In defense of publishing baseline data from clinical trials In this issue of Fertility and Sterility, we have published the baseline data from a multicenter, randomized clinical trial for the treatment of infertility known as the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) study (1). I now would like to justify this practice. As a coauthor of the article and as an associate editor of this journal, I acknowledge a conflict of interest, but there are important reasons for publishing such baseline data. The practice of publishing baseline data is well established for clinical trials testing interventions for diabetes or cardiovascular disease, but such publications have been less common in reproductive medicine. Leading journals in our field such as Fertility and Sterility (ranked 1 in Reproductive Medicine by our preferred publication metric, the Eigenfactor) have been reluctant to publish what appears to be such a small slice of the trial; instead, we as editors want to publish the main manuscript reporting the key outcomes of the trial. Many of the highest impact medical journals will not even review such a baseline paper and will send it back with the admonishment to return with the outcome paper. Pundits can argue that publishing a baseline paper is a form of salami publication, a practice we recently decried (2). Yet I believe such data are important and worthy of publication, and here are my reasons. A baseline article for a large clinical trial introduces the readership to a more complete summary of the protocol and the baseline characteristics of the participants. Only a fraction of the baseline data can be presented in a main outcome article, given the word restrictions and limitations on the number of tables and figures at most journals. In the main outcome article, the focus is on the results and their interpretation, and usually only a single table of carefully chosen representative baseline characteristics can be included in the main outcome article. For many trials, that represents only a fraction of the data collected. For example, the baseline article published in this issue contains three tables of baseline characteristics in the print version and an additional figure as well as two supplemental tables online and a table on assay quality control. These are important data for determining the generalizability of the trial to the larger population of infertile couples, including the couples our readership treats. There is a wealth of questions that such data can raise, especially when compared with other studies of unexplained infertility or with other infertility populations such as women with polycystic ovary syndrome. For one small example, why are male partners more often smokers than female partners? Are we not reaching them or counseling them adequately? The 900 couples described in this baseline article represent one of the largest cohorts of infertile couples ever described in the literature. Epidemiologists may cringe, but I will suggest that these data may teach us something about the larger population of infertile couples, especially as they were more extensively characterized than is typical in clinical practice and were also phenotyped in a standardized fashion according to protocol, including with the assays reported in this article that were run in a central laboratory. The participants were also re902
cruited at multiple distinct sites spread across the United States, and they are thus more representative of the larger U.S. infertility population than any cohort characterized at a single center. We along with our colleagues at Human Reproduction (ranked 1 in Reproductive Medicine by their preferred publication metric, the Impact Factor) recently recommended that clinical researchers report more complete data on the participants in clinical trials of infertility, including a more complete reproductive history and the cause of infertility and means of determining it, as well as reporting such data on both partners, even if only one of them received treatment (3, 4). The AMIGOS trial answers many of these calls for reform by reporting the male biometric, demographic, and baseline semen analysis parameters as well as providing details of the male (and female) medical history. Though this is a small step toward rectifying the gap in clinical trials addressing male factor infertility, it is another important precedent toward more expansive studies of the male. These data ultimately belong to everyone in the United States—as taxpayers, we footed the bill for this study. The clinical trial was funded by the National Institutes of Health (NIH), and under NIH guidelines we have established a datasharing policy such that the complete data set including outcomes will eventually be available to all. (The details are at the Reproductive Medicine Network Web site under Resource Sharing: http://c2s2.yale.edu/rmn/resourcesharing.html.) Providing a complete description of the data collected at baseline will allow for greater dissemination to other researchers of the data collected, allowing for a variety of post hoc hypotheses to be tested when the outcomes are known. Although the trial was designed and powered to answer only the primary hypothesis, it was also designed to capture additional data beyond a pragmatic clinical trial so that we and outside investigators may explore our favorite secondary hypotheses, many of which will emerge when the outcomes are known. Even with our busy print and online supplemental tables, we are still only publishing a segment of the baseline data. Many of the variables were collected at multiple time points as the study progressed, allowing additional analyses of treatment effects. We have also established a specimen repository, which includes serum and DNA from male and female participants and semen from male participants (5) (caveat: not all patients consented to participate in the repository), which will also be available by request so that investigators may more completely explore their post hoc hypotheses from the trial. Both as an associate editor and as a reader, I would rather read an article that explores a secondary hypothesis in a preexisting, large, well-designed database with follow-up observations of the participants over time, especially if it is enhanced with new or additional data obtained by using stored specimens, than read yet another poorly conceived meta-analysis of a treatment or test that includes only small and heterogeneous clinical studies with a handful of patients in the exposed and unexposed groups. The AMIGOS study offers you close to 300 couples in each of the three treatment groups. We are entering an area of big data, greater transparency, and enhanced access as outside researchers use large databases from insurers, public health agencies, electronic
VOL. 103 NO. 4 / APRIL 2015
Fertility and Sterility® health records, and pharmaceutical trials. Let us take full advantage of these new and exciting opportunities. Richard S. Legro, M.D. Obstetrics and Gynecology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
REFERENCES 1.
2.
http://dx.doi.org/10.1016/j.fertnstert.2015.01.039
3.
You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/legror-baseline-data-clinicaltrials/
4.
5.
Use your smartphone to scan this QR code and connect to the discussion forum for this article now.*
Diamond MP, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P, et al. Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) Trial: baseline characteristics. Fertil Steril 2015;103:962–73.e4. Legro RS, Niederberger C, Pellicer A. Disclosure of duplicative studies: damned if you don't. Fertil Steril 2012;98:1347–9. Harbin Consensus Conference Workshop Group, Conference Chairs, Legro RS, Wu X, Scientific Committee, Barnhart KT, et al. Improving the reporting of clinical trials of infertility treatments (IMPRINT): modifying the CONSORT statement. Hum Reprod 2014;29:2075–82. Harbin Consensus Conference Workshop Group. Improving the Reporting of Clinical Trials of Infertility Treatments (IMPRINT): modifying the CONSORT statement. Fertil Steril 2014;102:952–9.e15. Krawetz SA, Casson PR, Diamond MP, Zhang H, Legro RS, Schlaff WD, et al. Establishing a biologic specimens repository for reproductive clinical trials: technical aspects. Syst Biol Reprod Med 2011;57:222–7.
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
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cruited at multiple distinct sites spread across the United States, and they are thus more representative of the larger U.S. infertility population than any cohort characterized at a single center. We along with our colleagues at Human Reproduction (ranked 1 in Reproductive Medicine by their preferred publication metric, the Impact Factor) recently recommended that clinical researchers report more complete data on the participants in clinical trials of infertility, including a more complete reproductive history and the cause of infertility and means of determining it, as well as reporting such data on both partners, even if only one of them received treatment (3, 4). The AMIGOS trial answers many of these calls for reform by reporting the male biometric, demographic, and baseline semen analysis parameters as well as providing details of the male (and female) medical history. Though this is a small step toward rectifying the gap in clinical trials addressing male factor infertility, it is another important precedent toward more expansive studies of the male. These data ultimately belong to everyone in the United States—as taxpayers, we footed the bill for this study. The clinical trial was funded by the National Institutes of Health (NIH), and under NIH guidelines we have established a datasharing policy such that the complete data set including outcomes will eventually be available to all. (The details are at the Reproductive Medicine Network Web site under Resource Sharing: http://c2s2.yale.edu/rmn/resourcesharing.html.) Providing a complete description of the data collected at baseline will allow for greater dissemination to other researchers of the data collected, allowing for a variety of post hoc hypotheses to be tested when the outcomes are known. Although the trial was designed and powered to answer only the primary hypothesis, it was also designed to capture additional data beyond a pragmatic clinical trial so that we and outside investigators may explore our favorite secondary hypotheses, many of which will emerge when the outcomes are known. Even with our busy print and online supplemental tables, we are still only publishing a segment of the baseline data. Many of the variables were collected at multiple time points as the study progressed, allowing additional analyses of treatment effects. We have also established a specimen repository, which includes serum and DNA from male and female participants and semen from male participants (5) (caveat: not all patients consented to participate in the repository), which will also be available by request so that investigators may more completely explore their post hoc hypotheses from the trial. Both as an associate editor and as a reader, I would rather read an article that explores a secondary hypothesis in a preexisting, large, well-designed database with follow-up observations of the participants over time, especially if it is enhanced with new or additional data obtained by using stored specimens, than read yet another poorly conceived meta-analysis of a treatment or test that includes only small and heterogeneous clinical studies with a handful of patients in the exposed and unexposed groups. The AMIGOS study offers you close to 300 couples in each of the three treatment groups. We are entering an area of big data, greater transparency, and enhanced access as outside researchers use large databases from insurers, public health agencies, electronic
VOL. 103 NO. 4 / APRIL 2015
Fertility and Sterility® health records, and pharmaceutical trials. Let us take full advantage of these new and exciting opportunities. Richard S. Legro, M.D. Obstetrics and Gynecology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
REFERENCES 1.
2.
http://dx.doi.org/10.1016/j.fertnstert.2015.01.039
3.
You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/legror-baseline-data-clinicaltrials/
4.
5.
Use your smartphone to scan this QR code and connect to the discussion forum for this article now.*
Diamond MP, Legro RS, Coutifaris C, Alvero R, Robinson RD, Casson P, et al. Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) Trial: baseline characteristics. Fertil Steril 2015;103:962–73.e4. Legro RS, Niederberger C, Pellicer A. Disclosure of duplicative studies: damned if you don't. Fertil Steril 2012;98:1347–9. Harbin Consensus Conference Workshop Group, Conference Chairs, Legro RS, Wu X, Scientific Committee, Barnhart KT, et al. Improving the reporting of clinical trials of infertility treatments (IMPRINT): modifying the CONSORT statement. Hum Reprod 2014;29:2075–82. Harbin Consensus Conference Workshop Group. Improving the Reporting of Clinical Trials of Infertility Treatments (IMPRINT): modifying the CONSORT statement. Fertil Steril 2014;102:952–9.e15. Krawetz SA, Casson PR, Diamond MP, Zhang H, Legro RS, Schlaff WD, et al. Establishing a biologic specimens repository for reproductive clinical trials: technical aspects. Syst Biol Reprod Med 2011;57:222–7.
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
VOL. 103 NO. 4 / APRIL 2015
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