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Contents lists available at ScienceDirect

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Review article

Evolution of European Union legislation on emergency research夽 Spyros D. Mentzelopoulos a , Michail Mantzanas b , Gerald van Belle c , Graham Nichol c,d,∗ a

University of Athens Medical School, Athens, Greece Ecclesiastical Academy of Athens, Greece c Clinical Trial Center, Department of Biostatistics, University of Washington, Seattle, WA, USA d University of Washington-Harborview Center for Prehospital Emergency Care, Department of Medicine, University of Washington, Seattle, WA, USA b

a r t i c l e

i n f o

Article history: Received 24 December 2014 Received in revised form 24 February 2015 Accepted 11 March 2015 Keywords: Regulation Legislation Emergency medicine Informed consent Medical ethics

a b s t r a c t Aim: Emergency research is necessary to prevent exposure of patients to unvalidated clinical practice (nonmaleficence), and to improve the dismal prognosis of disorders requiring emergent treatment such as cardiac arrest (beneficence). Regulations that govern clinical research should conform to bioethical principles of respect for nonmaleficence, beneficence, autonomy, and justice. Our objectives are to review the evolution of European Union (EU) legislation on emergency research, and to identify potentially remaining problems. Data sources: EU legislative sources on clinical research and medical literature describing the impact of EU Regulations on emergency research. Results: Article 5 of EU Directive 2001/20/EC required consent before enrolment in a research study to ensure the autonomy of potentially incapacitated research subjects. However, obtaining such consent is often impossible in emergency situations. Directive 2001/20/EC was criticized for potentially preventing emergency research. Several EU Member States addressed this problem by permitting deferred consent. International ethical guidelines supporting deferred consent were also cited by Good Clinical Practice Directive 2005/28/EC. However, Directive 2001/20/EC was not revised to achieve harmonization of EU emergency research, thus resulting in ongoing “ambiguity” as regards to emergency research legitimacy. This will be definitively addressed by applying EU Regulation No. 536/2014 and repealing Directive 2001/20/EC. The new EU Regulation permits using deferred consent under clearly specified conditions, and may foster emergency research that evaluates interventions posing minimal risk relative to standard practice. Conclusions: Legislation related to emergency research in Europe has evolved to increase concordance with bioethical principles so as to increase evidence-based improvements in emergency care. © 2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Enrolment in a randomized clinical trial usually requires a priori consent. Regulations that govern consent for clinical research are grounded in four basic ethical principles that constitute the framework of biomedical research ethics: nonmaleficence, beneficence, respect for autonomy, and justice.1,2 The principle of nonmaleficence specifies abstention from causing harm to patients and, in medical ethics, is equivalent to the Hippocratic maxim “Primum non nocere”.2 The principle of beneficence refers to maximizing the

夽 A Spanish translated version of the abstract of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2015.03.006. ∗ Corresponding author at: Clinical Trial Center, Department of Biostatistics, University of Washington, Seattle, WA, USA. E-mail addresses: [email protected], [email protected] (G. Nichol).

patient’s welfare.2 Autonomy, derived from the Greek autos (self) and nomos (rule), is defined on the basis of liberty and agency. Liberty refers to absence of external control of behaviour and agency to the capacity for intentional action. Respect for individual autonomy is expressed via informed patient or proxy/legal representative (LR) consent obtained before enrolment in a clinical study (i.e. preenrolment or prior consent). Principles of justice can be examined using different approaches (e.g. utilitarian, libertarian, egalitarian, communitarian theories, theories of capabilities, and well-being theories). A common core to most of these approaches relates to the equality of rights to health and health care and the practical difficulties of allocating, rationing, and setting priorities.2 It is difficult to conduct prospective emergency research that adheres to fundamental principles of bioethics because of the inherent need to quickly establish diagnosis, verify study eligibility and initiate study intervention as well as standard care. A characteristic example pertains to out-of-hospital cardiac arrest (OHCA), which

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is common and debilitating. In Europe, the incidence of emergency medical service-treated, out-of-hospital cardiac arrest varies within 17–51 per 100,000 person-years.3–6 Observational studies can be conducted without informed consent but cannot establish a causal relationship between use of an intervention and subsequent outcome.7 Adequately powered randomized clinical trials must be conducted to test commonly used therapies with uncertain efficacy8 or new, potentially beneficial treatments. Improvements in outcomes after OHCA that have occurred over the past 15 years suggest that effective treatments exist.4–6 The conduct of emergency research/OHCA clinical trials clearly accords with nonmaleficience, beneficence, and justice (if clinical equipoise is assumed). Regarding respect of autonomy, deferred consent may constitute an ethically acceptable alternative.2,9–13 After inclusion in the research study, the patient or his/her proxy/LR are informed as soon as possible and their consent for continued research participation is requested. Proxies (relatives, spouse, and close friends, i.e. “family” in a broad sense) and/or LRs may be designated by nation-specific laws exhibiting variability or appointed through a legal process.14,15 Deferred consent has been criticized for the absence of legal definition of consent for procedures that have occurred previously.16,17 However, deferred consent may ensure respect of family autonomy until the emergency research participant regains decision-making capacity. Family autonomy is generally considered as “the best possible substitute” to the individual autonomy of an incapacitated patient. A possibly improved alternative to deferred consent could be exception to informed consent (EFIC) with prior community consultation, and in conjunction with the option for community members to opt out from an EFIC study by wearing “NO STUDY” bracelets.18 Emergency research involving EFIC [19, Appendix I] or deferred consent,20 and collectively, exception to pre-enrolment consent seems generally acceptable by the public in North America and the European Union (EU),21–28 particularly when research interventions pose minimal risk.23,28 A relevant analysis of prior randomized clinical trial data showed that pre-enrolment consentassociated delays in investigational treatments may hamper their benefit to patients, or even increase the risk of death.29 EU legislation now includes specific provisions for deferred consent [20, Appendix II], after a 15 year-long period of repeated and often-criticized changes. The purpose of this paper is to review these changes and their impact on EU emergency research. 2. EU legislative sources In the EU, there are currently three sources of applicable legislation for the consideration of clinical research proposals by Research Ethics Committees (RECs). These sources include (a) the EU Directives 2001/20/EC30 and 2005/28/EC [or Good Clinical Practice (GCP) Directive31 ], (b) the Oviedo Convention32 and its related Additional Protocol on Biomedical Research,33 and (c) national legislations – sections pertaining to deferred consent have been provided in the supplement of a recent article.34 EU Directives 2001/20/EC and 2005/28/EC were to be incorporated into national legislations of EU Member States within 2004 and 2006, respectively. 3. The directives system and the barrier of prior consent Article 5 of EU Directive 2001/20/EC sets out seven prerequisite conditions for the inclusion of incapacitated adults in clinical trials (Appendix III). The first condition was pre-enrolment obtainment of a (valid) proxy/LR informed consent. However, it is widely accepted that it is impossible to obtain such consent in emergency research, due in part to the limited time frames for the initiation of the (tested) treatment(s).9,14,35–46

Directive 2001/20/EC has also been characterized as an important, comprehensive document, primarily aimed at harmonizing and fostering clinical research in Europe.37 However, the strict application of pre-enrolment consent would have resulted in a complete halt of EU clinical emergency and resuscitation research.14,38,42–46 The response of the scientific community resulted in the publication of several scholarly articles that described this major problem, defined its dimensions, and proposed measures of amelioration and/or definitive solutions.9,14,35–48 For example, it was repeatedly argued that the inability to conduct potentially beneficial research in the emergency setting would result in the exposure of many incapacitated patients to the hazards of unvalidated clinical practice.14,36–38,42 This counteracts the principles of nonmaleficence and beneficence.1,2,14 Regarding emergency research, the Vienna Initiative to Save European Academic Research46 recommended that “Article 5(a) be construed purposively or amended if necessary (by extension, waiver, or deferral) to permit and harmonize emergency research involving incapacitated persons where treatment must be commenced as a matter of urgency.” Notably, paragraph 5.2.3 of a Consultation Letter on clinical trials regulations49 [published on May 1, 2003 by the Medicines Control Agency of the United Kingdom (UK)] included the following interpretation: “There is no intention in the Directive (2001/20/EC), or the implementing Regulations, to prevent such emergency research being carried out.” Recital 8 and Article 3 of the GCP Directive (Appendix IV) respectively cite the International Conference on Harmonization (ICH) consensus paper12 and the Helsinki Declaration.10,11 More specifically, recital 8 states that the “ICH consensus paper should be taken into account” (for clinical trial conduct), whereas Article 3 states that “Clinical trials shall be conducted in accordance with the Declaration of Helsinki. . .” (see also Appendix IV and relevant Notes). Notably, both documents/policy statements address the impossibility of obtaining pre-enrolment informed consent in emergency research [Paragraph 4.8.15 of ICH Topic E 6 (R1)12 and Paragraph 30 of the Helsinki Declaration11 ]. The cornerstone of these provisions comprises the possibility of research to proceed, under the obligation of the researcher’s seeking deferred consent. The citation of the ICH consensus paper and the Helsinki Declaration by the GCP Directive as “whole documents” (that is without the exclusion of any part of their texts) is consistent with the abovecited, UK interpretation of Directive 2001/20/EC49 (i.e. that there was no intentional prevention of emergency research). Furthermore, the rationale of the 2006 UK Amendment of Clinical Trial Regulations (aimed at permitting deferred consent in emergency research) is actually based on the GCP Directive [Paragraph 4.3,50 Appendix V], and also, most importantly, cites European Commission correspondence with the UK which “strongly implies that emergency situations are outside the scope of EU Directive 2001/20/EC” [Paragraph 4.4,50 Appendix V]. Provisions for emergency care research were already in-place before the publication date (i.e. April 9, 2005) of the GCP Directive in the national legislations of Austria, Belgium, France, Germany, Italy, the Netherlands, Norway, and Spain.45 Multicenter studies in cardiac arrest employing deferred consent were conducted in several of the aforementioned countries; for example, the “Thrombolysis during resuscitation for out-of-hospital cardiac arrest” study43,50,51 was performed from January 2004 to March 2006 in Austria, Belgium, France, Germany, Italy, the Netherlands, Norway, Spain, Sweden, and Switzerland. By May 2004, EU Directive 2001/20/EC was incorporated into national law across the EU. However, its interpretation varied widely in the different Member States.9,45 Notably, countries that applied the Directive in a more liberal manner (e.g. as detailed above for the UK) did not elicit any criticism from the Regulatory

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Bodies of Brussels.9,44,45 Most importantly, the “correctness” of the more liberal interpretation is definitively validated by the fact that specific provisions with respect to consent in emergency situations are included in Article 35 of the recently published, new EU Regulation No. 536/2014 on clinical trials.20 EU Regulation No. 536/2014 will be applicable within 2016, and this will result in the repealing of EU Directive 2001/20/EC.20 In Greece, national legislation does not explicitly refer to emergency research,52 but Common Ministerial Decisions Y3(␣)69150/2004 (Article 2), and Y3␣/79602/2007 [Article 3, 53] mandate that clinical trials be approved/conducted according to the Helsinki Declaration, and the Guidelines of the European Medicines Agency (which include the ICH paper). Accordingly, the National Bioethics Commission’s Guidelines for RECs cite international ethical guidelines for biomedical research that include provisions for deferred consent in emergency research.10–12,33,53 This is consistent with the Guide for REC Members of the European Council.54 4. Additional barriers of the directives system, and the revision process of the new EU regulation Besides the repeatedly criticized “ambiguity”14 of EU Directive 2001/20/EC with respect to consent in emergency research, other provisions of the Directives System have also been criticized for hindering non-commercial academic research in general,48,55 and emergency research in particular.9,14,35–48,55 In summary, regarding non-profit organization-funded, academic research, the GCP-related “bureaucratic requirements” have been attributed to be a major cause of reduction in the number of studies.48,55,56 This contrasts GCP Directive’s Recital 11, which acknowledges that “non-commercial trials may be for great benefit to the patients concerned”.31 Regarding emergency research, the following provisions of EU Directive 2001/20/EC have also been criticized: (a) Paragraph e of Article 5 mandates a “direct relation of the research and the life-threatening/debilitating condition”; this may potentially prevent research on supportive therapies such as mechanical ventilation in traumatic brain injury14,42 ; (b) Paragraph i of Article 5 requires an expectation of protocol-related “direct benefit” to the research participant. This may not always be consistent with the principle of clinical equipoise, which comprises “genuine uncertainty in the expert medical community about the preferred treatment”.57 Furthermore, in the presence of a high level of certainty that a specific research intervention is beneficial, the deprivation of such a probable benefit from control patients counteracts the principle of justice1,2,9,43,46 ; and (c) Paragraph i of Article 5 requires that the research will be associated with “minimal risk or no risk at all”; this excludes potentially “non-innocuous”, non-therapeutic, investigational procedures such as bronchoscopy.14 These provisions have been collectively criticized as “additional barriers”.9,14,42,43,46 Regarding the new EU Regulation,20 its drafting procedure was not devoid of criticism. More specifically, certain Paragraphs of Article 32 of the text proposed by the Commission [58, left column of Table 1] were subject to criticism. Paragraph 1e, still included the “minimal risk/minimal burden” prerequisite59,60 ; this was subsequently revised according to the “proportionate risk concept” [58, right column of Table 1]. This revision was in concordance with the suggestions of the criticizing, academic authors52,59,60 ; in the final version of the Regulation [Article 35,20 Appendix II], the “concept of proportionality” was replaced by the prerequisite that the experimental intervention poses “minimal risk/minimal burden relative to standard treatment”. This is still an improvement,61 and corresponds to “low-intervention” trials.20,62 For such trials, the new Regulation also includes specific provisions aimed at reducing their administrative burden.20,62

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Paragraph 1b included the concept of “unavailability of an LR”.52 This was subsequently revised according to the “impossibility of obtaining pre-enrolment informed consent from the LR in a sufficiently timely manner” [58, right column of Table 1]. This revision was in concordance with suggestions of criticizing, academic authors,52,61 and is still included in the final version of the new Regulation (Appendix II). Paragraph 1d required “direct relation of the research and the life-threatening/debilitating condition”.52 This was removed during the revision [58, right column of Table 1], but was again added in a potentially improved form61 to the final version of the new Regulation (Appendix II). Article 35 of the new EU Regulation is intended to reduce regulatory barriers that could delay evidence-based improvements in emergency care. Notably, the “mandatory expectation of an individual benefit for the subject” (Paragraph i of Article 5 of EU Directive 2001/20/EC) was ultimately replaced by the “expectation of the potential for a direct clinically relevant benefit for the subject resulting in a measurable health-related improvement alleviating the suffering and/or improving the health of the subject, or in the diagnosis of its condition” (Paragraph 1b, of new Regulation’s Article 35); this effectively corresponds to a scientifically sound research rationale and hypothesis, aimed at improving the clinical practice in the investigated emergency condition. Lastly, Paragraph 3 of Article 35 maintains a possibility for the use of the patient data, even if deferred consent is not obtained, but under the condition of “no objection”. However, exclusion of patients with missing deferred consent may jeopardize the validity of study results.63 On the other hand, compliance with EU Directive 95/46/EC on personal data protection must be ensured [Recital 76 of the new Regulation20 ]. Key contributors to the re-drafting of the new Regulation included EU lawmakers such as Philippe Juvin (Emergency Physician) and Glenis Willmott.

5. The new EU regulation: projected effects, and possible, future improvements The new Regulation is expected to harmonize and foster lowintervention emergency research across EU Member States.61 It will result in the termination of a 12-year period of ambiguity with respect to emergency research legitimacy,14 as it permits omission of pre-enrolment consent on grounds of immediate necessity.9,20 This is especially applicable in cardiac arrest studies exhibiting very short to non-existent therapeutic windows for the provision of information on tested treatments. Larger therapeutic windows [e.g. 4–5 h64,65 ] may allow for flexibility on a study-specific and individual case basis. Factors such as protocol complexity, and proxy emotional stress, capability of informed decision based on potential risks and benefits, and knowledge-level of the patient’s wishes and values can affect consent validity.9,52 Interpretation/assessment of therapeutic window adequacy and consent validity will require input from researchers originating from their preceding experience and from ongoing trial-associated, interaction with proxies and patients regaining post-enrolment decision-making capacity.66 Despite the beneficial addition of Article 35,20,61 unresolved problems may still be present. Firstly, there is a requirement for “direct relation of the research and the life-threatening/debilitating condition” [Paragraph 1e, 14,42,52]. A second problem comprises the potential for patient exclusion secondary to patient or proxy objection for using already collected data [Paragraph 1e, 63,67]; however, such objections are anyway “very rare”.63,67,68 Lastly, further regulatory improvements may still be needed for emergency surgical research,60 and for emergency research on non-medicinal interventions69 ; indeed, the former may still be hindered by the “minimal risk” requirement,60 and the latter requires

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Table 1 The revision process of European Commission (2012) regulation (proposal for a) of the European parliament and of the council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC (58). Proposal for a regulation Article 32 Text proposed by the Commission

Amendment

1. By way of derogation from points (c) and (d) of Article 28(1), from points (a) and (b) of Article 30(1) and from points (a) and (b) of Article 31(1), informed consent may be obtained after the start of the clinical trial to continue the clinical trial and information on the clinical trial may be given after the start of the clinical trial provided that all of the following conditions are fulfilled: (a) Due to the urgency of the situation caused by a sudden life-threatening or other sudden serious medical condition, it is impossible to obtain prior informed consent from the subject and it is impossible to supply prior information to the subject; (b) No legal representative is available;

1. By way of derogation from points (c) and (d) of Article 28(1), from points (a) and (b) of Article 30(1) and from points (a) and (b) of Article 31(1), informed consent may be obtained after the start of the clinical trial to continue the clinical trial and information on the clinical trial may be given after the start of the clinical trial provided that all of the following conditions are fulfilled: (a) Due to the urgency of the situation caused by a sudden life-threatening or other sudden serious medical condition, it is impossible to obtain prior informed consent from the subject and it is impossible to supply prior information to the subject;

(c) The subject has not previously expressed objections known to the investigator; (d) The research relates directly to a medical condition which causes the impossibility to obtain prior informed consent and to supply prior information; (e) The clinical trial poses a minimal risk to, and imposes a minimal burden on, the subject.

2. The informed consent referred to in paragraph 1 shall be obtained, and information on the clinical trial shall be given, in accordance with the following requirements: (a) Regarding incapacitated subjects and minors, the informed consent referred to in paragraph 1 shall be obtained as soon as possible from the legal representative and the information referred to in paragraph 1 shall be given as soon as possible to the subject; (b) Regarding other subjects, the informed consent referred to in paragraph 1 shall be obtained as soon as possible from the legal representative or the subject, whichever is sooner and the information referred to in paragraph 1 shall be given as soon as possible to the legal representative or the subject, whichever is sooner. For the purposes of point (b), where informed consent has been obtained from the legal representative, informed consent to continue the trial shall be obtained from the subject as soon as it is capable of giving informed consent.

(b) Due to the urgency of the situation, it is impossible to obtain prior informed consent from the legal representative in a sufficiently timely manner; (c) The subject or the legal representative of an incapacitated subject or a minor has not previously expressed objections known to the investigator;

(e) The clinical trial poses a risk proportionate to the underlying life threatening medical condition, and imposes a proportionate burden on, the subject; (ea) where there are grounds to expect that the research would result in a clinically relevant benefit but where the direct benefit for the subject cannot be ensured, that research shall have the aim of contributing, through significant improvement in the scientific understanding of the individual’s condition, disease or disorder, to the ultimate attainment of results capable of conferring benefit to subject or to other persons afflicted with the same disease or disorder or having the same condition; (eb) the protocol has been approved specifically for the emergency situation. 2. The informed consent referred to in paragraph 1 shall be obtained, and information on the clinical trial shall be given, in accordance with the following requirements: (a) Regarding incapacitated subjects and minors, the informed consent referred to in paragraph 1 shall be obtained as soon as possible from the legal representative and the information referred to in paragraph 1 shall be given as soon as possible to the subject and the legal representative by the investigator or a member of the investigating team; (b) Regarding other subjects, the informed consent referred to in paragraph 1 shall be obtained as soon as possible from the legal representative or the subject, whichever is sooner and the information referred to in paragraph 1 shall be given as soon as possible to the legal representative or the subject, whichever is sooner by the investigator or a member of the investigating team. For the purposes of point (b), where informed consent has been obtained from the legal representative, informed consent to continue the trial shall be obtained from the subject as soon as it is capable of giving informed consent. 2a. If the subject or, where applicable, the legal representative does not give consent, he or she shall be informed of the right to object to the use of data obtained from the trial.

Proposed amendments are highlighted in bold script.

harmonization through a future, specific EU Regulation or regulatory amendment.

Graham Nichol initiated the concept of the review and performed subsequent critical revisions. The contributions of the second and third author were equally important.

6. Conclusions The new EU Regulation No 536/2014 will facilitate and harmonize emergency research across the EU. This conclusion is consistent with a recent statement of the European Group on Ethics and New Technologies.70 Furthermore, the new regulatory provisions for emergency research clearly validate prior liberal interpretations of EU Directive 2001/20/EC, and are consistent with the ICH guidelines, the Helsinki Declaration, and the fundamental principles of bioethics.

Conflict of interest statement The authors declare no conflicts of interest. Funding support No funding has been received in relation to the preparation of the current paper.

Authors’ contributions

Disclosure

Spyros Mentzelopoulos wrote the first draft of the current review. Michail Mantzanas also contributed to the writing of the first draft and its subsequent revisions. Gerald van Belle and

G.N. receives salary support from the University of Washington via the Leonard A Cobb Medic One Foundation Endowed Chair in Prehospital Emergency Care. He holds Research Grants from

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the following: (1) Resuscitation Outcomes Consortium (NIH U01 HL077863-05) 2004–2015; Co-PI; (2) Randomized Trial of Hemofiltration After Resuscitation from Cardiac Arrest (NIH NHLBI R21 HL093641-01A1) 2009–2014; PI; (3) Food and Drug Administration, Silver Spring, MD; Cardiac Science Corp, Waukesha, WI; Heartsine Technologies Inc., Newtown, PA; Philips Healthcare Inc., Bothell, WA; Physio-Control Inc., Redmond, WA; ZOLL Inc., Chelmsford, MA. University of Washington Dynamic AED Registry, PI. 2013–2015; (4) American Heart Association, Dallas, TX. Simple EMS Registry. PI. 2014; (5) Velomedix Inc., Menlo Park, CA. Velocity Pilot Study of Ultrafast Hypothermia in Patients with ST-Elevation Myocardial Infarction, National Co-PI. 2014–2015. *Waived personal compensation. He did not receive any other Research Support. He is not a member of Speakers Bureau and does not hold an Honorary post in any company. He has no other conflict of interest to declare. He received travel reimbursement from AHA.

Appendix I. The United States code of federal regulations 21 CFR 50.24 (19) Protection of human subjects; informed consent and waiver of informed consent requirements in certain emergency research

1. The humans are in a life-threatening situation, available treatments are unproven or unsatisfactory, and the collection of valid scientific evidence, which may include evidence obtained through randomized placebo controlled investigations, is necessary to determine the safety and effectiveness of particular interventions. 2. Obtaining informed consent is not feasible. 3. Participation in the research holds out the prospect of direct benefit to the subjects. 4. The clinical investigation could not practicably be carried out without the waiver. 5. The proposed investigational plan defines the length of the potential therapeutic window based on scientific evidence, and the investigator has committed to attempt to contact a legally authorized representative for each subject within that window of time and, if feasible, to asking the legally authorized representative contacted for consent within that window rather than proceeding without consent. The investigator will summarize efforts made to contact the legally authorized representatives and make this information available to the Institutional Review Board (IRB) at the time of continuing review. 6. The IRB has reviewed and approved informed consent procedures and an informed consent document. 7. Additional protections of the rights and welfare of the patients will be provided, including, at least consultation with representatives of the communities in which the clinical investigation will be conducted and from which the subjects will be drawn; public disclosure to the communities in which the clinical investigation will be conducted.

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1. By way of derogation from points (b) and (c) of Article 28(1), from points (a) and (b) of Article 31(1) and from points (a) and (b) of Article 32(1), informed consent to participate in a clinical trial may be obtained, and information on the clinical trial may be given, after the decision to include the subject in the clinical trial, provided that this decision is taken at the time of the first intervention on the subject, in accordance with the protocol for that clinical trial” and that all of the following conditions are fulfilled: (a) due to the urgency of the situation, caused by a sudden life-threatening or other sudden serious medical condition, the subject is unable to provide prior informed consent and to receive prior information on the clinical trial; (b) there are scientific grounds to expect that participation of the subject in the clinical trial will have the potential to produce a direct clinically relevant benefit for the subject resulting in a measurable healthrelated improvement alleviating the suffering and/or improving the health of the subject, or in the diagnosis of its condition; (c) it is not possible within the therapeutic window to supply all prior information to and obtain prior informed consent from his or her legally designated representative; (d) the investigator certifies that he or she is not aware of any objections to participate in the clinical trial previously expressed by the subject; (e) the clinical trial relates directly to the subject’s medical condition because of which it is not possible within the therapeutic window to obtain prior informed consent from the subject or from his or her legally designated representative and to supply prior information, and the clinical trial is of such a nature that it may be conducted exclusively in emergency situations; (f) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the subject in comparison with the standard treatment of the subject’s condition. 2. Following an intervention pursuant to paragraph 1, informed consent in accordance with Article 29 shall be sought to continue the participation of the subject in the clinical trial, and information on the clinical trial shall be given, in accordance with the following requirements: (a) regarding incapacitated subjects and minors, the informed consent shall be sought by the investigator from his or her legally designated representative without undue delay and the information referred to in Article 29(2) shall be given as soon as possible to the subject and to his or her legally designated representative; (b) regarding other subjects, the informed consent shall be sought by the investigator without undue delay from the subject or his or her legally designated representative, whichever is sooner and the information referred to in Article 29(2) shall be given as soon as possible to the subject or his or her legally designated representative, whichever is sooner. For the purposes of point (b), where informed consent has been obtained from the legally designated representative, informed consent to continue the participation in the clinical trial shall be obtained from the subject as soon as he or she is capable of giving informed consent. 3. If the subject or, where applicable, his or her legally designated representative does not give consent, he or she shall be informed of the right to object to the use of data obtained from the clinical trial.

Appendix III. Appendix II. Article 5 of EU directive 2001/20/EC (30) Article 35 of regulation (EU) no 536/2014 of the European parliament and of the council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing directive 2001/20/EC (20) Clinical trials in emergency situations

Clinical trials on incapacitated adults not able to give informed legal consent in the case of other persons incapable of giving informed legal consent, all relevant requirements listed for persons capable of giving such consent shall apply. In addition to these requirements, inclusion in clinical trials of incapacitated adults who

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have not given or not refused informed consent before the onset of their incapacity shall be allowed only if: (a) the informed consent of the legal representative has been obtained; consent must represent the subject’s presumed will and may be revoked at any time, without detriment to the subject; (b) the person not able to give informed legal consent has received information according to his/her capacity of understanding regarding the trial, the risks and the benefits; (c) the explicit wish of a subject who is capable of forming an opinion and assessing this information to refuse participation in, or to be withdrawn from, the clinical trial at any time is considered by the investigator or where appropriate the principal investigator; (d) no incentives or financial inducements are given except compensation; (e) such research is essential to validate data obtained in clinical trials on persons able to give informed consent or by other research methods and relates directly to a life-threatening or debilitating clinical condition from which the incapacitated adult concerned suffers; (f) clinical trials have been designed to minimize pain, discomfort, fear and any other foreseeable risk in relation to the disease and developmental stage; both the risk threshold and the degree of distress shall be specially defined and constantly monitored; (g) the Ethics Committee, with expertise in the relevant disease and the patient population concerned or after taking advice in clinical, ethical and psychosocial questions in the field of the relevant disease and patient population concerned, has endorsed the protocol; (h) the interests of the patient always prevail over those of science and society; and (i) there are grounds for expecting that administering the medicinal product to be tested will produce a benefit to the patient outweighing the risks or produce no risk at all. Appendix IVa. Recital 8 of EU Directive 2005/28/EC (31) The International Conference on Harmonisation (ICH) reached a consensus in 1995 to provide a harmonised approach for Good Clinical Practice. The consensus paper should be taken into account as agreed upon by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency, hereinafter ‘the Agency’, and published by the Agency. Appendix IVb. Article 3 of EU Directive 2005/28/EC (31) The available non-clinical and clinical information on an investigational medicinal product shall be adequate to support the proposed clinical trial. Clinical trials shall be conducted in accordance with the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects, adopted by the General Assembly of the World Medical Association (1996). Note 1 The European Commission has also referred to subsequent revisions of the Helsinki Declaration: Ethical dimension of the European and Developing Countries Clinical Trials Partnership programme; Sixth framework programme 2002–2006. Accessed July 18, 2014 at http://ec.europa.

eu/research/info/conferences/edctp/edctp ethics en. html#fn1. Note 2 Annex I part 4 (B) of Directive 2001/83/EC (on the Community code relating to medicinal products for human use) also refers to the 2000 version of the Helsinki Declaration “All clinical trials shall be carried out in accordance with the ethical principles laid down in the current revision of the Declaration of Helsinki”. Published November 28, 2001: Official Journal of the European Communities 2001; L311/67-L311/128. Note 3 In accordance with the relevance of the preceding Notes: In its Official Website, the World Medical Association has published the following text: “The Declaration of Helsinki (DoH) is the WMA’s best-known policy statement. The first version was adopted in 1964 and has been amended seven times since, most recently at the General Assembly in October 2013. The current (2013) version is the only official one; all previous versions have been replaced and should not be used or cited except for historical purposes. The WMA thanks all those who submitted comments and suggestions for the most recent (2012–2013) revision of the DoH.” Accessed July 18, 2014 at http://www.wma.net/en/20activities/10ethics/10helsinki/. Note 4 Articles of legislative acts are legally binding, but Recitals are not. However, Recitals present the rationale for subsequent Articles.

Appendix V. Paragraphs 4.3 and 4.4 of the explanatory memorandum to the medicines for human use (clinical trials) amendment regulations 2006, 2006 No. 2984 (50) 4.3 These Regulations amend Schedule 1 and in doing so derogate from the general rule at Article 5(a) of the Directive. The amendment will allow incapacitated adults to be entered in to a trial prior to consent having been obtained from a legal representative in trials of emergency medicines where certain conditions are met. This derogation from article 5(a) is justified on the basis that: The title of the Directive shows that it relates “to the implementation of good clinical practice in the conduct of clinical trials” and its underlying purpose is clearly to ensure trials are conducted in accordance with “good clinical practice” (see Article 1(4)). This is a set of internationally recognized requirements to be reflected in principles and detailed guidelines to be adopted and published by the Commission (see Article 1(2) and (3)). It is Directive 2005/28/EC (the Good Clinical Practice Directive) which lays down those principles. At recital (8) it states that the International Conference on Harmonisation’s 1996 “Guideline for Good Clinical Practice” should be taken into account. This guideline was adopted by the Committee for Proprietary Medicinal Products in 1997 as applicable in Europe, and specifically envisages (at paragraph 4.8.15) that there will be emergency situations in which neither the trials subject’s consent nor that of a legal representative can be obtained. The guideline is clear that trials may take place in such circumstances so long as suitable safeguards are contained in the trial protocol to protect the subject, and are approved by the relevant ethics committee. 4.4 The approach is also consistent with Commission correspondence with the UK which sees emergency situations as being for Member State to make provisions for and strongly implies that they are outside the scope of the Clinical Trials Directive. The approach is also consistent with that taken by France, Germany, Italy, Spain and Sweden.

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