Table 3. Challenges and Opportunities of Harmonization and Streamlining.

Challenge	Considerations for Harmonization or Streamlining
Comparative effectiveness research (CER)	CER directly compares two treatments that are already routinely used in clinical practice. The assessment of risk in CER, being discussed at the national level, is critical because it directly determines whether or not informed consent can be waived or modified (e.g., oral consent (in person or by phone, or electronic consent).23,24 As this debate continues, individual IRBs and institutions may come to different determinations of risk that could undermine multisite CER research, with some sites requiring written consent and others waiving or altering consent. If the research community could reach consensus in concert with federal regulations on the issue of risk in CER, it would provide a basis for increased harmonization.25-28
Social media	Social media has become an important tool for outreach; for example, interactive social media can be used to recruit participants, answer questions during consent, or gather data. Traditional IRB review of information provided to potential participants (informed consent forms, informational sheets, letters, advertising, etc.) will need to accommodate these new media.29 A second concern is that many social media interfaces (Twitter, blogs, etc.) are not private and may increase the risk for HIPAA violation.30 Potential partial remedies include allowing monitoring of the social media interaction or limiting use to one-way postings (i.e., not allowing responses/conversations). As social media applications increase in number and variety, the critical need for IRBs and privacy boards, in concert with federal regulations and guidance to develop “best practices,” is apparent.
Software applications	Many “apps” now monitor personal health information such as exercise, heart rate, blood pressure, sleep patterns, and other data from wearable devices.31-33 By 2018, approximately 50% of the more than 3.4 billion smartphone and tablet users will have downloaded mobile health apps.34 Many issues must be addressed if they are used for research, including ensuring data accuracy, authenticity, and validity; details about the app's platform; data security; ownership of the data; and access or use of the data for research or other purposes.35 Additional questions arise if app data is to be included in the electronic medical record. Will a clinician be expected to review these data to arrange for appropriate follow-up? Will there be liability issues if the data are not reviewed and acted on? A standardized approach for how to assess a specific app and its platform would encourage harmonization between institutions. The question of what can or should be included in the medical record also must be addressed. Problem-solving on this topic will require input from privacy and security experts, the patient community, medical records professionals, and clinicians as well as virtually every component of the HRPP.
Sponsor requirements	Negotiating research grants and contracts can differ widely among institutions. Costs of laboratories, testing, procedures, differences in standard of care (and thus what might not be considered a research procedure), policies for caring for injuries secondary to research participation, and differing efforts of research team members can be institution-specific. Negotiating these details takes time and can delay study initiation. Although local variability challenges general harmonization, it would be worthwhile to identify those elements of grants and contracts that could be harmonized.
Patients and patient advocates as members of the research team	The increased call to involve patients or advocates in the design and conduct of research is increasing not only in PCTs but also in research in general. Patient roles include consultants, members of advisory groups, and investigators. Institutions and IRBs should consider what levels of education, institutional credentialing, or oversight are required. While many institutions have processes for allowing nonemployees to participate as a researcher, these same processes may need to be tailored to address specific issues when patients are on the research team. Standardization of study team roles for patients and patient advocates would increase harmonization and encourage the involvement of patients on research teams.
Privacy	A number of HIPAA issues must be considered if patient-researchers have access to protected health information (PHI).36 HIPAA has different rules for allowing access to PHI for workforce members (people who report in some way to that entity) versus non-workforce members. When a patient is a member of the research team, his or her workforce status must be considered. If the patient cannot be considered part of the workforce, then any access to PHI becomes a disclosure to an external entity, and disclosures bring their own required actions (e.g., if pursuant to a waiver of authorization, disclosure must be tracked). One potential solution is to allow patient-researchers access only to deidentified data because such data would not be considered PHI. However, one goal of pragmatic research is to include patients as active and empowered study team members, and so access to PHI may be critical to their role. A broad discussion and common approach to this issue across IRBs would increase harmonization. This would require input from HIPAA experts as well as IRBs and the institutions.
Cluster randomization	Cluster randomization is a common study design in PCTs in which the unit of randomization is a cluster of participants rather than individual participants.37 When randomization is at the system or unit level, and not at the level of the individual patient, obtaining informed consent may not be practicable. It also might not be possible for the individual to “opt out” of receiving the research intervention. Oversight of cluster-randomized trials (CRTs) remains unclear, with questions about criteria for informed consent, mechanisms for opting out, and delineations of the types of interventions that might be studied using cluster randomization.38 In the absence of guidance on how to consider CRTs, there will be numerous institution-specific approaches. Before CRTs become routine, efforts to develop best practices would be invaluable and lead to harmonization.
Local context	While it has been stated that local context “issues are relatively straightforward in most multisite studies and do not play a major role in IRB deliberations,”39 local context has been a sticking point in advancing centralized review. Local context issues may be based in state or local law as well as institutional policy. Law-based issues may include age of majority and laws around when minors are emancipated; rules guiding surrogate consent (e.g., who if anyone can give surrogate consent for research); HIPAA privacy regulations; or state laws regarding specific information (e.g., HIV test results, genetic information). Institutional policy issues may include handling of investigational drugs/agents/biologics; contraception and birth control; engagement of vulnerable populations; conflict of interest management; research billing; language for radiation risks; and institutional biosafety (e.g., handling and storage of live viruses for vaccines). While many of these are part of the non-IRB institutional review, some are closely integrated into the IRB review, and institutional nuances must be considered by the reviewing IRB. In addition, local IRBs are often the most familiar with the researchers and the local research environment, and these can be difficult to adequately relate to an external IRB. As the mandates for CIRBs increase, local institutions/IRBs will need to identify, describe, and communicate these local issues. There should be a concerted effort to identify ways of handling common “local issues” and distinguishing those that may have an impact on the review of a specific protocol.
Conflict of interest	Conflict of interest has been considered a local context issue. However, all institutions and oversight bodies address the same (or very similar) conflict-of-interest issues. We suggest a national standardized method of managing conflicts of interest, with the option for local oversight to increase the stringency if needed. Standards for determining which conflicts require disclosure, implementation of additional safeguards (such as transferring oversight to a non-conflicted party), or removal of the conflicted party could be agreed upon nationally by a consortium of institutions and applied across institutions.
Payment	Payment for the nonresearch care of patients who participate in research has become complicated. Specifically, some payments are controlled by the Centers for Medicare and Medicaid Services (CMS), with plan coverage varying by region. Until these variations are reduced, CIRBs or HRPPs may need to tailor consent forms to accurately inform participants at each participating institution about which costs will be covered by the research and which will not be. A national standard for CMS plan coverage would help to resolve one aspect of this issue.
Federal-wide assurance (FWA)	Federal regulations require an FWA agreement with institutions engaged in research funded by federal monies. Traditionally, academic medical centers and large hospitals or healthcare systems have been the recipients of these funds. However, with the growth of patient-centered research, pragmatic trial designs, and the Patient-Centered Outcomes Research Institute (PCORI), smaller community clinics that are not affiliated with academic medical centers are becoming engaged in federally funded research. These smaller clinics often do not have an FWA or their own (or designated) IRB and are uncertain how to proceed The expansion of research into nontraditional clinics and practice sites emphasizes the need to identify what options are available to nontraditional sites in order to comply with these federal requirements.