The
n e w e ng l a n d j o u r na l
of
m e dic i n e
1. Lewis G, ed. Saving mothers’ lives: reviewing maternal deaths
Joel Singer Ph.D. Providence Health Care Research Institute Vancouver, BC, Canada
Peter von Dadelszen, M.B., Ch.B., D.Phil. University of British Columbia Vancouver, BC, Canada
for the CHIPS Study Group Since publication of their article, the authors report no further potential conflict of interest.
to make motherhood safer — 2003-2005: the seventh report on confidential enquiries into maternal deaths in the United Kingdom. London: The Confidential Enquiry into Maternal and Child Health (CEMACH), December 2007 (http://www.hqip.org.uk/ assets/NCAPOP-Library/CMACE-Reports/18.-December-2007 -Saving-Mothers-Lives-reviewing-maternal-deaths-to-make -motherhood-safer-2003-2005-Executive-Summary.pdf). DOI: 10.1056/NEJMc1503870
Burden of Clostridium difficile Infection in the United States To the Editor: Lessa et al. (Feb. 26 issue)1 estimate the incidence of community-acquired Clostridium difficile infection at 30 to 120 cases per 100,000 persons per year in the United States. The investigators used active laboratory surveillance without correction for underestimation. We recently estimated the true incidence of C. difficile infection in the Netherlands in the community by testing 12,714 submitted stool samples for C. difficile regardless of whether such a report was requested by physicians.2 After correction for cases in which the patient did not visit a general practitioner or that were not diagnosed owing to the lack of a stool sample, the estimated crude incidence of 6.7 per 100,000 person-years was adjusted to 390 to 730 per 100,000 personyears, similar to the incidence of campylobacter species and higher than the incidence of salmonella species.3 On polymerase-chain-reaction (PCR) assay, the most commonly found ribotypes were 002 (NAP6 strain, in 11% of samples) and 078 (NAP7 strain, in 11% of samples); in the U.S. study, these two strains were identified in 7.6% and 3.4% of samples, respectively. Identical C. difficile 078 clones were found in Dutch farm animals, farmers, and patients with C. difficile infection, which would suggest zoonotic transmission.4 Since for other enteropathogens the effect of correcting for underestimation was similar in the United States and the Netherlands,5,6 we suspect that the true incidence of C. difficile infection in the United States is substantially higher than that reported by Lessa et al. Martijn Bouwknegt, Ph.D. National Institute for Public Health and the Environment Bilthoven, the Netherlands [email protected]
2368
Sofie van Dorp, M.D. Ed Kuijper, M.D., Ph.D. Leiden University Medical Center Leiden, the Netherlands No potential conflict of interest relevant to this letter was reported. 1. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium
difficile infection in the United States. N Engl J Med 2015;372:82534. 2. Hensgens MP, Dekkers OM, Demeulemeester A, et al. Diarrhoea in general practice: when should a Clostridium difficile infection be considered? Results of a nested case-control study. Clin Microbiol Infect 2014;20:O1067-O1074. 3. Havelaar AH, Ivarsson S, Löfdahl M, Nauta MJ. Estimating the true incidence of campylobacteriosis and salmonellosis in the European Union, 2009. Epidemiol Infect 2013;141:293-302. 4. Knetsch CW, Connor TR, Mutreja A, et al. Whole genome sequencing reveals potential spread of Clostridium difficile between humans and farm animals in the Netherlands, 2002 to 2011. Euro Surveill 2014;19:20954. 5. Havelaar AH, Haagsma JA, Mangen MJJ, et al. Disease burden of foodborne pathogens in the Netherlands, 2009. Int J Food Microbiol 2012;156:231-8. 6. Scallan E, Hoekstra RM, Angulo FJ, et al. Foodborne illness acquired in the United States — major pathogens. Emerg Infect Dis 2011;17:7-15. DOI: 10.1056/NEJMc1505190
To the Editor: From July 1, 2012, to January 4, 2014, Stanford Health Care screened 5934 adults with unformed stools for C. difficile infection with the use of a PCR assay for the toxin B gene (GeneXpert C. difficile assay, Cepheid). Of 785 patients (13.2%) with positive results, 628 (80.0%) had adequate documentation to determine the presence or absence of clinically significant diarrhea, which was defined as three or more unformed stools in a 24-hour period.1 Only 210 of these patients (33.4%) had clinically significant diarrhea, and half the patients had received laxatives in the 48 hours preceding collection. These findings indicate that many of our positive re-
n engl j med 372;24 nejm.org june 11, 2015
The New England Journal of Medicine Downloaded from nejm.org at NYU WASHINGTON SQUARE CAMPUS on June 16, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
correspondence
sults may derive from C. difficile colonization rather than infection. Because of overdiagnosis in patients without clinically significant diarrhea, such results would falsely elevate the incidence of clinically significant C. difficile infection. Direct and indirect evidence suggests that the overdiagnosis of C. difficile infection is widespread.2-5 Therefore, the study by Lessa and colleagues, in which C. difficile infection was defined according to positive laboratory results, probably overestimated the incidence of infection. Interventions are needed to improve adherence of physicians to the clinical indications for testing. Reduction in the overdiagnosis of C. difficile infection will have an effect on the treatment of patients, antibiotic stewardship, and health care spending. Niaz Banaei, M.D. Victoria Anikst, B.S. Stanford University Stanford, CA [email protected]
Lee Frederick Schroeder, M.D., Ph.D. University of Michigan Ann Arbor, MI No potential conflict of interest relevant to this letter was reported. 1. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice
guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010;31:431-55. 2. Dubberke ER, Han Z, Bobo L, et al. Impact of clinical symptoms on interpretation of diagnostic assays for Clostridium difficile infections. J Clin Microbiol 2011;49:2887-93. 3. Peterson LR, Manson RU, Paule SM, et al. Detection of toxigenic Clostridium difficile in stool samples by real-time polymerase chain reaction for the diagnosis of C. difficile-associated diarrhea. Clin Infect Dis 2007;45:1152-60. 4. Guerrero DM, Chou C, Jury LA, Nerandzic MM, Cadnum JC, Donskey CJ. Clinical and infection control implications of Clostridium difficile infection with negative enzyme immunoassay for toxin. Clin Infect Dis 2011;53:287-90. 5. Buckel WR, Avdic E, Carroll KC, Gunaseelan V, Hadhazy E, Cosgrove SE. Gut check: Clostridium difficile testing and treatment in the molecular testing era. Infect Control Hosp Epidemiol 2015;36:217-21. DOI: 10.1056/NEJMc1505190
The Authors Reply: Banaei and colleagues express concern that C. difficile infection may be overdiagnosed with the use of PCR assay, given that in their study only one third of patients had clinically significant diarrhea, and half these patients had recent exposure to laxatives. Because positive predictive value is influenced by the preva-
lence of true disease, care must be taken to ensure that the appropriate population is tested. This is especially true with the use of nucleic acid amplification testing (NAAT), in which a prevalence of C. difficile of approximately 20% has been associated with increased accuracy in the diagnosis of C. difficile infection.1 In the Supplementary Appendix of our article (available with the full text of the article at NEJM.org), we included an evaluation of the effect of different rates of NAAT use on the burden of C. difficile infection in the United States. Meanwhile, Bouwknegt and colleagues are concerned that C. difficile infection may be underdiagnosed in outpatient settings because C. difficile is frequently detected in diarrheal stool samples submitted by general practitioners for other diagnostic tests.2 It is possible that there is a hidden burden of C. difficile infection in the United States owing to a lack of clinical suspicion. However, noninfectious conditions and brief, self-limited infections often cause diarrhea, and testing of diarrheal specimens obtained from patients without clinically significant symptoms may lead to detection of C. difficile colonization rather than infection.3 As noted by Banaei et al. and Bouwknegt et al., there are several limitations to the diagnosis of C. difficile infection that can have an effect on the estimates of disease burden and consequently result in limitations to any surveillance definition or approach that is used. Fernanda C. Lessa, M.D., M.P.H. Centers for Disease Control and Prevention Atlanta, GA [email protected]
Lisa G. Winston, M.D. University of California, San Francisco, School of Medicine San Francisco, CA
L. Clifford McDonald, M.D. Centers for Disease Control and Prevention Atlanta, GA
for the Emerging Infections Program C. difficile Surveillance Team The findings and conclusions are those of the correspondents and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Since publication of their article, the authors report no further potential conflict of interest. 1. Deshpande A, Pasupuleti V, Rolston DD, et al. Diagnostic
accuracy of real-time polymerase chain reaction in detection of Clostridium difficile in the stool samples of patients with suspected Clostridium difficile infection: a meta-analysis. Clin Infect Dis 2011;53(7):e81-e90.
n engl j med 372;24 nejm.org june 11, 2015
2369
The New England Journal of Medicine Downloaded from nejm.org at NYU WASHINGTON SQUARE CAMPUS on June 16, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
The
n e w e ng l a n d j o u r na l
2. Hensgens MP, Dekkers OM, Demeulemeester A, et al. Diar-
rhoea in general practice: when should a Clostridium difficile infection be considered? Results of a nested case-control study. Clin Microbiol Infect 2014;20:O1067-O1074.
of
m e dic i n e
3. Dubberke ER, Han Z, Bobo L, et al. Impact of clinical symp-
toms on interpretation of diagnostic assays for Clostridium difficile infections. J Clin Microbiol 2011;49:2887-93. DOI: 10.1056/NEJMc1505190
Compliance with Results Reporting at ClinicalTrials.gov To the Editor: The low compliance with ClinicalTrials.gov reporting requirements that Anderson et al. (March 12 issue)1 documented among clinical research sponsors should garner attention. As the research enterprise addresses this serious ethical breach, however, we must remember an equally binding obligation to share research findings with the clinical trial participants who make scientific advances possible.2 Most participants (77%) are never informed of the trial’s results, and 72% say that it is “very important” to address this issue.3 In a new report, the Institute of Medicine calls the sharing of results in understandable language a “matter of public transparency and respect” and cites research by the authors of this letter demonstrating feasibility.4 The Multi-Regional Clinical Trials Center at Harvard developed a comprehensive guidance document and toolkit to deconstruct and ease the process.5 Although ClinicalTrials.gov currently does not address this unethical situation, it could — the Food and Drug Administration (FDA) Amendments Act of 2007 authorized the Department of Health and Human Services to require technical and narrative results summaries. We hope the work by Anderson et al. will serve as a call to improve registration and reporting not only for the scientific community but also for patients and the public. It is our obligation, and it is the right thing to do. Zachary P. Hallinan, B.A. Kenneth A. Getz, M.B.A. Center for Information and Study on Clinical Research Participation Boston, MA [email protected]
Barbara E. Bierer, M.D. Multi-Regional Clinical Trials Center at Harvard University Boston, MA No potential conflict of interest relevant to this letter was reported. 1. Anderson ML, Chiswell K, Peterson ED, Tasneem A, Topping J,
Califf RM. Compliance with results reporting at ClinicalTrials.gov. N Engl J Med 2015;372:1031-9.
2370
2. World Medical Association. World Medical Association Dec-
laration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013;310:2191-4. 3. Kost RG, Lee LM, Yessis J, Wesley RA, Henderson DK, Coller BS. Assessing participant-centered outcomes to improve clinical research. N Engl J Med 2013;369:2179-81. 4. The clinical trial life cycle and when to share data. In: Sharing clinical trial data: maximizing benefits, minimizing risk. Washington, DC: National Academies Press, 2015:91-138. 5. Multi-Regional Clinical Trials Center at Harvard University return of results guidance document (http://mrct.globalhealth .harvard.edu/file/341171). DOI: 10.1056/NEJMc1504513
The Authors Reply: Hallinan et al. underscore the ethical duty of research sponsors to share findings with trial participants and suggest that providing nontechnical and technical narrative summaries could help fulfill this obligation. Notably, the notice of proposed rulemaking for the FDA Amendments Act1 has delayed enactment of these summaries, pending public feedback. Additional issues are presented when sponsors delay reporting while pursuing marketing approval for novel products. We estimated that 44 to 45% of industry-funded trials (as compared with 6% of trials funded by the National Institutes of Health and 9% of other trials) were not required to report because they involved an unapproved or unlabeled product. Under proposed rules, sponsors seeking approval for new products or indications may delay reporting to ClinicalTrials .gov for 2 more years if a certification of delay is filed before the 1-year deadline. Trials involving unapproved products that do not include plans for seeking approval must report within 1 year. Although this rule ensures eventual public access to data, it also highlights tensions between desires to protect trade secrets and obligations to share knowledge. Furthermore, delays in public reporting may lead to unnecessarily duplicative trials and expose participants to unwarranted risks. Monique L. Anderson, M.D. Duke University School of Medicine Durham, NC [email protected]
n engl j med 372;24 nejm.org june 11, 2015
The New England Journal of Medicine Downloaded from nejm.org at NYU WASHINGTON SQUARE CAMPUS on June 16, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
n e w e ng l a n d j o u r na l
of
m e dic i n e
1. Lewis G, ed. Saving mothers’ lives: reviewing maternal deaths
Joel Singer Ph.D. Providence Health Care Research Institute Vancouver, BC, Canada
Peter von Dadelszen, M.B., Ch.B., D.Phil. University of British Columbia Vancouver, BC, Canada
for the CHIPS Study Group Since publication of their article, the authors report no further potential conflict of interest.
to make motherhood safer — 2003-2005: the seventh report on confidential enquiries into maternal deaths in the United Kingdom. London: The Confidential Enquiry into Maternal and Child Health (CEMACH), December 2007 (http://www.hqip.org.uk/ assets/NCAPOP-Library/CMACE-Reports/18.-December-2007 -Saving-Mothers-Lives-reviewing-maternal-deaths-to-make -motherhood-safer-2003-2005-Executive-Summary.pdf). DOI: 10.1056/NEJMc1503870
Burden of Clostridium difficile Infection in the United States To the Editor: Lessa et al. (Feb. 26 issue)1 estimate the incidence of community-acquired Clostridium difficile infection at 30 to 120 cases per 100,000 persons per year in the United States. The investigators used active laboratory surveillance without correction for underestimation. We recently estimated the true incidence of C. difficile infection in the Netherlands in the community by testing 12,714 submitted stool samples for C. difficile regardless of whether such a report was requested by physicians.2 After correction for cases in which the patient did not visit a general practitioner or that were not diagnosed owing to the lack of a stool sample, the estimated crude incidence of 6.7 per 100,000 person-years was adjusted to 390 to 730 per 100,000 personyears, similar to the incidence of campylobacter species and higher than the incidence of salmonella species.3 On polymerase-chain-reaction (PCR) assay, the most commonly found ribotypes were 002 (NAP6 strain, in 11% of samples) and 078 (NAP7 strain, in 11% of samples); in the U.S. study, these two strains were identified in 7.6% and 3.4% of samples, respectively. Identical C. difficile 078 clones were found in Dutch farm animals, farmers, and patients with C. difficile infection, which would suggest zoonotic transmission.4 Since for other enteropathogens the effect of correcting for underestimation was similar in the United States and the Netherlands,5,6 we suspect that the true incidence of C. difficile infection in the United States is substantially higher than that reported by Lessa et al. Martijn Bouwknegt, Ph.D. National Institute for Public Health and the Environment Bilthoven, the Netherlands [email protected]
2368
Sofie van Dorp, M.D. Ed Kuijper, M.D., Ph.D. Leiden University Medical Center Leiden, the Netherlands No potential conflict of interest relevant to this letter was reported. 1. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium
difficile infection in the United States. N Engl J Med 2015;372:82534. 2. Hensgens MP, Dekkers OM, Demeulemeester A, et al. Diarrhoea in general practice: when should a Clostridium difficile infection be considered? Results of a nested case-control study. Clin Microbiol Infect 2014;20:O1067-O1074. 3. Havelaar AH, Ivarsson S, Löfdahl M, Nauta MJ. Estimating the true incidence of campylobacteriosis and salmonellosis in the European Union, 2009. Epidemiol Infect 2013;141:293-302. 4. Knetsch CW, Connor TR, Mutreja A, et al. Whole genome sequencing reveals potential spread of Clostridium difficile between humans and farm animals in the Netherlands, 2002 to 2011. Euro Surveill 2014;19:20954. 5. Havelaar AH, Haagsma JA, Mangen MJJ, et al. Disease burden of foodborne pathogens in the Netherlands, 2009. Int J Food Microbiol 2012;156:231-8. 6. Scallan E, Hoekstra RM, Angulo FJ, et al. Foodborne illness acquired in the United States — major pathogens. Emerg Infect Dis 2011;17:7-15. DOI: 10.1056/NEJMc1505190
To the Editor: From July 1, 2012, to January 4, 2014, Stanford Health Care screened 5934 adults with unformed stools for C. difficile infection with the use of a PCR assay for the toxin B gene (GeneXpert C. difficile assay, Cepheid). Of 785 patients (13.2%) with positive results, 628 (80.0%) had adequate documentation to determine the presence or absence of clinically significant diarrhea, which was defined as three or more unformed stools in a 24-hour period.1 Only 210 of these patients (33.4%) had clinically significant diarrhea, and half the patients had received laxatives in the 48 hours preceding collection. These findings indicate that many of our positive re-
n engl j med 372;24 nejm.org june 11, 2015
The New England Journal of Medicine Downloaded from nejm.org at NYU WASHINGTON SQUARE CAMPUS on June 16, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
correspondence
sults may derive from C. difficile colonization rather than infection. Because of overdiagnosis in patients without clinically significant diarrhea, such results would falsely elevate the incidence of clinically significant C. difficile infection. Direct and indirect evidence suggests that the overdiagnosis of C. difficile infection is widespread.2-5 Therefore, the study by Lessa and colleagues, in which C. difficile infection was defined according to positive laboratory results, probably overestimated the incidence of infection. Interventions are needed to improve adherence of physicians to the clinical indications for testing. Reduction in the overdiagnosis of C. difficile infection will have an effect on the treatment of patients, antibiotic stewardship, and health care spending. Niaz Banaei, M.D. Victoria Anikst, B.S. Stanford University Stanford, CA [email protected]
Lee Frederick Schroeder, M.D., Ph.D. University of Michigan Ann Arbor, MI No potential conflict of interest relevant to this letter was reported. 1. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice
guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010;31:431-55. 2. Dubberke ER, Han Z, Bobo L, et al. Impact of clinical symptoms on interpretation of diagnostic assays for Clostridium difficile infections. J Clin Microbiol 2011;49:2887-93. 3. Peterson LR, Manson RU, Paule SM, et al. Detection of toxigenic Clostridium difficile in stool samples by real-time polymerase chain reaction for the diagnosis of C. difficile-associated diarrhea. Clin Infect Dis 2007;45:1152-60. 4. Guerrero DM, Chou C, Jury LA, Nerandzic MM, Cadnum JC, Donskey CJ. Clinical and infection control implications of Clostridium difficile infection with negative enzyme immunoassay for toxin. Clin Infect Dis 2011;53:287-90. 5. Buckel WR, Avdic E, Carroll KC, Gunaseelan V, Hadhazy E, Cosgrove SE. Gut check: Clostridium difficile testing and treatment in the molecular testing era. Infect Control Hosp Epidemiol 2015;36:217-21. DOI: 10.1056/NEJMc1505190
The Authors Reply: Banaei and colleagues express concern that C. difficile infection may be overdiagnosed with the use of PCR assay, given that in their study only one third of patients had clinically significant diarrhea, and half these patients had recent exposure to laxatives. Because positive predictive value is influenced by the preva-
lence of true disease, care must be taken to ensure that the appropriate population is tested. This is especially true with the use of nucleic acid amplification testing (NAAT), in which a prevalence of C. difficile of approximately 20% has been associated with increased accuracy in the diagnosis of C. difficile infection.1 In the Supplementary Appendix of our article (available with the full text of the article at NEJM.org), we included an evaluation of the effect of different rates of NAAT use on the burden of C. difficile infection in the United States. Meanwhile, Bouwknegt and colleagues are concerned that C. difficile infection may be underdiagnosed in outpatient settings because C. difficile is frequently detected in diarrheal stool samples submitted by general practitioners for other diagnostic tests.2 It is possible that there is a hidden burden of C. difficile infection in the United States owing to a lack of clinical suspicion. However, noninfectious conditions and brief, self-limited infections often cause diarrhea, and testing of diarrheal specimens obtained from patients without clinically significant symptoms may lead to detection of C. difficile colonization rather than infection.3 As noted by Banaei et al. and Bouwknegt et al., there are several limitations to the diagnosis of C. difficile infection that can have an effect on the estimates of disease burden and consequently result in limitations to any surveillance definition or approach that is used. Fernanda C. Lessa, M.D., M.P.H. Centers for Disease Control and Prevention Atlanta, GA [email protected]
Lisa G. Winston, M.D. University of California, San Francisco, School of Medicine San Francisco, CA
L. Clifford McDonald, M.D. Centers for Disease Control and Prevention Atlanta, GA
for the Emerging Infections Program C. difficile Surveillance Team The findings and conclusions are those of the correspondents and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Since publication of their article, the authors report no further potential conflict of interest. 1. Deshpande A, Pasupuleti V, Rolston DD, et al. Diagnostic
accuracy of real-time polymerase chain reaction in detection of Clostridium difficile in the stool samples of patients with suspected Clostridium difficile infection: a meta-analysis. Clin Infect Dis 2011;53(7):e81-e90.
n engl j med 372;24 nejm.org june 11, 2015
2369
The New England Journal of Medicine Downloaded from nejm.org at NYU WASHINGTON SQUARE CAMPUS on June 16, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
The
n e w e ng l a n d j o u r na l
2. Hensgens MP, Dekkers OM, Demeulemeester A, et al. Diar-
rhoea in general practice: when should a Clostridium difficile infection be considered? Results of a nested case-control study. Clin Microbiol Infect 2014;20:O1067-O1074.
of
m e dic i n e
3. Dubberke ER, Han Z, Bobo L, et al. Impact of clinical symp-
toms on interpretation of diagnostic assays for Clostridium difficile infections. J Clin Microbiol 2011;49:2887-93. DOI: 10.1056/NEJMc1505190
Compliance with Results Reporting at ClinicalTrials.gov To the Editor: The low compliance with ClinicalTrials.gov reporting requirements that Anderson et al. (March 12 issue)1 documented among clinical research sponsors should garner attention. As the research enterprise addresses this serious ethical breach, however, we must remember an equally binding obligation to share research findings with the clinical trial participants who make scientific advances possible.2 Most participants (77%) are never informed of the trial’s results, and 72% say that it is “very important” to address this issue.3 In a new report, the Institute of Medicine calls the sharing of results in understandable language a “matter of public transparency and respect” and cites research by the authors of this letter demonstrating feasibility.4 The Multi-Regional Clinical Trials Center at Harvard developed a comprehensive guidance document and toolkit to deconstruct and ease the process.5 Although ClinicalTrials.gov currently does not address this unethical situation, it could — the Food and Drug Administration (FDA) Amendments Act of 2007 authorized the Department of Health and Human Services to require technical and narrative results summaries. We hope the work by Anderson et al. will serve as a call to improve registration and reporting not only for the scientific community but also for patients and the public. It is our obligation, and it is the right thing to do. Zachary P. Hallinan, B.A. Kenneth A. Getz, M.B.A. Center for Information and Study on Clinical Research Participation Boston, MA [email protected]
Barbara E. Bierer, M.D. Multi-Regional Clinical Trials Center at Harvard University Boston, MA No potential conflict of interest relevant to this letter was reported. 1. Anderson ML, Chiswell K, Peterson ED, Tasneem A, Topping J,
Califf RM. Compliance with results reporting at ClinicalTrials.gov. N Engl J Med 2015;372:1031-9.
2370
2. World Medical Association. World Medical Association Dec-
laration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013;310:2191-4. 3. Kost RG, Lee LM, Yessis J, Wesley RA, Henderson DK, Coller BS. Assessing participant-centered outcomes to improve clinical research. N Engl J Med 2013;369:2179-81. 4. The clinical trial life cycle and when to share data. In: Sharing clinical trial data: maximizing benefits, minimizing risk. Washington, DC: National Academies Press, 2015:91-138. 5. Multi-Regional Clinical Trials Center at Harvard University return of results guidance document (http://mrct.globalhealth .harvard.edu/file/341171). DOI: 10.1056/NEJMc1504513
The Authors Reply: Hallinan et al. underscore the ethical duty of research sponsors to share findings with trial participants and suggest that providing nontechnical and technical narrative summaries could help fulfill this obligation. Notably, the notice of proposed rulemaking for the FDA Amendments Act1 has delayed enactment of these summaries, pending public feedback. Additional issues are presented when sponsors delay reporting while pursuing marketing approval for novel products. We estimated that 44 to 45% of industry-funded trials (as compared with 6% of trials funded by the National Institutes of Health and 9% of other trials) were not required to report because they involved an unapproved or unlabeled product. Under proposed rules, sponsors seeking approval for new products or indications may delay reporting to ClinicalTrials .gov for 2 more years if a certification of delay is filed before the 1-year deadline. Trials involving unapproved products that do not include plans for seeking approval must report within 1 year. Although this rule ensures eventual public access to data, it also highlights tensions between desires to protect trade secrets and obligations to share knowledge. Furthermore, delays in public reporting may lead to unnecessarily duplicative trials and expose participants to unwarranted risks. Monique L. Anderson, M.D. Duke University School of Medicine Durham, NC [email protected]
n engl j med 372;24 nejm.org june 11, 2015
The New England Journal of Medicine Downloaded from nejm.org at NYU WASHINGTON SQUARE CAMPUS on June 16, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
