Anthony L. Asher, M.D., F.A.C.S.
Director, National Neurosurgery Quality and Outcomes Database
Director, Brain Tumor Program, Carolinas Medical Center
Carolina Neurosurgery and Spine Associates
225 Baldwin Road
Charlotte, North Carolina 28204
Dear Dr. Asher:
The Office for Human Research Protections (OHRP) has received your letter regarding the status of the National Neurosurgery Quality and Outcomes Database (N2QOD) with respect to the Department of Health and Human Services (HHS) regulations for the protection of human subjects in research at 45 CFR Part 46. The letter asks OHRP about whether and how the HHS regulations at 45 CFR Part 46 (hereafter “the regulations”) apply to the activities of the institutions contributing to, maintaining, or using the N2QOD. It also includes a number of specific questions related to the HHS regulations and the N2QOD registry.
From the information you provided, we understand the N2QOD to operate through the participation of various institutions in two ways. First, there are the practice groups, the neurosurgery practice groups and hospitals providing neurosurgery to patients as part of standard clinical care. For the first six patients who undergo certain identified types of common surgical procedures at that institution in a given week, the practice groups will be collecting identifiable private information from these patients’ medical records and from routine standard of care pre- and post-operative survey assessment procedures. The practice groups then send this identifiable private information to the institution serving as the registry, the Vanderbilt Institute for Medicine and Public Health (VIMPH). The registry will receive this information and analyze it to establish new national medical practice benchmarks for the quality of the surgical procedures, and to provide reports back to the practice groups about the quality of their services compared to the national benchmarks.
If this is an accurate description of the N2QOD activity, our belief is that the regulations do not apply to either of the two types of institutions. The rationale pertaining to each type of institution follows.
First, assuming that research involving human subjects is taking place (see below), OHRP would consider the practice groups to be institutions that are not engaged in human subjects research, in that the practice groups are only releasing identifiable private information obtained through the administration of standard clinical care to patients. (See Scenario B(6) in the OHRP guidance document titled “Guidance on Engagement of Institutions in Human Subjects Research”, available on the OHRP website at http://www.hhs.gov/ohrp/policy/engage08.html.) OHRP considers institutions whose agents simply release to investigators at another institution identifiable private information pertaining to the subjects of research to not be engaged in the research, and do not have to meet any regulatory requirements of the regulations in this regard. This conclusion applies to any clinical providers releasing data obtained during the course of clinical care to investigators at another institution, including the submission of data to clinical registries. The regulations do not apply to the releasing activity of the practice groups regardless of the funding status of the clinical registry project and independent of the potential use of private health information for research purposes.
You specifically asked whether OHRP would apply the regulations to healthcare provider outreach to patients in the context of therapeutic interventions (i.e., preceding or following those interventions) with the primary intent of gathering information related to quality care improvement (with or without the use of scientifically validated outcomes instruments), if this information will also be used in research analyses. An enhancement or extension of an existing standard of care, including patient follow-up questions, would not fall within OHRP’s regulations, if this change in care would have taken place regardless of any secondary purpose relating to the collection of information about that change. On the other hand, if that patient outreach/follow-up is not part of the existing or extended standard of care, but rather is initiated in part for data collection purposes for a clinical trial or other research study and where the trial or other research meets the definition of research in the regulations, then these patient outreach/follow-up activities would appear to fall under the regulations.
Second, the N2QOD registry will be prospectively obtaining and analyzing identifiable private information about patients served by the practice groups. One of the purposes of the N2QOD registry is to design and conduct an analysis the results of which will be new information about the quality of the surgical procedures for a nationally representative sample, which is consistent with the idea of being “a systematic investigation… designed to develop or contribute to generalizable knowledge” which is the definition of “research” in the regulations. In contrast, a second purpose of the N2QOD registry activity is to generate and provide reports back to the practice groups about the quality of the surgical procedures they are using at their own institution, compared to the findings at the national level, so that they can use that information to guide their use of those procedures; this second purpose and element of the N2QOD registry is a quality improvement activity that is not research. OHRP would consider the N2QOD activity related to the first purpose to be nonexempt research involving human subjects. However, the N2QOD registry is not supported or conducted by HHS, and the registry institution, VIMPH, has not elected to extend the application of the regulations to nonfederally funded research activities on its HHS Federalwide Assurance. Consequently, this registry institution does not have to meet any of the requirements of the regulations, including review by an institutional review board (IRB), for this non-HHS funded activity.
Federal Funding Issues
You ask whether federal funding for N2QOD would impact the applicability of the regulations to the N2QOD registry or the practice group sites. If federal funding were provided by HHS, then the regulations would apply to research activities (as defined in the regulations), if any, of the N2QOD registry, that are conducted using such federal funding. The regulations would still not apply to the practice group sites because, as explained above, they would not be considered to be engaged in research involving human subjects.
We also note that if N2QOD was receiving HHS funding, and your organization were to decide to add onto the project the merging of the N2QOD medical data set with other administrative data sets containing financial data, (which your letter suggests might happen in the future) the design of N2QOD could be modified in a way that would affect its status under the regulations; if a computer program were to be utilized to merge the separate datasets without any of the researchers ever being able to see the identifiers used to merge the data, then OHRP would consider the researchers to not be conducting research involving “human subjects”, because nobody at VIMPH would have access to identifiable private information, assuming that the information is transmitted directly through the computer program. Consequently, the regulations would not apply to VIMPH. We understand that VIMPH already has such an information technology capacity for merging separate data sets within VIMPH; you might want to consider consulting with VIMPH about whether to utilize that capacity if and when you decide to modify N2QOD in this fashion.
Single IRBs and Multi-Site Studies
You have also requested guidance regarding OHRP’s view of the use of a single or central IRB in the review of multi-site studies. I refer you to OHRP’s correspondence with the Carolinas Healthcare System, where Dr. Menikoff states that “I want to assure you that the Office for Human Research Protections fully agrees with FDA’s position on the benefits of relying on a single central IRB for multicenter research.” He also says the following with regard to IRB review of the local context of research: “… we have archived prior guidance documents that suggested OHRP favors local IRB review over review by a non-local IRB, a position that OHRP no longer holds. (The reviewing IRB should nonetheless have appropriate knowledge of the local context.)” This correspondence is available on our website at http://www.hhs.gov/ohrp/policy/Correspondence/mcdeavitt20100430letter.html. Where appropriate, OHRP would support the use of single or central IRB review and approval of research conducted by clinical registries in circumstances where more than one institution is engaged in the research. We note that with regard to the N2QOD registry as it is currently envisioned, if the study were subject to the HHS regulations, only the registry institution would be engaged in the research, and thus would be required to have the study undergo IRB review. As discussed above, OHRP would not consider the practice groups to be engaged in human subjects research if they are only releasing identifiable private information obtained through the administration of standard clinical care to patients, so the practice groups sites would not be required to have an IRB review their activities.
Secondary Analysis Research
We also understand that the N2QOD is also contemplating for the future that it will release de-identified data from its database to secondary analysis researchers who will use the de-identified data for various research analyses. OHRP would consider the activity of the institutions of the secondary analysis researchers as not being research involving “human subjects”, according to the definition of “human subject” in the regulations, which is “…a living individual about whom an investigator (whether professional or student) conducting research obtains (1) Data through intervention or interaction with the individual, or (2) Identifiable private information….”. (45 CFR Part 46.102(f)) Since the secondary analysis researchers are obtaining de-identified data, and are not intervening or interacting with the subjects in any way, their research does not involve “human subjects” as defined by the regulations. Consequently, the regulations do not apply to the activities of these secondary analysis researchers, and there is no requirement for review and approval by an IRB.
OHRP recognizes that serious questions and concerns have been raised about the appropriateness of oversight of quality improvement and research activities in health care. We share your concerns about creating unnecessary impediments to improving the quality of healthcare or to the use of data to improve healthcare. At the same time, it is of course important to provide appropriate safeguards for the protection of the rights and welfare of human subjects in research. We welcome any contributions you would like to make regarding appropriate solutions to these issues. Please feel free to contact us if you would like to pursue this discussion further.
[/s/ Ivor A. Pritchard]
Ivor A. Pritchard, Ph.D.
Senior Advisor to the Director
Office for Human Research Protections