PERS PE C T IV E
Geography as Destiny for Transplant Candidates
1. Scientific Registry of Transplant Recipi ents home page (http://www.srtr.org). 2. Ubel P, Caplan A. Geographic favoritism in liver transplantation. N Engl J Med 1999; 340:963-5. 3. Institute of Medicine Committee on Or gan Procurement and Transplantation Policy. Organ procurement and transplantation: as
sessing current policies and the potential impact of the DHHS Final Rule. Washington, DC: National Academies Press, 1999. 4. Neergaard L. Mapping a better organ transplant list. Herald-Tribune. August 20, 2013 (http://health.heraldtribune.com/2013/ 08/20/mapping-a-better-organ-transplant-list). 5. Merion RM, Guidinger MK, Newmann
JM, Ellison MD, Port FK, Wolfe RA. Preva lence and outcomes of multiple-listing for cadaveric kidney and liver transplantation. Am J Transplant 2004;4:94-100. DOI: 10.1056/NEJMp1407639 Copyright © 2014 Massachusetts Medical Society.
Transparency and the European Medicines Agency — Sharing of Clinical Trial Data Sergio Bonini, M.D., Hans-Georg Eichler, M.D., Noël Wathion, Pharm., and Guido Rasi, M.D.
T
ransparency, whether in politics, finance, or science, is a fundamental value of our society. In health care, decisions about medicines made by governments, regulators, and clinicians are, whenever possible, based on clinical trial results. We believe that patients have a right to know about the scientific basis for the approval and use of their medicines and that transparency of clinical trial data is therefore essential. Over the past 4 years, we at the European Medicines Agency (EMA) have set new standards for clinical trial data transparency by adopting two landmark policies. A 2010 policy on access to documents1 and a 2014 policy on publication of clinical data for medicinal products for human use2 demonstrate the EMA’s commitment to continuing on its path toward transparency, within the boundaries of its mandate and in the interest of public health. The policy on document access, adopted in November 2010, enables interested parties to request data from clinical trials that have been submitted for marketing authorization of medicinal
2452
products. It represents the first step in implementing the principle of allowing the widest possible access to data while respecting the privacy of personal data and confidential commercial information that might be contained in a marketing-authorization dossier. Between 2010 and 2013, there were 750 requests for document access, with the number increasing substantially each year. The majority of the requests referred to agency documents and correspondence; only 25.5% referred to clinical trial data. Access to 2,064,035 pages of documents was granted. The largest number of requests came from the pharmaceutical industry (33.5%), followed by law firms (17.5%) and the lay press (15.9%; see graph). Fewer requests were received from academics or research institutes (10.4%), but 43.6% of those requests referred to clinical trial data, resulting in the release of the largest number of documents and pages (see graph). Only 5.5%, 1.5%, and 0.5% of applications were submitted by the general public, patient organizations, and nonprofit organizations, respectively.
Although the access policy is generally considered successful, some aspects of it were not universally welcomed. In 2013, three cases were brought to the General Court of the European Union (EU) by pharmaceutical companies seeking annulment of decisions to grant access to clinical reports underpinning EMA marketing authorization for their products, claiming that the EMA violated the protection of confidential commercial information. Two of these cases were withdrawn, however, after the plaintiffs accepted the agency’s position regarding the portions of the documents that were confidential. Absent clear legislation regarding confidential commercial information, the EMA often had to challenge companies’ views. When it believed that information did not warrant redaction, it had to defend its position and override companies’ objections. Between September 2013 and June 2014, the EMA and pharmaceutical companies had differences of opinion on suggested redactions in almost half the documents to be released (44 of 95 documents, or 46.3%). Against this back-
n engl j med 371;26 nejm.org december 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF OTAGO on December 24, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
PE R S PE C T IV E
Transparency and the European Medicines Agency
Refused
Pharmaceutical Industry
Granted
97
Law Firms
43
Lay Media
30
Academic or Research Institutes
31
Consultants
16
General Public 14
17.5% (182,240)
88
15.9% (414,511)
89
10.4% (646,207)
47 26 27
5.6% (85,044)
51
Pharmaceutical Industry 30
Law Firms
5.5% (206,868)
15 5.2%
9.4%
18
EU National Competent Authority 2 1.0% Regulators Outside EU 3 1.6% EU Institutions (e.g., EC) 1 0.5%
EU Institutions (e.g., EC) 4 7 1.5% (71)
Patients’ Organizations 2 1.0% Other 2 1.0%
Patients’ Organizations 3 8 1.5% (15,766)
Nonprofit Organizations 2 1.0% 0
Other 6 4 1.3% (1,202)
10
20
30
40
50
No. and Distribution of Requests for Access to Clinical Trial Data
1 3 0.5% (16,509) 25
17.8%
7.9%
10
General Public Health Care Professionals
Regulators Outside EU 6 5 1.5% (324)
0
11.0% 34
Consultants
EU National Competent Authority 5 8 1.7% (1,882)
26.7% 15.7%
21
Lay Media Academic or Research Institutes
Health Care Professionals 14 14 3.7% (21,055)
Nonprofit Organizations
33.5% (472,356)
154
50
75
100
125
150
175
200
225
250
No. and Distribution of Requests for Access to Documents Handled by European Medicines Agency
Number and Distribution of Requests for Access to Documents Handled by the European Medicines Agency, 2010–2013. Numbers in parentheses are the numbers of pages released. The inset graph shows the number and distribution of requests for access to clinical trial data. EC denotes European Commission, and EU European Union. Percentages do not sum to 100 because of rounding.
ground, the fact that only one court case is still pending and no new cases have been initiated is an encouraging sign of the industry’s changing attitude toward transparency. Indeed, the EMA’s view that such transparency benefits drug developers3 is supported by the decisions of several major pharmaceutical companies to join a scheme for providing access to data from industrysponsored trials in order to promote innovation and progress in research and development.4
The access-to-documents policy involves a reactive procedure requiring a written application for documents. Access is considered on a case-by-case basis, and if it’s granted, the documents are made available only to the requester. With the 2014 adoption of the policy on publication of clinical data for medicinal products for human use, the EMA has shifted to a more proactive approach, permitting publication of data from clinical trials submitted in drug marketing-authoriza-
n engl j med 371;26
nejm.org
tion applications, regardless of whether the authorization was granted. The final publication policy was developed with public input that stressed the need to protect both patient confidentiality and confidential commercial information and to avoid inappropriate use — especially commercial use — of data. Although the initial plan was to make the information available on-screen only, to avert unfair commercial use, the policy now allows identified
december 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF OTAGO on December 24, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
2453
PERS PE C T IV E
Transparency and the European Medicines Agency
requesters to download, save, and print clinical data for academic and noncommercial research purposes. Under the policy, clinical data are generally not considered confidential, and information in clinical reports is redacted only in specific circumstances, when such action is justified by the sponsor and agreed to by the agency. Justifications can include, for instance, the need to protect original laboratory methods used for drug development or to protect exploratory end points or biomarkers that do not support the current label claims and benefit–risk evaluation but represent the basis for future potential development of the medicine by the sponsor. The policy, approved in Oc tober 2014, will complement a new European Clinical Trial Regu lation,5 which requires transparency regarding the authorization, conduct, and results of clinical trials. The EMA policy covers the time gap before the EU regulation’s transparency requirements are implemented, which won’t happen before May 28, 2016. It also applies to clinical reports of studies that are conducted outside the EU but submitted to the EMA for marketing authorization in Europe, which are beyond the scope of the EU regulation. In the first phase of implementation, clinical study reports will be published; in a second phase, after all technical and legal implications have been investigated and clarified, patient-level data will be made available. Recognizing the potential benefits to them, patients and patient associations strongly supported the EMA’s efforts to develop a
2454
transparency policy. The limited number of document requests from such parties suggests that the agency needs to communicate better about the transparency initiative and that when clinical study reports are published, more practical and accessible information should be made publicly available. The media also play a key role and need to provide accurate information gleaned from documents they receive from the EMA. We believe that broader use of clinical trial data by academia and research institutes should also be promoted, since methodologically sound and unbiased reanalyses of data may advance science and help regulators review their decisions, as appropriate. Transparency carries some risks. Patients’ privacy, for instance, must be protected by adequate policy and technological measures, particularly in cases in which persons with rare diseases could potentially be identifiable through patient-level data. Justi fiably confidential commercial information should also be protected to avoid discouraging companies from investing further in drug development. We are confident that our commitment to transparency will be reciprocated by users of the data. Asking people seeking to download data to first identify themselves may prevent unfair use and permit intervention in the case of illegal behavior such as commercial use. The EMA encourages reanalysis of data to expand our body of knowledge and improve drug research. Data recipients should be granted complete freedom to engage in exploratory reanalyses
aimed, for example, at optimizing future study designs with regard to population selection and sample size, choice of outcomes, definition of clinically relevant differences for various end points, or identification of biomarkers for better disease phenotyping. By contrast, when data are reanalyzed for confirmatory purposes, the aim of the study, methods, and outcomes should be publicized in advance, as is usually requested when trials are registered. Certainly, access to clinical data imposes a high ethical standard on anyone using those data, lest inappropriate reanalyses breed unjustified concern about the efficacy or safety of marketed drugs. With its data-publication policy, the EMA has tried to consider the various, often conflicting, positions taken by many different parties. The agency was guided by the conviction that public health interests must outweigh any private intellectual or commercial interest. Implementing transparency, however, is a learning process requiring broad collaboration and implementation of unequivocal legislation. We hope that lawmakers, recognizing society’s expectation for increasing transparency, will guide us to the “sunlight” that, according to the 20th-century Supreme Court Justice Louis Brandeis, is “the best of disinfectants.” The views expressed in this article are those of the authors and do not necessarily reflect those of the European Medicines Agency or any of its committees. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From the European Medicines Agency (S.B., H.-G.E., N.W., G.R.), London; the Second University of Naples, Naples, Italy (S.B.); the
n engl j med 371;26 nejm.org december 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF OTAGO on December 24, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
PE R S PE C T IV E
Transparency and the European Medicines Agency
Institute of Translational Pharmacology, Italian National Research Council (S.B.), and the University of Rome Tor Vergata (G.R.) — both in Rome; and the Medical University of Vienna, Vienna (H.-G.E.). 1. European Medicines Agency. European Medicines Agency policy on access to docu ments (related to medicinal products for hu man and veterinary use): policy/0043. No vember 30, 2010 (http://www.ema.europa .eu/docs/en_GB/document_library/Other/ 2010/11/WC500099473.pdf).
2. European Medicines Agency. European Medicines Agency policy on publication of clinical data for medicinal products for human use: policy/0070. October 2, 2014 (http://www.ema.europa.eu/docs/en_GB/ document_library/Other/2014/10/ WC500174796.pdf). 3. Eichler H-G, Pétavy F, Pignatti F, Rasi G. Access to patient-level trial data — a boon to drug developers. N Engl J Med 2013;369: 1577-9. 4. Strom BL, Buyse M, Hughes J, Knoppers BM. Data sharing, year 1 — access to data
from industry-sponsored trials. N Engl J Med 2014;371:2052-4. 5. Legislation: Regulation (EU) no. 536/2014 of the European Parliament and of the Coun cil of 16 April 2014 on clinical trials on me dicinal products for human use, and repeal ing Directive 2001/20/EC. Official Journal of the European Union 2014;57:1-77 (http:// eur-lex.europa.eu/legal-content/EN/TXT/ PDF/?uri=OJ:L:2014:158:FULL&from=DE). DOI: 10.1056/NEJMp1409464 Copyright © 2014 Massachusetts Medical Society.
n engl j med 371;26 nejm.org december 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF OTAGO on December 24, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
2455
Geography as Destiny for Transplant Candidates
1. Scientific Registry of Transplant Recipi ents home page (http://www.srtr.org). 2. Ubel P, Caplan A. Geographic favoritism in liver transplantation. N Engl J Med 1999; 340:963-5. 3. Institute of Medicine Committee on Or gan Procurement and Transplantation Policy. Organ procurement and transplantation: as
sessing current policies and the potential impact of the DHHS Final Rule. Washington, DC: National Academies Press, 1999. 4. Neergaard L. Mapping a better organ transplant list. Herald-Tribune. August 20, 2013 (http://health.heraldtribune.com/2013/ 08/20/mapping-a-better-organ-transplant-list). 5. Merion RM, Guidinger MK, Newmann
JM, Ellison MD, Port FK, Wolfe RA. Preva lence and outcomes of multiple-listing for cadaveric kidney and liver transplantation. Am J Transplant 2004;4:94-100. DOI: 10.1056/NEJMp1407639 Copyright © 2014 Massachusetts Medical Society.
Transparency and the European Medicines Agency — Sharing of Clinical Trial Data Sergio Bonini, M.D., Hans-Georg Eichler, M.D., Noël Wathion, Pharm., and Guido Rasi, M.D.
T
ransparency, whether in politics, finance, or science, is a fundamental value of our society. In health care, decisions about medicines made by governments, regulators, and clinicians are, whenever possible, based on clinical trial results. We believe that patients have a right to know about the scientific basis for the approval and use of their medicines and that transparency of clinical trial data is therefore essential. Over the past 4 years, we at the European Medicines Agency (EMA) have set new standards for clinical trial data transparency by adopting two landmark policies. A 2010 policy on access to documents1 and a 2014 policy on publication of clinical data for medicinal products for human use2 demonstrate the EMA’s commitment to continuing on its path toward transparency, within the boundaries of its mandate and in the interest of public health. The policy on document access, adopted in November 2010, enables interested parties to request data from clinical trials that have been submitted for marketing authorization of medicinal
2452
products. It represents the first step in implementing the principle of allowing the widest possible access to data while respecting the privacy of personal data and confidential commercial information that might be contained in a marketing-authorization dossier. Between 2010 and 2013, there were 750 requests for document access, with the number increasing substantially each year. The majority of the requests referred to agency documents and correspondence; only 25.5% referred to clinical trial data. Access to 2,064,035 pages of documents was granted. The largest number of requests came from the pharmaceutical industry (33.5%), followed by law firms (17.5%) and the lay press (15.9%; see graph). Fewer requests were received from academics or research institutes (10.4%), but 43.6% of those requests referred to clinical trial data, resulting in the release of the largest number of documents and pages (see graph). Only 5.5%, 1.5%, and 0.5% of applications were submitted by the general public, patient organizations, and nonprofit organizations, respectively.
Although the access policy is generally considered successful, some aspects of it were not universally welcomed. In 2013, three cases were brought to the General Court of the European Union (EU) by pharmaceutical companies seeking annulment of decisions to grant access to clinical reports underpinning EMA marketing authorization for their products, claiming that the EMA violated the protection of confidential commercial information. Two of these cases were withdrawn, however, after the plaintiffs accepted the agency’s position regarding the portions of the documents that were confidential. Absent clear legislation regarding confidential commercial information, the EMA often had to challenge companies’ views. When it believed that information did not warrant redaction, it had to defend its position and override companies’ objections. Between September 2013 and June 2014, the EMA and pharmaceutical companies had differences of opinion on suggested redactions in almost half the documents to be released (44 of 95 documents, or 46.3%). Against this back-
n engl j med 371;26 nejm.org december 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF OTAGO on December 24, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
PE R S PE C T IV E
Transparency and the European Medicines Agency
Refused
Pharmaceutical Industry
Granted
97
Law Firms
43
Lay Media
30
Academic or Research Institutes
31
Consultants
16
General Public 14
17.5% (182,240)
88
15.9% (414,511)
89
10.4% (646,207)
47 26 27
5.6% (85,044)
51
Pharmaceutical Industry 30
Law Firms
5.5% (206,868)
15 5.2%
9.4%
18
EU National Competent Authority 2 1.0% Regulators Outside EU 3 1.6% EU Institutions (e.g., EC) 1 0.5%
EU Institutions (e.g., EC) 4 7 1.5% (71)
Patients’ Organizations 2 1.0% Other 2 1.0%
Patients’ Organizations 3 8 1.5% (15,766)
Nonprofit Organizations 2 1.0% 0
Other 6 4 1.3% (1,202)
10
20
30
40
50
No. and Distribution of Requests for Access to Clinical Trial Data
1 3 0.5% (16,509) 25
17.8%
7.9%
10
General Public Health Care Professionals
Regulators Outside EU 6 5 1.5% (324)
0
11.0% 34
Consultants
EU National Competent Authority 5 8 1.7% (1,882)
26.7% 15.7%
21
Lay Media Academic or Research Institutes
Health Care Professionals 14 14 3.7% (21,055)
Nonprofit Organizations
33.5% (472,356)
154
50
75
100
125
150
175
200
225
250
No. and Distribution of Requests for Access to Documents Handled by European Medicines Agency
Number and Distribution of Requests for Access to Documents Handled by the European Medicines Agency, 2010–2013. Numbers in parentheses are the numbers of pages released. The inset graph shows the number and distribution of requests for access to clinical trial data. EC denotes European Commission, and EU European Union. Percentages do not sum to 100 because of rounding.
ground, the fact that only one court case is still pending and no new cases have been initiated is an encouraging sign of the industry’s changing attitude toward transparency. Indeed, the EMA’s view that such transparency benefits drug developers3 is supported by the decisions of several major pharmaceutical companies to join a scheme for providing access to data from industrysponsored trials in order to promote innovation and progress in research and development.4
The access-to-documents policy involves a reactive procedure requiring a written application for documents. Access is considered on a case-by-case basis, and if it’s granted, the documents are made available only to the requester. With the 2014 adoption of the policy on publication of clinical data for medicinal products for human use, the EMA has shifted to a more proactive approach, permitting publication of data from clinical trials submitted in drug marketing-authoriza-
n engl j med 371;26
nejm.org
tion applications, regardless of whether the authorization was granted. The final publication policy was developed with public input that stressed the need to protect both patient confidentiality and confidential commercial information and to avoid inappropriate use — especially commercial use — of data. Although the initial plan was to make the information available on-screen only, to avert unfair commercial use, the policy now allows identified
december 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF OTAGO on December 24, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
2453
PERS PE C T IV E
Transparency and the European Medicines Agency
requesters to download, save, and print clinical data for academic and noncommercial research purposes. Under the policy, clinical data are generally not considered confidential, and information in clinical reports is redacted only in specific circumstances, when such action is justified by the sponsor and agreed to by the agency. Justifications can include, for instance, the need to protect original laboratory methods used for drug development or to protect exploratory end points or biomarkers that do not support the current label claims and benefit–risk evaluation but represent the basis for future potential development of the medicine by the sponsor. The policy, approved in Oc tober 2014, will complement a new European Clinical Trial Regu lation,5 which requires transparency regarding the authorization, conduct, and results of clinical trials. The EMA policy covers the time gap before the EU regulation’s transparency requirements are implemented, which won’t happen before May 28, 2016. It also applies to clinical reports of studies that are conducted outside the EU but submitted to the EMA for marketing authorization in Europe, which are beyond the scope of the EU regulation. In the first phase of implementation, clinical study reports will be published; in a second phase, after all technical and legal implications have been investigated and clarified, patient-level data will be made available. Recognizing the potential benefits to them, patients and patient associations strongly supported the EMA’s efforts to develop a
2454
transparency policy. The limited number of document requests from such parties suggests that the agency needs to communicate better about the transparency initiative and that when clinical study reports are published, more practical and accessible information should be made publicly available. The media also play a key role and need to provide accurate information gleaned from documents they receive from the EMA. We believe that broader use of clinical trial data by academia and research institutes should also be promoted, since methodologically sound and unbiased reanalyses of data may advance science and help regulators review their decisions, as appropriate. Transparency carries some risks. Patients’ privacy, for instance, must be protected by adequate policy and technological measures, particularly in cases in which persons with rare diseases could potentially be identifiable through patient-level data. Justi fiably confidential commercial information should also be protected to avoid discouraging companies from investing further in drug development. We are confident that our commitment to transparency will be reciprocated by users of the data. Asking people seeking to download data to first identify themselves may prevent unfair use and permit intervention in the case of illegal behavior such as commercial use. The EMA encourages reanalysis of data to expand our body of knowledge and improve drug research. Data recipients should be granted complete freedom to engage in exploratory reanalyses
aimed, for example, at optimizing future study designs with regard to population selection and sample size, choice of outcomes, definition of clinically relevant differences for various end points, or identification of biomarkers for better disease phenotyping. By contrast, when data are reanalyzed for confirmatory purposes, the aim of the study, methods, and outcomes should be publicized in advance, as is usually requested when trials are registered. Certainly, access to clinical data imposes a high ethical standard on anyone using those data, lest inappropriate reanalyses breed unjustified concern about the efficacy or safety of marketed drugs. With its data-publication policy, the EMA has tried to consider the various, often conflicting, positions taken by many different parties. The agency was guided by the conviction that public health interests must outweigh any private intellectual or commercial interest. Implementing transparency, however, is a learning process requiring broad collaboration and implementation of unequivocal legislation. We hope that lawmakers, recognizing society’s expectation for increasing transparency, will guide us to the “sunlight” that, according to the 20th-century Supreme Court Justice Louis Brandeis, is “the best of disinfectants.” The views expressed in this article are those of the authors and do not necessarily reflect those of the European Medicines Agency or any of its committees. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From the European Medicines Agency (S.B., H.-G.E., N.W., G.R.), London; the Second University of Naples, Naples, Italy (S.B.); the
n engl j med 371;26 nejm.org december 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF OTAGO on December 24, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
PE R S PE C T IV E
Transparency and the European Medicines Agency
Institute of Translational Pharmacology, Italian National Research Council (S.B.), and the University of Rome Tor Vergata (G.R.) — both in Rome; and the Medical University of Vienna, Vienna (H.-G.E.). 1. European Medicines Agency. European Medicines Agency policy on access to docu ments (related to medicinal products for hu man and veterinary use): policy/0043. No vember 30, 2010 (http://www.ema.europa .eu/docs/en_GB/document_library/Other/ 2010/11/WC500099473.pdf).
2. European Medicines Agency. European Medicines Agency policy on publication of clinical data for medicinal products for human use: policy/0070. October 2, 2014 (http://www.ema.europa.eu/docs/en_GB/ document_library/Other/2014/10/ WC500174796.pdf). 3. Eichler H-G, Pétavy F, Pignatti F, Rasi G. Access to patient-level trial data — a boon to drug developers. N Engl J Med 2013;369: 1577-9. 4. Strom BL, Buyse M, Hughes J, Knoppers BM. Data sharing, year 1 — access to data
from industry-sponsored trials. N Engl J Med 2014;371:2052-4. 5. Legislation: Regulation (EU) no. 536/2014 of the European Parliament and of the Coun cil of 16 April 2014 on clinical trials on me dicinal products for human use, and repeal ing Directive 2001/20/EC. Official Journal of the European Union 2014;57:1-77 (http:// eur-lex.europa.eu/legal-content/EN/TXT/ PDF/?uri=OJ:L:2014:158:FULL&from=DE). DOI: 10.1056/NEJMp1409464 Copyright © 2014 Massachusetts Medical Society.
n engl j med 371;26 nejm.org december 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF OTAGO on December 24, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
2455
