We found that the administrative burden experienced by the Reproductive Medicine Network, as measured by the length and requirements of the IRB submission, has increased significantly over the past 7 years. Further, we observed that there was significant variability in the performance of individual IRBs, though none ultimately demanded significant changes in the clinical protocols. While there is a widespread sense that the administrative and regulatory burdens are increasing in infertility research, we are not aware of any previous data that demonstrate these trends in a quantitative manner. We acknowledge that our study is based on data from a small number of sites. Further, we appreciate that it is difficult to be completely certain that all sites included and excluded exactly the same material in determining their total page counts despite clear definitions and our best efforts. We have much greater confidence in the uniformity and accuracy of the other three parameters studied. Finally, we acknowledge that time from submission to approval could have been prolonged if investigators were not efficient in providing the necessary responses and clarifications to their IRB in a timely way. However, we confirmed that the turn-around times for investigators corresponding with IRBs were efficient at all sites. Delays did not appear to be unduly long; in practice such delays are part of the review and approval process and, as such, should be considered in a comprehensive analysis of the present system. We accept that these are all potential weaknesses of our study, but nevertheless feel that these findings, being among the very first hard data on this subject, can provide important observations to aid in our analysis of the present state of research review in infertility trials.
Several important observations are clear. First, the amount of information required by IRBs is increasing significantly. There can be no question that amassing all the required information and completing the increasingly numerous attachments in the necessary format takes more time and effort by investigators and their teams. Interestingly, we noted that the new RMN sites did not take any longer from the time of submission to approval than did the established sites, suggesting that more experience did not translate to more rapid or efficient completion of the review process. It is possible that new sites required more time to compile their materials before actual submission to their IRB as compared to the established sites, but we did not have a way to ascertain these data.
A somewhat hidden but critically important question is whether the IRBs themselves are reviewing the submitted material as carefully as they have in the past. If the total pages submitted and the length of the consent form have more than doubled, and the number of required attachments has tripled, we wonder how IRBs can review all this additional material in roughly the same amount of time as they have in the past. We must speculate that either IRB members are more efficient at reviewing material now than they were 7 years ago, or that some or even much of the submitted material is not being scrutinized as closely as it was previously. We hope that it is the former, but fear that it is the latter. If the review of research protocols is more superficial than it has been in the past, the entire research community must ask if this increasingly bureaucratic process is likely to be more or less effective at the most basic goal of the IRB process, that is, protecting the interests and safety of research participants.
A second important observation is the dramatically increasing length of consent forms, a problem which some RMN members have attributed to IRB “mission creep”. Our data show that our informed consent documents are more than twice as long as they were 7 years ago. While a small portion of this can be explained by the additional pages required to consent the male partners of our female participants (another important and controversial question to consider), we are struck by the increasing and often numbing detail required by IRBs in designing consent forms. Many elements of consent forms as presently required by numerous IRBs appear to be aimed more at legal indemnification than explaining the nature of the proposed research with an emphasis on the point of the research and a description of potential risks and possible benefits. Further, many have suggested that the level of detail used to explain each and every minute detail of numerous research interactions as is now required by many IRBs is not only unnecessary but may well adversely impact the ability of potential participants to fully understand the research study to which they are enrolling (9
). We also fear that increasingly long and detailed consent forms have the potential to erode the important personal relationships between subjects and members of a research team. By making the process excessively bureaucratic, we wonder if there may be an adverse effect on the “team” feeling often shared by subjects and researchers which is so important to participant interaction and retention. In any case, it behooves the research community to thoughtfully consider whether lengthier and more detailed informed consent is better informed consent.
The first two points relate to review of any research protocol in any individual institution. Our third key observation relates specifically to the particular challenges in obtaining approval for multicenter trials. As shown in , there is a huge amount of variability between the various sites. This observation does not appear to be unique to our multicenter trials (11
). Given that all sites submitted exactly the same protocol to their local IRB, we must question whether they are all consistent in their evaluations and their concerns. Based on discussions at meetings of the RMN Steering Committee, it is our sense that the major barriers to IRB approval were quite different at each site. Furthermore, despite the increased burden to the investigators and the apparent inefficiency of the process, none of the IRBs substantially altered the study protocol. We must conclude that there is significant variability in the information and format required by IRBs, that the issues which provoke greatest concern may well be site-specific, and that the multiple IRB reviews of the same protocol do not seem to have much impact on the final form of the study.
There has been increasing recognition of the unbridled growth in regulatory burden and a call for reform by investigators (12
), and perhaps most importantly by the federal government (13
). The administrative challenges which individual investigators experience in obtaining IRB approval for a research study may be exponentially increased by those participating in multicenter trials. Therefore, as the research community addresses the issues discussed above, there should be a similar effort at reducing the regulatory burden for multicenter trials. Effective approaches could include accepting cooperative agreements between local IRBs with one IRB taking on the main review burden (2
), or the creation of independent central IRBs such as have been instituted by the National Cancer Institute for cancer trials (15
). While these remedies can generate their own unique set of problems (16
), they may well represent a significant step forward for both investigators and potential study subjects.
Thoughtful investigators have expressed concerns that IRBs have become overly expansive in interpreting regulatory requirements, have increasingly focused on inconsequential details, and have lost sight of their mission as they have become bureaucratically stilted and progressively unresponsive (18
). Indeed, in a recent commentary in the Journal of the American Medical Association, Christine Grady posed the question “Do IRBs Protect Human Research Participants?” (20
) The research community should strive to develop strategies to answer this most critical question. Unfortunately, in our study, we do not feel that we could point to any outcome data which would allow us to address this issue. We believe that the observations described in this study demonstrate the degree to which the burden of research review has increased over a relatively short period of time, and how the experience at individual institutions can be extremely different in considering identical, well-designed multicenter trials. The RMN strongly endorses initiatives intended to streamline research review for multicenter infertility trials as well as efforts to explore whether the increasing regulatory burden experienced by many investigators actually leads to improvement in the protection and safety of participants in clinical research studies.