Background
In order to evaluate and improve care practices and outcomes, Clinical Data Registries (CDRs) have been established to collect and analyze detailed information on the therapies that patients receive and changes in their clinical condition over time. The Center for Medicare and Medicaid Services (CMS) further recognizes Qualified Clinical Data Registries (QCDRs), a sub-set of CDRs. A QCDR is a CMS-approved entity that has successfully completed a qualification process.[1] CDRs and QCDRs have tremendous potential to facilitate quality improvement and research activities using the data contained in the registries. Understanding the regulatory pathway in order to optimize research use of the data contained in CDRs is critical for improving the quality and efficiency of healthcare.
The Medicare Access and CHIP Reauthorization Act of 2015
On April 15, 2015 the Medicare Access and CHIP Reauthorization Act of 2015 (H.R. 2) was signed into law. The bill includes a section addressing the regulatory status of clinical data registries under 45 CFR 46. Specifically, the law requires the Secretary of Health and Human Services to either issue clarifying guidance or modify the regulations with respect to CDRs including those that CMS has designated as a QCDR.
SEC. 511. GUIDANCE ON APPLICATION OF COMMON RULE TO CLINICAL DATA REGISTRIES.
Not later than one year after the date of the enactment of this section, the Secretary of Health and Human Services shall issue a clarification or modification with respect to the application of subpart A of part 46 of title 45, Code of Federal Regulations, governing the protection of human subjects in research (and commonly known as the 'Common Rule'), to activities, including quality improvement activities, involving clinical data registries, including entities that are qualified clinical data registries pursuant to section 1848(m)(3)(E) of the Social Security Act (42 U.S.C. 1395w-4(m)(3)(E)).
Establishing the status of CDRs under 45 CFR 46 will also facilitate implementation of the law’s requirement that QCDRs can request claims data under the Medicare program under Title XVIII of the Social Security Act and, if the Secretary determines appropriate, claims data under the Medicaid program under Title XIX of the Act and the State Children's Health Insurance Program under Title XXI of the Act for purposes of linking such data with clinical outcomes data and performing risk-adjusted, scientifically valid analyses and research to support quality improvement or patient safety.
General Comments
SACHRP recommends that OHRP issue guidance that makes clear that human subject research implemented or facilitated by CDRs is subject to 45 CFR 46 and all current applicable guidance. SACHRP supports the established approach to reviewing and approving research involving data. SACHRP believes that creating of a special regulatory designation for CDRs is not advisable and would likely create confusion within the regulated community. A special regulatory designation may also raise larger concerns about the existence of different ethical standards for similar types of data. The current regulations afford IRBs ample flexibility when evaluating research with data, and IRBs should be encouraged to continue to apply the regulations in accordance with existing guidance.
SACHRP recommends that those who are establishing registries consider ways to enhance transparency regarding the use of clinical healthcare data for quality improvement activities and research unrelated to individual healthcare. Enhanced transparency serves the public good, and has the potential to improve the American public’s trust and understanding of the importance of quality improvement activities and research that aims to improve public health. The research enterprise is built on trust, and any measures to buttress that trust are encouraged.
IRB Evaluation of Proposed Activities Involving Clinical Data Registries
Transmission of Data into CDRs
The primary intent of the CDR is to support quality improvement (QI) activities related to the provision of healthcare. The transmission of data into a CDR to support QI activities is not human subjects research as defined by 46.101(d) and does not require prospective review and approval by an IRB. In this context the healthcare providers and institutions providing data are not engaged in research. This position has been affirmed by OHRP in written communication with the research community and in its Guidance on Engagement of Institutions in Human Subjects Research.
Regulatory Status of the CDR
CDRs that are established with the primary intent of conducting quality improvement activities and benchmarking activities may not be subject to IRB oversight. When there is a need for IRB oversight, review by a single IRB is sufficient.
SACHRP recommends that OHRP guidance clarify that determinations that certain activities are not human subject research are not required to be made by an IRB. Institutions should be encouraged to establish procedures for making these determinations in an efficient manner with the least amount of administrative burden.
Research Determination
IRBs and institutions have applied the longstanding framework endorsed by OHRP for determining the regulatory status of proposed activities. Under this framework, the initial step is to determine whether or not a proposed activity is “research” as defined by the regulation. 45 CFR 46.102(d) defines research as “a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.” Activities that are determined to not be research are not subject to the requirements of 45 CFR 46.
Human Subjects Determination
After the research status of a project has been determined, the second step is to determine whether or not the activity involves “human subjects.” Human subjects are defined as living individuals 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 46.102(f)) In the case of CDRs, the presence of identifiable private information will likely be the primary trigger for making a determination that human subjects are involved. Under the current regulatory framework, research protocols involving specimens that are not linked to identifiers are not typically considered human subjects research. As a result, numerous activities involving data, specimens, and records are routinely determined to be not human subjects research and IRB review and approval is not required. When it has been determined that an activity is not research (e.g., a quality improvement activity) the presence of identifiable data from humans does not alter that determination and so 45 CFR 46 does not apply.
Assessment for Level of Review
Activities that are research and involve human subjects must be evaluated through one of three regulatory pathways:
- Exempt determination
- Review by expedited procedures
- Review by convened IRB
Exempt Determinations
Exempt activities are those activities that are research involving human subjects, but meet criteria that exempt them from the full requirements of 45 CFR 46. A list of six categories that are eligible for exemption is contained in 45 CFR 46.101(b). Exempt activities are not required to undergo annual review, and are not required to obtain informed consent. Exempt categories four and five may have wide applicability to CDRs depending on the nature of the activity.
Exempt category four covers “Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects.” (45 CFR 46.101(b)(4)) Exempt category 4 was created to provide a regulatory pathway for research in which identifiable information would be accessed for the purpose of creating research data, but the research data itself would not retain identifiers thereby minimizing risks to subjects to the extent that the three basic regulatory mechanisms including IRB review would not provide additional meaningful protection.
The applicability of category four requires that the data are either publicly available or that that investigators who are analyzing the data for research purposes create datasets without identifiers or receive the data in a coded state.
Exempt category five may be applicable when the research activities are focused on CMS programs. Category five exempts “Research and demonstration projects which are conducted by or subject to the approval of department or agency heads, and which are designed to study, evaluate, or otherwise examine: (i) Public benefit or service programs; (ii) procedures for obtaining benefits or services under those programs; (iii) possible changes in or alternatives to those programs or procedures; or (iv) possible changes in methods or levels of payment for benefits or services under those programs.” (45 CFR 46(b)(5)) Research that will be conducted under a category five exemption will require documentation from the relevant department or agency indicating that the activity meets the criteria. There is a similar regulation in 45 CFR 46.116(c), which allows the exemption of just the informed consent requirement for research under the approval of state or local government officials, but unlike the federal research exemption, it carries a “practicability” requirement.
Activities that do not meet the criteria for exemption may qualify for expedited review.
Expedited Review
SACHRP recommends that the new OHRP guidance specifically state that the expedited review categories apply to research involving CDRs. Research activities that are reviewed under expedited procedures are subject to all requirements of 45 CFR 46, including the requirements for obtaining and documenting informed consent, and for undergoing continuing review no less than once per year. A list of ten categories of minimal risk research for which expedited review is permissible has been published by the Secretary and the Commissioner of the FDA. Expedited category five covers non-exempt research involving data. This category allows “research involving materials (data, documents, records, or specimens) that have been collected, or will be collected solely for non-research purposes (such as medical treatment or diagnosis).” Because it is expected that data in CDRs is derived from the provision of healthcare, it is likely that this category will apply to the majority of the non-exempt research conducted utilizing CDRs.
Research that cannot be exempted and does not qualify for expedited review requires review by a convened IRB. It is unlikely that research utilizing CDRs will routinely require this level of review.
Informed Consent Requirements
Non-exempt human subjects research must satisfy the requirements for informed consent at §46.116 and documentation of consent (signature) at §46.117. The regulations provide IRBs with the ability to determine when the informed consent requirements may be altered or waived in their entirety. Some CDRs collect data for non-research purposes, typically either without explicit consent for research use or under a “blanket” statement that healthcare facilities may use data for research and quality improvement purposes. Other CDRs are established to aggregate data for the purpose of facilitating research, typically with explicit consent to send data to the repository for broad future use. In either case, IRBs may determine for subsequent research utilizing data maintained in CDRs that it is appropriate to waive informed consent. SACHRP recommends that OHRP guidance should encourage IRBs to grant waivers of informed consent for research on data from CDRs when the criteria at §46.116(c) or (d) are met.
Summary of Recommendations
- SACHRP recommends that OHRP issue guidance that makes clear that human subject research implemented or facilitated by CDRs is subject to 45 CFR 46 and all current applicable guidance.
- SACHRP does not support creating a special regulatory designation for CDRs.
- SACHRP recommends that those who are establishing registries consider ways to enhance transparency regarding the use of clinical healthcare data for quality improvement activities and research unrelated to individual healthcare.
- SACHRP recommends that OHRP guidance clarify that determinations that certain activities are not human subject research are not required to be made by an IRB.
- SACHRP recommends that the new OHRP guidance specifically state that the expedited review categories apply to research involving CDRs.
- SACHRP recommends that OHRP guidance should encourage IRBs to grant waivers of informed consent for research on data from CDRs when the criteria at §46.116(c) or (d) are met.
