Table 3.

Key issues in deploying pragmatic cluster randomized trials in contemporary health systems

	Issue type
Domains	Ethical	Regulatory	Practical	Responsible parties	Next steps
Trial design					Guidance
Subject identification	X	X	X	FDA, NIH, ORHP
Indirect participant/bystander	X		X	Ethicists, trialists	Scholarship
Gatekeepers and governance
Gatekeepers	X		X	Healthcare system leaders, research and/or clinical oversight committees, ethicists	Research to include stakeholder perspectives, scholarship, develop and evaluate governance models
Governance	X		X
Consent	X	X		Ethicists, FDA, NIH, OHRP	Guidance and policy development, research with stakeholders, scholarship, and evaluation
Ethical aspects
Feasibility	X	X	X
Differential risk/benefit balance in arms	X	X	X
Regulatory considerations
When can consent be waived?	X	X
Determination of minimal risk	X	X
FDA regulation		X
Institutional review boards				HHS, OHRP, IRBs	Guidance and policy development, curriculum development and implementation
Education	X	X
Local, shared, and central review	X	X	X
Data monitoring				Ethicists, statisticians, DMC experts	Scholarship, guidance development
Use in CRTs	X		X
Stopping rules	X		X
Data sources for interim analysis	X		X
Privacy		X		Office of Civil Rights, ethicists, CRT experts	Policy development
Application to CRTs		X
Alteration or waiver Use		X
Gatekeepers	X		X
Special populations				Ethicists, FDA, NIH, OHR, CRT Researchers	Guidance and policy development; think tanks, public hearings
Vulnerable populations	X	X	X

CRT: cluster-randomized trial; HHS: U.S. Department of Health and Human Services; DMC: data monitoring committee; FDA: U.S. Food and Drug Administration; IRB: institutional review board; NIH: National Institutes of Health; OHRP: Office for Human Research Protections