responsibilities of clinical assessors and GCP inspectors. Table 1 shows that, at best, GCP articles cover 40.4% of the imperatives in a given section. Given this gap, the question of who should be enforcing these must be raised. Some areas will be covered by RECs, but it would be unfair to say that the uncovered areas are, by default, to be enforced by the REC. We have two options: the mandate of the regulators can be expanded to include the areas within the gap or the cooperation between regulators and RECs must be further developed and expanded for the specific purpose of covering these gap areas. Intuitively, the latter seems more reasonable. Further studies are needed to explore the current state of affairs in terms of REC–regulator cooperation, how this cooperation may be improved to cover the gap areas, and how the gap areas must be delegated to either the RECs or the regulators, among others. Apart from identifying areas in the ethics framework that are not covered by GCP, we noted that there are also regulations that are not directly pairable to any imperative (Table 2). As stated above, these regulations fall well within the sections of informed consent, independent review, and special populations. As such, these sections are undeniably not only regulatory mandates, but also imperatives. Given their ethical relevance, it might be best to consider the inclusion of such specifications in future versions of international ethics guidelines for human research. Lastly, in the Recommendations section above, we showed that some regulations are in fact stricter than the imperatives (i.e., that in a few sections, there are discordances between regulations and imperatives). The persistence of this discordance might cause unwanted divergence between regulators and RECs, for example, on the issue of what constitutes undue inducement on trials with pregnant women. This discordance must be addressed through the cooperation of regulatory and ethics-guideline bodies. Hence, further studies on how to address the discordant areas are also needed. Box 2 presents a summary of the recommendations. This study is limited by the fact that we concentrated on European Commission documents on harmonized GCP. There are other regulatory guidelines on the use of placebo, for example, that we did not consult. However, because we are working at the level of mandates, principles, and imperatives, we thought it sufficient to limit ourselves to GCP regulations and to not include study-type specific guidelines. Also, we excluded the appendices of the ethics guidelines (and the CIOMS appendix contained the list of necessary contents of a protocol) in our analysis, and hence Annex 1 in EU 536/2014 and Section 6 of Directive 75/318/EEC that enumerated the required contents of a protocol were also excluded. Concluding remarks
Ethics imperatives and GCP regulation corresponded, at least in some aspects, within the following areas: upholding the basic principles; favorable benefit:risk ratio; scientific validity; publication registration, and regulatory sanctions; IC; respect for participants; and special populations. This means that, at most, the ethics mandate of regulators lies within these areas. Further studies are needed to specify the responsibilities of assessors and GCP inspectors within these areas. Next, because the ethics mandate of the regulators, even within these areas, is understandably limited by GCP, closer cooperation between RECs and regulators must be developed specifically to cover the gaps. We also saw that there were GCP requirements that were more specific than the imperatives. We recommend these specificities to be covered in future versions of ethics guidelines. Lastly, there were discordant areas (i.e., areas where the ethics imperatives and GCP regulations conflict). We recommend the cooperation of GCP legislative bodies and ethics-guideline making bodies specifically to resolve these discordant areas. Conflicts of interest R.D.L.C.B. and G.J.M.W.vT. received funding for this research from the Dutch Medicines Evaluation Board. N.S.B. works as a clinical assessor in the Dutch Medicines Evaluation Board. Acknowledgement This project was funded by the Dutch Medicines Evaluation Board. The views expressed by the authors are their personal views and may not be understood or quoted as being made on behalf of or reflecting the position of the Dutch Medicines Evaluation Board.
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References 1 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (1996) Guideline for Good Clinical Practice E6(R1), ICH 2 EMA, (2012) Reflection Paper on Ethical and GCP Aspects of Clinical Trials of Medicinal Products for Human Use Conducted Outside of the EU/EEA and Submitted in Marketing Authorization Applications to the EU Regulatory Authorities, EMA 3 World Medical Association, (2013) Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects, WMA / 4 US National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1979) The Belmont Report, Department of Health, Education, and Welfare 5 Council of Europe (2005) Additional Protocol to the Convention on Human Rights and Biomedicine, Concerning Biomedical Research, COE 6 Council for International Organizations of Medical Sciences (2002) International Ethical Guidelines for Biomedical Research Involving Human Subjects, CIOMS 7 Tobin, J.J. and Walsh G. (2008) Medical Product Regulatory Affairs: Pharmaceuticals, Diagnostics, Medical Devices, Wiley-VCH 8 Commission of the European Communities (2005) Commission Directive 2005/28/EC Laying Down Principles and Detailed Guidelines for Good Clinical Practice as Regards Investigational Medicinal Products for Human Use, as well as the Requirements for Authorisation of the Manufacturing or Importation of such Products, CEC 9 European Parliament and the Council of the European Union (2014) Regulation (EU) No 536/2014 on Clinical Trials on Medicinal Products for Human Use, and Repealing Directive 2001/20/EC, EUR-Lex
Box 1. Correspondences between ethical imperatives and GCP guidelines and/or regulations I Comparison of the basic principles (preambles)
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1. The interests and welfare of the human being participating in research shall prevail over the sole interest of society or science (2005/28/EC Art. 2; EU/536/2014 Art 3.a).
IV Scientific validity Scientific design research (ICH E6 Art 2.5; 2005/28/EC Art. 2.3.; EU/536.2016 Art. 3.b).
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1. Scientific design and statistical methods satisfy generally accepted standards and achieve research objectives before approval and throughout 2. Study justified by previous studies and current knowledge (ICH E6 Art. 2.4; 5.12.1; 2005/28/EC Art. 3).
Protocol
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9. Design and performance of study must be justified in the protocol (ICH E6 Art 2.5; 5.23.1; 4.5.1; 4.5.3). Professionalism
11. Research conducted only by scientifically qualified persons. Highest degree of skill and care required through all stages (ICH E6 Art 2.8; 2005/28/EC Art. 2.2.; EU/526/2014 Art. 49; 73).
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12. Physicians who supervise patients must be competent and qualified (EU/536/2014 Art. 28.1.f).
VI Favorable benefit/risk ratio
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Risks
1. Risks and burdens minimized (EU/536/2014 Art. 28.1.e).
4. Risks monitored, assessed, and documented (ICH E6 Art. 5.18.1.a-c; EU/536/2014 Art. 28.1.a,e; Art. 48).
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Assessment
12. Risk justified: risk does not outweigh potential benefits (risk to subjects outweighed by anticipated benefit to subject + anticipated benefit to society (ICH E6 Art. 2.2; EU/536/2014 Art. 28.1. a).
VII Independent review
REC Composition/requirements
1. Independent and competent (EU/536/2014 Art. 9.1.-2). 2. REC provides reasons for decision (ICH E6 Art. 3.1.2). 3. REC members should declare possible COI (EU/536/2014 Art. 9.1). 4. REC member with interest on a proposal should not take part in assessment (EU/536/2014 Art. 9.1). 5. REC must be multidisciplinary (EU/536/2014 Art. 9.2). 10. Financial assistance should not be provided directly to the REC to avoid conflict of interest and to safeguard the independence of their review. Instead, funds should be made available to appropriate authorities or to the host research institute (EU/536/2014 Art. 9.1). 11. Participation of laypersons important; the layperson should not be a healthcare professional nor have experience in carrying out biomedical research (EU/536/2014 Art. 9.3). 13. An REC must examine the following: (ICH E6 Art. 3.1.1). 13.3. If monetary and in-kind recompense constitute undue inducement (ICH E6 Art. 3.1.8).
For the investigator/sponsor 17. Every interventional study should be submitted to an REC for independent examination and approval (ICH E6 Art. 2.6.; EU/536/2014 Art. 4). 21. The following shall be provided to the REC: 21.1. Info about principal researcher (ICH E6 Art. 3.1.2-3). 21.9. Nature and degree of foreseeable risks (ICH E6 Art. 3.1.2). 21.12. Timing and details of info and the means proposed for the provision of info (ICH E6 Art. 3.1.2). 21.13. Documentation for IC/authorization for participation (ICH E6 Art. 3.1.2). 21.16. Details of all payments/rewards (ICH E6 Art. 3.1.2.; 3.1.8).
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22. REC may request for additional necessary information (ICH E6 Art. 3.1.2.; 3.1.5). 23. No protocol amendment w/o REC approval (ICH E6 Art. 3.1.2). 24. Unexpected or unforeseen adverse reactions must be reported to the REC for prompt review as they occur (EU/536/2014 Art. 41.1-4; 42.1.a.c.; 44.3.3.; 53.1).
VIII Informed consent Securing consent 4. Consent preferably in writing; if not, must be formally documented and witnessed (EU/536/2014 Art. 29.1.; 29. 3.; 29.7).
Information
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7. Potential participants must be informed of the following: 7.1. Anticipated benefits (EU/536/2014 Art. 29.2.a.i). 7.2. Right to withdraw without reprisal (EU/536/2014 Art. 28.2.-3; 29.2.a.iii). 7.3. Aims (EU/536/2014 Art. 29.2.a.i).
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7.4. Methods/procedures (EU/536/2014 Art. 29.2.a.iii). 7.6. Institutional affiliations of researchers (EU/536/2014 Art. 28.1.g).
7.7. All risks and discomforts that a reasonable person would consider material (EU/536/2014 Art. 29.2.a.i). 7.11. Rights to refuse to participate (EU/536/2014 Art. 29.2.a.ii).
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7.8. Any current alternative interventions (EU/536/2014 Art. 29.2.a.iv). 7.20. Compensation, if any, in case of damage, disability or death (EU/536/2014 Art. 29.2.d).
7.37. Duration of participation (including number and duration of visits (EU/536/2014 Art. 29.2.a.iii). 7.38. Possibility of early termination of trial or of participation (EU/536/2014 Art. 29.2.a.iv).
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8. Information complete, accurate, and not overwhelming (EU/536/2014 Art. 29.2.b).
Comprehension
15. Participants’ comprehension of information must be ensured (EU/536/2014 Art. 29.5).
17. Means must be used to ensure potential participant’s understanding of procedure (EU/536/2014 Art. 29.2.c;29.4).
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Voluntariness
20. IC must be voluntarily obtained for all biomedical research involving humans (ICH E6 Art. 2.9). 21. Participants must be actually free to refuse or to withdraw (EU/536/2014 Art. 28.2.-3). 22. Potential participant must be given enough time to decide (EU/536/2014 Art. 29.1). 23. Prospective subject must not be exposed to undue influence (e.g., asking spouse or community leader to influence decision) (EU/536/2014
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Art. 28.1.h).
Person obtaining consent
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24. Payments/services should not lead to undue inducement to participate (EU/536/2014 Art.28.1.h).
35. Person obtaining informed consent must be knowledgeable about the research and is capable of answering questions (EU/536/2014 Art. 29.2.c).
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Use of data/specimen
37. IC necessary for research using identifiable human material or data; when consent is impossible or impracticable, permission from REC still necessary (EU/536/2014 Art. 28.2).
IX Respect for participants Participant safety
2. Criteria for changing dose or procedures for stopping the study for the health of the participants must be adequate (EU/536/2014 Art. 54.1). 3. All reasonable means should be taken to ensure safety (that death or disabling injury will not occur) (EU/536/2014 Art. 3.a). 4. To protect participants from injury, disability or death: 4.1. Adequate healthcare facilities provided and incorporated in study for the safe conduct of research (EU/536/2014 Art. 50). 7. Research shall not delay nor deprive participants of medically necessary preventative, diagnostic, or therapeutic procedures. Treatment of patient should not be altered in a detrimental manner to facilitate research (EU/536/2014 Art. 54.1).
Dissemination of research results to participants/community 13. Everyone is entitled to know the information collected about one’s health; however, one’s wishes to not be informed shall be respected (EU/536/2014 Art. 29.6). 17. There must be sufficient care on the manner of disseminating research results to the participants and the community (EU/536/2014 Art. 29.6).
Privacy/confidentiality 18. Confidentiality procedures must be effectively implemented (EU/536/2014 Art. 56.2). 19. The confidentiality of the subject’s research data must be protected (ICH E6 Art. 2.11.; EU/536/2014 Art. 28.1.d.; 56.1.-2).
Compensation 23. There must be appropriate compensation for subjects harmed due to research participation; in case of death, compensation goes to dependents (EU/536/2014 Art. 29.2.d.; 76.1.; 76.3). 25. A subject who withdraws due to research related reasons (such as unacceptable side-effects). or due to health grounds should be paid in full (ICH E6 Art. 3.1.8).
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26. A subject who withdraws for any other reason other than research or health related should be paid in proportion to the amount of participation (ICH E6 Art. 3.1.8).
Physicians and participants 30. Clinical professional who supervises the research should always be accessible to the participants and ready to respond to their health concerns (EU/536/2014 Art. 28.1.g).
XI Special populations Vulnerable population in general 5. RECs reviewing proposals directed at specific diseases or impairments or involving vulnerable people should invite representatives or
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advocates (EU/536/2014 Art. 10.2.; 10.4).
Persons not able to consent (including minors). 9. Research on a person without the capacity to consent may be undertaken only if all are met:
9.2. Assent is secured and dissent respected (EU/536/2014 Art. 29.8.; 31.1.c.; 32.1.c).
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9.1. Necessary authorization given specifically in writing by the legal representative, taking into account the individual’s previously expressed wishes and objections (EU/536/2014 Art. 31.1.a; 32.1.a).
9.3. Research of comparable effectiveness cannot be carried out on individuals capable of consent (i.e., condition necessary characteristic of
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the research group). (EU/536/2014 Art. 31.1.e., f.; 32.1.e.,f).
9.4. Results of the research must have the potential to produce real and direct benefit (EU/536/2014 Art. 31.1.g.,i.; 32.1.g.,i). 9.6. An adult not able to consent shall as far as possible take part in the authorization procedure. The opinion of a minor shall be taken into consideration as an increasingly determining factor in proportion to age and degree of maturity (EU/536/2014 Art. 29.8; 31.1.b.; 31.3.; 32.1.b.;32.2).
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10. Non-therapeutic research may be authorized subject to the following: (ICH E6 3.1.6).
10.1. Minimal (low). risk and minimal (low). burden (i.e., medical test standard).; any consideration of additional potential benefits of the research shall not be used to justify an increased level of risk or burden (EU/536/2014 Art.31.1.g.ii.; 32.1.g.ii). 10.2. Research aims to contribute through significant improvement in scientific understanding of the individual’s condition, disease or disorder (EU/536/2014 Art. 31.1.g.ii.; 32.1.g.ii).
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13. When subjects initially unable to consent become capable of consenting, their consent for continued participation must be secured (EU/536/2014 Art. 32.3).
18. The guardian asked to give permission should be offered no recompense other than a refund of travel and related expenses (EU/536/2014 Art. 31.1.d.; 32.1.d).
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19. For individuals physically or mentally unable to consent, and consent from a legal rep cannot be obtained, study may proceed provided that reasons stated in protocol and REC approved. Consent must be secured a.s.a.p. (ICH E6 Art. 3.1.7). 21. In emergency research where prior research is not possible, participants, or their representatives if relevant, should be given all relevant
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information as soon as they are in the state to receive it, and their consent to continued participation should be obtained as soon as is reasonably possible (EU/536/2014 Art. 35.1.a.,c.; 35.2.a.-b).
24. Research of comparable effectiveness cannot be carried out in persons in nonemergency situations (EU/536/2014 Art. 35.1.e).
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30. Nontherapeutic emergency research may be justifiable given the following, 30.2. Minimal risk and minimal burden (EU/536/2014 Art. 35.1.f).
Pregnant women
33. Research in this population should be performed only if 33.1. it is relevant to the particular health needs of a pregnant woman or her fetus, or to the health needs of pregnant women in general (broadly understood). (EU/536/2014 33.a).
33.3. Special safeguards should be established to prevent undue inducement to pregnant women to participate in research in which interventions hold out the prospect of direct benefit to the fetus (EU/536/2014 Art. 33.d). 34. Research on a pregnant woman that does not have the potential to produce results of direct benefit to her health, or to that of her embryo, fetus or child after birth, may only be undertaken if the following additional conditions are met: 34.1. 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, fetuses or children, broadly understood; (EU/536/2014 Art. 33.b.ii). 34.2. Research of comparable effectiveness cannot be carried out on women who are not pregnant; (EU/536/2014 Art. 33.b.i). 34.3. The research entails only minimal risk and minimal burden (EU/536/2014 Art. 33.b.iii). 35. Where research is undertaken on a breastfeeding woman, particular care shall be taken to avoid any adverse impact on the health of the child (EU/536/2014 Art. 33.c).
Box 2. Recommendations based on the correspondences (and lack thereof) between ethical imperatives and GCP regulations Within areas with correspondences between imperatives and GCP regulations, there is the need to further specify what exactly the ethical responsibilities are of clinical assessors and GCP inspectors. The cooperation between regulators and research ethics committees must be further developed and expanded for the specific purpose of covering the gap areas (i.e., areas covered by ethical imperatives but not by GCP regulations). The inclusion of the GCP regulations that are not directly pairable to any imperative, but are nevertheless ethical in nature, must be considered in future versions of international ethics guidelines for human research.
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The discordant areas between ethical imperatives and GCP regulations must be addressed through the cooperation of regulatory and ethicsguideline bodies.
Percentage correspondence between GCP articles and framework imperatives (no. of GCP articles/number of framework imperatives)
Principles (10) Collaborative partnerships (7) Social value (25) Scientific validity (37) Fair participant selection (8) Favorable benefit:risk ratio (25) Independent review (80) Informed consent (98) Respect for participants (36) Publication, registration, and regulatory sanctions (6) Special populations (52)
10% (1/10) None (0/7) None (0/25) 13.5% (5/37) None (0/8) 12% (3/25) 22.5% (18/80) 22.4% (22/98) 36.1% (13/36) 16.7% (1/6)
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Ethical framework sections (no. of imperatives per section)
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Table 2. Percentage of the pairing of GCP articles with ethics imperatives
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40.4% (21/52)
Table 3. GCP guidelines/regulations that are ethically relevant but are not directly pairable to any ethical imperative Regulations that are ethically relevant but are not pairable to any imperative
Informed consent
EU/536/2014, Art. 30. 1-4: discusses the requirements for informed consent in cluster randomized trials; specifically, it provides the requirements for the acceptability of simplified informed consent in such trials EU/536/2014, Art. 31.1.d. For clinical trials on incapacitated subjects, it states that no incentives or financial inducements must be given to the subjects (and not only to the legal representatives) EU/536/2014, Art. 35.1.d. For clinical trials in emergency situations, it states that, before the inclusion of participants without IC, the investigator must certify that they are not aware of previously expressed objections to participation in clinical trials by the participant EU/536/2014, Art. 35.3. For clinical trials in emergency situations, it states that, once IC is sought and the participant or the legal representative denied consent, the participant or legal representative shall be informed of the right to object to the use of data obtained from the study 2005/28/EC, Art. 6.2: states that RECs should retain essential documents of a clinical trial for at least 3 years 2005/28/EC, Art. 6.3: states that efficient and appropriate communication of information between RECs and competent authorities should be maintained 2005/28/EC, Art. 8.3: states that the sponsor should validate and update the investigator’s brochure yearly
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Independent review
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Special populations
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Sections from the ethics framework
*Note that, although we included the explanatory reports from these guidelines in our ethics framework, the appendices were excluded. †As stated in footnote*, the appendices of the ethics guidelines were not included in the framework. Given that the CIOMS appendices include the list of the sections that ought to be present in a protocol, Annex 1 in EU 536/2014 and Section 6 of Directive 75/318/EEC that enumerate the required contents of a protocol were also not included in our analysis.
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