EDITORIALS MACGAM Study Group. Adjuvant interferon gamma in patients with pulmonary atypical mycobacteriosis: a randomized, double-blind, placebo-controlled study. BMC Infect Dis 2008;8:17. 10. Chakravarty EF, Fries JF. Science as experiment; science as observation. Nat Clin Pract Rheumatol 2006;2:286–287. 11. Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000;342:1887–1892.
12. Kobashi Y, Abe M, Mouri K, Obase Y, Kato S, Oka M. Relationship between clinical efficacy for pulmonary MAC and drug-sensitivity test for isolated MAC in a recent 6-year period. J Infect Chemother 2012;18:436–443.
Copyright © 2015 by the American Thoracic Society
New European Regulation for Clinical Trials of Medicinal Products In 2001, the European Parliament and Council issued Clinical Trials Directive 2001/20/EC, which applies to member states of the European Union (EU) and regulates clinical trials throughout the EU. Members of both academia and the pharmaceutical industry have criticized this directive for placing regulatory burdens on the conduct of clinical trials that impair their progress (1). Responding to these concerns, in 2012, the European Commission recognized that the administrative burdens and costs associated with this directive contributed to the approximately 25% decline in the number of clinical trials conducted in the EU between 2007 and 2011 (2) and proposed a draft revision of directive, 2001/20. In April 2014, the European Parliament and Council replaced the current directive governing clinical trials of medicinal products with a regulation aimed to reduce these hindrances (3). The previous 2001 directive, enforced in all states of the EU since 2004, required that all clinical trials of drugs be authorized by a competent authority (usually, the national drug agency) and approved by a research ethics committee. However, the directive failed to provide processes for the approval of multinational trials or to define adapted regulatory constraints for trials of drugs with low risk to patients. Several of these issues are addressed in the new legislation. The 2014 regulation provides a process for multinational trials in which a single reporting member state delivers a “single advice” on the technical and scientific contents of protocols, valid for all countries, whereas ethical review remains performed by each of the participating member states. The term “single advice” means that a unique “reporting” member state gives the final advice valid for all the other “concerned” member states. They can refuse to authorize the trial in their territory on limited grounds only. The 2014 regulation also eases administrative procedures for “low-intervention” research, recognizes the issues of consent in emergency research and in cluster trials, and recognizes the issues of the use of data after withdrawal of consent. In addition, it requires more transparency in terms of access to collected data. As the 2014 regulation is strictly limited to interventional clinical trials of medicinal products, it does not interfere with existing national legislation for noninterventional research or nonpharmaceutical research (e.g., medical devices, surgery, or pathophysiology).
Low-Intervention Research One of the major improvements in the new regulation is the introduction of a new category of research: low-intervention 16
research. Responding to arguments from academic investigators and sponsors that many clinical trials use drugs with potential major public health benefits and few risks (1), the new regulation incorporates a “risk-adjusted approach.” A low-intervention trial is defined as one in which the investigational medicinal product has been authorized and is used in accordance with the terms of the marketing authorization, or if it is used off label, its use is supported by published evidence of safety and efficacy. Additional diagnostic or monitoring procedures cannot “pose more than minimal additional risk or burden to the safety of the subjects compared with normal clinical practice.” Methods to ease procedural burdens for low-intervention research range from adapted monitoring and vigilance rules to suppressing specific labeling of experimental but authorized medicinal products. The consequences are likely to be significant. For example, French legislators introduced the concept of “risk-adjusted approach” in 2004 by creating a special category of “research on usual care” (4). However, the 2001 EU directive did not authorize, and therefore effectively precluded, the extension of this novel “low-risk” category to drug research. The new regulation allows this approach to be applied to interventions that include commonly used drugs.
Consent Emergency Research
In emergency situations, such as shock states and respiratory and circulatory distress, research is often precluded unless it can begin without prior consent from patients (5). Several national legislations in Europe have allowed for waiver or deferral of consent in emergency research, including France (1988) and the United Kingdom (2005) (6). Although emergency research has been formally possible in the United States (7), it is rarely conducted (8). The new regulation allows for emergency research without obtaining prior consent provided several conditions are fulfilled (9). We are concerned by the requirement that the clinical trial “will have the potential to produce a direct clinically relevant benefit for the subject.” Although the regulation remains cautious and says that individual benefit is only expected, the reappearance the concept of “direct individual benefit” of research, which was removed from the 2000 revised Helsinki
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 1 | January 1 2015
EDITORIALS declaration as likely to be misleading or even dishonest, is unfortunate (10, 11). Withdrawal of Consent
The suppression of collected data is commonplace after consent withdrawal and threatens the validity and robustness of the trial results (12). Recognizing this concern, the new regulation states that “the withdrawal of consent should not affect.the storage and use of data obtained based on consent before withdrawal.” A similar provision applies to emergency research, when a clinical trial has started without prior consent and when, later, the participant or the surrogate decision-maker refuses consent but does not object to the use of data collected before that refusal. Also, to facilitate further use of research data sometimes years after the trial ended, the regulation authorizes “broad consent,” given by participants at inclusion. Consent in Cluster Trials
In cluster trials, groups of subjects are randomized instead of individuals, creating a situation in which obtaining individual consent is sometimes impossible (13). The new regulation allows research ethics committees to consider studies employing “simplified consent” procedures, provided that subjects are provided with adequate information and are offered the opportunity to “opt out” of the study. There is concern that all these modifications to consent procedures may threaten patient autonomy. However, the regulation, as rewritten by the Council of member states, is sufficiently restrictive that it will apply only to interventional trials involving the use of authorized drugs, in agreement with the marketing authorization (“on label”) in a setting in which “there are no interventions other than the standard treatment of the subjects concerned,” corresponding to conditions in which a waiver of consent is usually granted by institutional review boards (14).
Transparency: Access to Data Supported by efforts of the Cochrane collaboration (15), among others, the new legislation guarantees greater access to research data to the research community and the public. The existing EU database will be modified to contain most of research data (application dossier, investigator brochure, information and consent forms, safety reporting, substantial modifications, final report of research, and summary of results), and will “enable citizens of the Union to have access to clinical information about medicinal products.” Protection of personal data and industry confidentiality will remain guaranteed. A long-standing complaint by epidemiologists has been lack of access to raw data, which has been at least partially addressed, but agreement by the sponsor is still required; the European Commission responsible for the regulation shall produce guidance documents before this provision is enforced.
Conclusions The 2014 European regulation for clinical trials of medicinal products addresses the worldwide difficulties in managing the Editorials
bureaucracy of research and the slow process of authorization (16). Easing of regulatory restrictions necessarily raises concerns about individual patient privacy and safety, but individual patient privacy concerns are allayed by strong and evolving European regulations on data protection and privacy. Safety concerns are addressed by the numerous precautions and safeguards placed all over the text, and in particular by the European Parliament. As a result, there is a hope that the new legislation will provide relief from some of the administrative burdens that impede research in the EU while preserving patient autonomy, privacy, and safety. n Author disclosures are available with the text of this article at www.atsjournals.org. François Lemaire, M.D. Professor Emeritus Universite´ Paris Est Creteil ´ Paris, France Mihaela Matei, L.L.M. Centre Europeen ´ d’Etudes et de Recherche Droit et Sante´ Universite´ Montpellier 1 Montpellier, France Philippe Juvin, M.D. Assistance Publique–Hopitaux ˆ de Paris Universite´ Paris Descartes Paris, France
References 1. Liddell K, Chamberlain D, Menon DK, Bion J, Kompanje EJO, Lemaire F, Druml C, Vrhovac B, Wiedermann CJ, Sterz F. The European Clinical Trials Directive revisited: the VISEAR recommendations. Resuscitation 2006;69:9–14. 2. European Commission. Impact assessment report on the revision of the “Clinical Trials Directive” 2001/20/EC. 2012 [accessed 2014 Dec 3]. Available from: http://ec.europa.eu/health/files/clinicaltrials/2012_07/ impact_assessment_part1_en.pdf 3. European Parliament and Council. 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. 2014 [accessed 2014 Aug 18]. Available from: http:// eur-lex.europa.eu/legal-content/EN/TXT/?uri=uriserv:OJ.L_.2014.158.01. 0001.01.ENG 4. Matei M, Thalabard JC, Laude A, Misse C, Chassany O. Research on usual care: assessing the qualification criteria of the current legal framework [in French]. Presse Med 2011;40:e189–e196. 5. Lemaire F. Emergency research: only possible if consent is waived? Curr Opin Crit Care 2007;13:122–125. 6. Coats TJ, Shakur H. Consent in emergency research: new regulations. Emerg Med J 2005;22:683–685. 7. Halperin H, Paradis N, Mosesso V Jr, Nichol G, Sayre M, Ornato JP, Gerardi M, Nadkarni VM, Berg R, Becker L, et al.; American Heart Association Emergency Cardiovascular Care Committee; American Heart Association Council on Cardiopulmonary, Perioperative and Critical Care. Recommendations for implementation of community consultation and public disclosure under the Food and Drug Administration’s “Exception from informed consent requirements for emergency research”: a special report. Circulation 2007;116:1855–1863. 8. Biros M. Struggling with the rule: the exception from informed consent in resuscitation research. Acad Emerg Med 2007;14:344–345. 9. Kompanje EJO, Maas AIR, Menon DK, Kesecioglu J. Medical research in emergency research in the European Union member states: tensions between theory and practice. Intensive Care Med 2014;40: 496–503.
17
EDITORIALS 10. Lemaire F. Patient care versus research: does clinical research provide individual benefit to patients enrolled in trials? Curr Opin Crit Care 2004;10:565–569. 11. Levine RJ. The need to revise the Declaration of Helsinki. N Engl J Med 1999;341:531–534. 12. Tu JV, Willison DJ, Silver FL, Fang J, Richards JA, Laupacis A, Kapral MK; Investigators in the Registry of the Canadian Stroke Network. Impracticability of informed consent in the Registry of the Canadian Stroke Network. N Engl J Med 2004;350:1414–1421. 13. Taljaard M, Weijer C, Grimshaw JM, Eccles MP; Ottawa Ethics of Cluster Randomised Trials Consensus Group. The Ottawa Statement on the ethical design and conduct of cluster randomised trials: precis for researchers and research ethics committees. BMJ 2013;346:f2838.
18
14. HHS.gov. Human Research Protections FAQ: what are the criteria under 45 CFR 46.116(d) for waiving or altering some or all of the required elements of informed consent or parental permission? [accessed 2014 Dec 3]. Available from: http://answers.hhs.gov/ohrp/ questions/7274 15. Gøtzsche PC. Why we need easy access to all data from all clinical trials and how to accomplish it. Trials 2011;12:249. 16. Henry LM. Introduction: revising the common rule: prospects and challenges. J Law Med Ethics 2013;41:386–389.
Copyright © 2015 by the American Thoracic Society
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 1 | January 1 2015
12. Kobashi Y, Abe M, Mouri K, Obase Y, Kato S, Oka M. Relationship between clinical efficacy for pulmonary MAC and drug-sensitivity test for isolated MAC in a recent 6-year period. J Infect Chemother 2012;18:436–443.
Copyright © 2015 by the American Thoracic Society
New European Regulation for Clinical Trials of Medicinal Products In 2001, the European Parliament and Council issued Clinical Trials Directive 2001/20/EC, which applies to member states of the European Union (EU) and regulates clinical trials throughout the EU. Members of both academia and the pharmaceutical industry have criticized this directive for placing regulatory burdens on the conduct of clinical trials that impair their progress (1). Responding to these concerns, in 2012, the European Commission recognized that the administrative burdens and costs associated with this directive contributed to the approximately 25% decline in the number of clinical trials conducted in the EU between 2007 and 2011 (2) and proposed a draft revision of directive, 2001/20. In April 2014, the European Parliament and Council replaced the current directive governing clinical trials of medicinal products with a regulation aimed to reduce these hindrances (3). The previous 2001 directive, enforced in all states of the EU since 2004, required that all clinical trials of drugs be authorized by a competent authority (usually, the national drug agency) and approved by a research ethics committee. However, the directive failed to provide processes for the approval of multinational trials or to define adapted regulatory constraints for trials of drugs with low risk to patients. Several of these issues are addressed in the new legislation. The 2014 regulation provides a process for multinational trials in which a single reporting member state delivers a “single advice” on the technical and scientific contents of protocols, valid for all countries, whereas ethical review remains performed by each of the participating member states. The term “single advice” means that a unique “reporting” member state gives the final advice valid for all the other “concerned” member states. They can refuse to authorize the trial in their territory on limited grounds only. The 2014 regulation also eases administrative procedures for “low-intervention” research, recognizes the issues of consent in emergency research and in cluster trials, and recognizes the issues of the use of data after withdrawal of consent. In addition, it requires more transparency in terms of access to collected data. As the 2014 regulation is strictly limited to interventional clinical trials of medicinal products, it does not interfere with existing national legislation for noninterventional research or nonpharmaceutical research (e.g., medical devices, surgery, or pathophysiology).
Low-Intervention Research One of the major improvements in the new regulation is the introduction of a new category of research: low-intervention 16
research. Responding to arguments from academic investigators and sponsors that many clinical trials use drugs with potential major public health benefits and few risks (1), the new regulation incorporates a “risk-adjusted approach.” A low-intervention trial is defined as one in which the investigational medicinal product has been authorized and is used in accordance with the terms of the marketing authorization, or if it is used off label, its use is supported by published evidence of safety and efficacy. Additional diagnostic or monitoring procedures cannot “pose more than minimal additional risk or burden to the safety of the subjects compared with normal clinical practice.” Methods to ease procedural burdens for low-intervention research range from adapted monitoring and vigilance rules to suppressing specific labeling of experimental but authorized medicinal products. The consequences are likely to be significant. For example, French legislators introduced the concept of “risk-adjusted approach” in 2004 by creating a special category of “research on usual care” (4). However, the 2001 EU directive did not authorize, and therefore effectively precluded, the extension of this novel “low-risk” category to drug research. The new regulation allows this approach to be applied to interventions that include commonly used drugs.
Consent Emergency Research
In emergency situations, such as shock states and respiratory and circulatory distress, research is often precluded unless it can begin without prior consent from patients (5). Several national legislations in Europe have allowed for waiver or deferral of consent in emergency research, including France (1988) and the United Kingdom (2005) (6). Although emergency research has been formally possible in the United States (7), it is rarely conducted (8). The new regulation allows for emergency research without obtaining prior consent provided several conditions are fulfilled (9). We are concerned by the requirement that the clinical trial “will have the potential to produce a direct clinically relevant benefit for the subject.” Although the regulation remains cautious and says that individual benefit is only expected, the reappearance the concept of “direct individual benefit” of research, which was removed from the 2000 revised Helsinki
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 1 | January 1 2015
EDITORIALS declaration as likely to be misleading or even dishonest, is unfortunate (10, 11). Withdrawal of Consent
The suppression of collected data is commonplace after consent withdrawal and threatens the validity and robustness of the trial results (12). Recognizing this concern, the new regulation states that “the withdrawal of consent should not affect.the storage and use of data obtained based on consent before withdrawal.” A similar provision applies to emergency research, when a clinical trial has started without prior consent and when, later, the participant or the surrogate decision-maker refuses consent but does not object to the use of data collected before that refusal. Also, to facilitate further use of research data sometimes years after the trial ended, the regulation authorizes “broad consent,” given by participants at inclusion. Consent in Cluster Trials
In cluster trials, groups of subjects are randomized instead of individuals, creating a situation in which obtaining individual consent is sometimes impossible (13). The new regulation allows research ethics committees to consider studies employing “simplified consent” procedures, provided that subjects are provided with adequate information and are offered the opportunity to “opt out” of the study. There is concern that all these modifications to consent procedures may threaten patient autonomy. However, the regulation, as rewritten by the Council of member states, is sufficiently restrictive that it will apply only to interventional trials involving the use of authorized drugs, in agreement with the marketing authorization (“on label”) in a setting in which “there are no interventions other than the standard treatment of the subjects concerned,” corresponding to conditions in which a waiver of consent is usually granted by institutional review boards (14).
Transparency: Access to Data Supported by efforts of the Cochrane collaboration (15), among others, the new legislation guarantees greater access to research data to the research community and the public. The existing EU database will be modified to contain most of research data (application dossier, investigator brochure, information and consent forms, safety reporting, substantial modifications, final report of research, and summary of results), and will “enable citizens of the Union to have access to clinical information about medicinal products.” Protection of personal data and industry confidentiality will remain guaranteed. A long-standing complaint by epidemiologists has been lack of access to raw data, which has been at least partially addressed, but agreement by the sponsor is still required; the European Commission responsible for the regulation shall produce guidance documents before this provision is enforced.
Conclusions The 2014 European regulation for clinical trials of medicinal products addresses the worldwide difficulties in managing the Editorials
bureaucracy of research and the slow process of authorization (16). Easing of regulatory restrictions necessarily raises concerns about individual patient privacy and safety, but individual patient privacy concerns are allayed by strong and evolving European regulations on data protection and privacy. Safety concerns are addressed by the numerous precautions and safeguards placed all over the text, and in particular by the European Parliament. As a result, there is a hope that the new legislation will provide relief from some of the administrative burdens that impede research in the EU while preserving patient autonomy, privacy, and safety. n Author disclosures are available with the text of this article at www.atsjournals.org. François Lemaire, M.D. Professor Emeritus Universite´ Paris Est Creteil ´ Paris, France Mihaela Matei, L.L.M. Centre Europeen ´ d’Etudes et de Recherche Droit et Sante´ Universite´ Montpellier 1 Montpellier, France Philippe Juvin, M.D. Assistance Publique–Hopitaux ˆ de Paris Universite´ Paris Descartes Paris, France
References 1. Liddell K, Chamberlain D, Menon DK, Bion J, Kompanje EJO, Lemaire F, Druml C, Vrhovac B, Wiedermann CJ, Sterz F. The European Clinical Trials Directive revisited: the VISEAR recommendations. Resuscitation 2006;69:9–14. 2. European Commission. Impact assessment report on the revision of the “Clinical Trials Directive” 2001/20/EC. 2012 [accessed 2014 Dec 3]. Available from: http://ec.europa.eu/health/files/clinicaltrials/2012_07/ impact_assessment_part1_en.pdf 3. European Parliament and Council. 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. 2014 [accessed 2014 Aug 18]. Available from: http:// eur-lex.europa.eu/legal-content/EN/TXT/?uri=uriserv:OJ.L_.2014.158.01. 0001.01.ENG 4. Matei M, Thalabard JC, Laude A, Misse C, Chassany O. Research on usual care: assessing the qualification criteria of the current legal framework [in French]. Presse Med 2011;40:e189–e196. 5. Lemaire F. Emergency research: only possible if consent is waived? Curr Opin Crit Care 2007;13:122–125. 6. Coats TJ, Shakur H. Consent in emergency research: new regulations. Emerg Med J 2005;22:683–685. 7. Halperin H, Paradis N, Mosesso V Jr, Nichol G, Sayre M, Ornato JP, Gerardi M, Nadkarni VM, Berg R, Becker L, et al.; American Heart Association Emergency Cardiovascular Care Committee; American Heart Association Council on Cardiopulmonary, Perioperative and Critical Care. Recommendations for implementation of community consultation and public disclosure under the Food and Drug Administration’s “Exception from informed consent requirements for emergency research”: a special report. Circulation 2007;116:1855–1863. 8. Biros M. Struggling with the rule: the exception from informed consent in resuscitation research. Acad Emerg Med 2007;14:344–345. 9. Kompanje EJO, Maas AIR, Menon DK, Kesecioglu J. Medical research in emergency research in the European Union member states: tensions between theory and practice. Intensive Care Med 2014;40: 496–503.
17
EDITORIALS 10. Lemaire F. Patient care versus research: does clinical research provide individual benefit to patients enrolled in trials? Curr Opin Crit Care 2004;10:565–569. 11. Levine RJ. The need to revise the Declaration of Helsinki. N Engl J Med 1999;341:531–534. 12. Tu JV, Willison DJ, Silver FL, Fang J, Richards JA, Laupacis A, Kapral MK; Investigators in the Registry of the Canadian Stroke Network. Impracticability of informed consent in the Registry of the Canadian Stroke Network. N Engl J Med 2004;350:1414–1421. 13. Taljaard M, Weijer C, Grimshaw JM, Eccles MP; Ottawa Ethics of Cluster Randomised Trials Consensus Group. The Ottawa Statement on the ethical design and conduct of cluster randomised trials: precis for researchers and research ethics committees. BMJ 2013;346:f2838.
18
14. HHS.gov. Human Research Protections FAQ: what are the criteria under 45 CFR 46.116(d) for waiving or altering some or all of the required elements of informed consent or parental permission? [accessed 2014 Dec 3]. Available from: http://answers.hhs.gov/ohrp/ questions/7274 15. Gøtzsche PC. Why we need easy access to all data from all clinical trials and how to accomplish it. Trials 2011;12:249. 16. Henry LM. Introduction: revising the common rule: prospects and challenges. J Law Med Ethics 2013;41:386–389.
Copyright © 2015 by the American Thoracic Society
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 1 | January 1 2015
