Common Rule Informed Consent: Complete Guide to Documentation Requirements for Researchers

Emily Perry Dec 02, 2025 351

This comprehensive guide details the informed consent documentation requirements under the revised Common Rule, essential for researchers, scientists, and drug development professionals.

Common Rule Informed Consent: Complete Guide to Documentation Requirements for Researchers

Abstract

This comprehensive guide details the informed consent documentation requirements under the revised Common Rule, essential for researchers, scientists, and drug development professionals. It covers foundational principles including the new 'key information' and 'reasonable person' standards, provides methodological guidance for creating compliant consent forms, addresses troubleshooting for health literacy and participant comprehension, and examines recent regulatory validations such as FDA harmonization for minimal-risk studies. The article synthesizes current regulations with practical application strategies to ensure ethical compliance and enhance research integrity.

Understanding the Revised Common Rule: Core Principles and Mandatory Consent Elements

The Federal Policy for the Protection of Human Subjects, known as the Common Rule, was significantly revised in 2017, marking the first major update since its inception in 1991 [1] [2]. The revised regulations were published on January 19, 2017, with a general compliance date of January 21, 2019 [3] [4] [5]. The overarching goals of the revisions are to strengthen protections for human research volunteers while reducing administrative burdens for low-risk research, and to modernize the regulations in response to advances in technology and research practices [6] [1] [2]. These changes apply to most federally funded studies, though at the time of implementation, they did not apply to FDA-regulated or Department of Justice-funded research, which continued to follow the pre-2018 requirements [3] [5].

Major Regulatory Changes and Implementation Timeline

The revisions to the Common Rule introduced substantial modifications across several key areas of human research protections. The table below summarizes the core changes and their implementation timelines.

Table 1: Key Common Rule Revisions and Implementation Dates

Regulatory Area	Nature of Change	Effective/Compliance Date
General Compliance	Most provisions of the revised Common Rule took effect	January 21, 2019 [3] [4] [5]
Single IRB Review	Mandate for use of a single IRB for multi-site research	January 20, 2020 [3] [4] [7]
Informed Consent	New "Key Information" section and additional elements	January 21, 2019 [6] [4] [8]
Exempt Categories	New categories and modifications to existing ones	January 21, 2019 [3] [4] [8]
Continuing Review	Elimination of requirement for some minimal risk research	January 21, 2019 [3] [4] [8]

The following diagram illustrates the sequential implementation of these major provisions:

The revised Common Rule established two new general requirements designed to enhance subject understanding [6]:

Reasonable Person Standard: Information must be provided that a "reasonable person" would want to have to make an informed decision about participation, with an opportunity to discuss that information [6].
Key Information Section: Informed consent must begin with a "concise and focused presentation of the key information" that is most likely to assist a prospective subject in understanding the reasons why they might or might not want to participate [6] [8]. This section, which cannot be waived, often includes a statement about voluntary participation, the research purpose, procedures, duration, risks, benefits, and alternatives to participation [6].

The revisions added one new basic element and three new additional elements to informed consent documentation.

Table 2: New Consent Form Elements in the Revised Common Rule

Element Type	Required Content	Applicability
New Basic Element	A statement on whether identifiers might be removed from private information or biospecimens and whether these deidentified materials could be used for future research without additional consent [3] [6] [8].	Required when research involves collecting identifiable private information or identifiable biospecimens.
New Additional Element	A statement that biospecimens (even if identifiers are removed) may be used for commercial profit and whether the subject will or will not share in this profit [3] [6] [2].	Included if/applicable.
New Additional Element	A statement regarding whether clinically relevant research results, including individual results, will be disclosed to subjects, and if so, under what conditions [3] [6] [2].	Included if/applicable.
New Additional Element	For research involving biospecimens, a statement as to whether the research will (if known) or might include whole genome sequencing [3] [6] [2].	Included if/applicable.

The process of creating a compliant informed consent form under the revised Common Rule involves specific steps for researchers and IRBs. The following diagram outlines this workflow:

The Researcher's Toolkit for Common Rule Compliance

Successfully navigating the revised regulations requires researchers to utilize specific administrative and documentation tools.

Table 3: Essential Research Reagent Solutions for Common Rule Compliance

Tool or Resource	Function and Application
Updated IRB Consent Template	A pre-formatted document from the institution's HRPP or IRB office that incorporates all mandatory structural changes and new consent elements, ensuring regulatory compliance [6] [1].
Exemption Determination Tool	A guide or checklist used to assess whether a study qualifies for a new or modified exemption category under the revised rule, such as for benign behavioral interventions [3] [8].
Limited IRB Review Protocol	The procedure followed by the IRB for certain exempt categories to ensure there are adequate provisions to protect participant privacy and maintain confidentiality of data [3] [4] [8].
sIRB Reliance Agreement	A formal agreement required for multi-institutional studies establishing which IRB will serve as the single IRB-of-record, streamlining the review process as mandated by the revised rule [4] [1] [8].
Broad Consent Framework	A standardized process and documentation for obtaining prospective consent for the storage, maintenance, and secondary research use of identifiable private information and biospecimens [1] [8].

Additional Significant Regulatory Modifications

Exemption Categories and Limited IRB Review

The revised Common Rule established new exempt categories and modified existing ones [3] [8]:

New Category for Benign Behavioral Interventions: Research involving benign behavioral interventions in conjunction with the collection of information from adult subjects may qualify for exemption, provided that the subjects prospectively agree to the intervention and the information is recorded in such a way that the identity of the subjects cannot readily be ascertained [3] [8].
Secondary Research with Identifiable Data: New exemptions were created for the storage, maintenance, and secondary research use of identifiable private information or identifiable biospecimens, though their implementation often depends on an institution's adoption of "broad consent" procedures [8].

For several exempt categories, the regulations introduced a new "limited IRB review" process [3] [4]. This review is focused on ensuring that adequate provisions are in place to protect the privacy of subjects and to maintain the confidentiality of data [3] [4].

Changes to Continuing Review and sIRB Requirements

Reduction in Continuing Review: The revised rule states that continuing review is generally not required for research that has progressed to the point where the only remaining activities are data analysis or accessing follow-up clinical data from procedures that subjects would undergo as part of clinical care [4] [8]. This change aims to reduce administrative burden without compromising subject protection.
Single IRB (sIRB) Mandate: For most federally funded, multi-institutional research studies conducted within the U.S., the use of a single IRB is required [3] [4]. This policy, effective January 20, 2020, aims to streamline the ethical review process and avoid duplication of effort across multiple institutions [3] [4] [7].

Transition Provisions and Legacy Studies

A critical aspect of implementation involved transition rules. Studies that were approved or determined exempt by the IRB prior to January 21, 2019, generally remained governed by the pre-2018 Common Rule for their duration [3] [4]. In contrast, any study approved or determined exempt on or after January 21, 2019, was required to comply with the 2018 Requirements [3] [4]. This created a two-track system for human subjects regulations at institutions during the transition period.

The reasonable person standard represents a fundamental shift in the ethical and legal framework governing informed consent, moving from a physician-centered to a patient-centered paradigm. This standard is crucial for researchers operating under the Common Rule (45 CFR Part 46), which mandates that prospective subjects must be provided with "the information that a reasonable person would want to have in order to make an informed decision about whether to participate" [9]. The landmark case of Montgomery v. Lanarkshire Health Board in the United Kingdom was pivotal in rejecting the traditional "reasonable doctor" standard, instead establishing that disclosure must be determined by what a reasonable person in the patient's position would consider material [10] [11]. This decision effectively transferred the justificatory constituency from the medical profession to the patient population, requiring researchers to consider informational needs from the subject's perspective rather than the professional's viewpoint [11].

For researchers conducting studies under Common Rule provisions, understanding this standard is not merely a regulatory obligation but an ethical imperative that directly impacts study validity and subject protection. The standard acknowledges the power imbalance in researcher-participant relationships and seeks to correct it through transparent communication and comprehensive disclosure of material information. The General Medical Council has reinforced this principle, instructing investigators to act 'reasonably' in obtaining consent from patients and research subjects, though the specific parameters of 'reasonableness' require further elaboration [11]. This application note provides detailed protocols for operationalizing this standard within Common Rule research frameworks, ensuring that consent processes meet both ethical mandates and regulatory requirements.

Regulatory Framework and the Common Rule

Core Regulatory Requirements

The Common Rule establishes specific requirements for informed consent that directly align with the reasonable person standard. According to 45 CFR 46.116(a), investigators must provide information "in language understandable to the subject" and present it in a way that "does not merely provide lists of isolated facts, but rather facilitates the prospective subject's... understanding of the reasons why one might or might not want to participate" [9]. This regulatory language codifies the reasonable person standard into federal policy, requiring a fundamental shift in how consent information is organized and presented.

The regulations mandate two distinct tiers of information disclosure: basic elements that must always be included and additional elements that must be provided when appropriate to the research context [9]. This structure ensures that all subjects receive core information while allowing for contextual adaptation to specific study designs and risks. The regulations further specify that the consent process must begin with "a concise and focused presentation of the key information that is most likely to assist a prospective subject or legally authorized representative in understanding the reasons why one might or might not want to participate in the research" [9]. This "key information first" approach represents a significant evolution in consent practices, prioritizing the most decision-critical information to facilitate genuine understanding.

Documentation Requirements Under the Common Rule

Table 1: Essential Elements of Informed Consent as Required by 45 CFR 46.116(b)

Element Number	Required Content	Common Rule Citation	Application Notes
(b)(1)	Statement that study involves research, purposes, duration, procedures, experimental components	45 CFR 46.116(b)(1)	Clearly distinguish research from clinical care; specify experimental procedures
(b)(2)	Reasonably foreseeable risks or discomforts	45 CFR 46.116(b)(2)	Include physical, psychological, social, economic, and legal risks
(b)(3)	Benefits to subjects or others	45 CFR 46.116(b)(3)	Distinguish direct benefits from societal benefits; avoid overstatement
(b)(4)	Appropriate alternative procedures or courses of treatment	45 CFR 46.116(b)(4)	Include standard treatment options outside the research context
(b)(5)	Extent of confidentiality protections	45 CFR 46.116(b)(5)	Describe data security measures, data sharing plans, and limits to confidentiality
(b)(6)	Compensation and treatment for research-related injuries	45 CFR 46.116(b)(6)	Required for research > minimal risk; specify availability and sources
(b)(7)	Contacts for questions, rights, and research-related injuries	45 CFR 46.116(b)(7)	Provide 24/7 emergency contacts when appropriate
(b)(8)	Voluntary participation statement	45 CFR 46.116(b)(8)	Explicitly state no penalty for refusal or withdrawal
(b)(9)	Statement on use of identifiable private information/biospecimens	45 CFR 46.116(b)(9)	Required for research collecting identifiable data or biospecimens

Table 2: Additional Elements of Informed Consent When Appropriate (45 CFR 46.116(c))

Element Number	Required Content	Common Rule Citation	Triggers for Inclusion
(c)(1)	Unforeseeable risks to subject/embryo/fetus	45 CFR 46.116(c)(1)	Pregnancy possible or relevant to research
(c)(2)	Circumstances for investigator-terminated participation	45 CFR 46.116(c)(2)	Protocol includes termination criteria
(c)(3)	Additional costs to subjects	45 CFR 46.116(c)(3)	Research imposes costs beyond standard care
(c)(4)	Consequences of subject withdrawal	45 CFR 46.116(c)(4)	Procedures for orderly termination important
(c)(5)	Significant new findings disclosure	45 CFR 46.116(c)(5)	Longitudinal studies where findings may affect willingness to continue
(c)(6)	Approximate number of subjects	45 CFR 46.116(c)(6)	May help contextualize risk or study importance
(c)(7)	Commercial profit from biospecimens	45 CFR 46.116(c)(7)	Research involves potentially valuable biospecimens
(c)(8)	Disclosure of clinically relevant research results	45 CFR 46.116(c)(8)	Research may generate individual clinical findings
(c)(9)	Whole genome sequencing plans	45 CFR 46.116(c)(9)	Research includes genomic sequencing

The Common Rule establishes specific documentation requirements for informed consent, generally requiring a written consent form that embodies the elements outlined in Tables 1 and 2 [9]. However, the regulations also provide for broad consent for the storage, maintenance, and secondary research use of identifiable private information or identifiable biospecimens as an alternative to standard informed consent for such future research [9]. This broad consent option, detailed in §46.116(d), requires a general description of the types of research that may be conducted, sufficient that "a reasonable person would expect that the broad consent would permit the types of research conducted" [9]. This represents a direct application of the reasonable person standard to future research authorization.

Operationalizing the Standard: Practical Protocols

Protocol 1: Information Materiality Assessment

Objective: To systematically identify and evaluate information that a reasonable person would consider material to their decision to participate in research.

Background: The materiality standard derived from Montgomery requires disclosure of information that a reasonable person in the subject's position would be likely to attach significance to when making a participation decision [10] [11]. This protocol provides a methodology for identifying such information during study design and consent development.

Procedure:

Comprehensive Risk-Benefit Inventory
- Compile all known risks from preclinical studies, prior clinical trials, and analogous interventions
- Document risk frequencies and severities using standardized terminology (e.g., CIOMS categories)
- Identify potential benefits, distinguishing direct benefits from societal contributions
- Catalog appropriate alternatives, including standard treatments and non-participation options
Stakeholder Consultation
- Convene focus groups representing the prospective subject population
- Engage patient advocates and community representatives
- Solicit input from former research participants with relevant experience
- Use structured interviews or surveys to assess what information participants consider material
Materiality Determination
- Apply the "reasonable person" test to each potential disclosure item
- Consider whether information would likely affect decision-making of someone in the subject's position
- Establish a significance threshold (e.g., risks ≥5% frequency generally warrant disclosure)
- Document rationale for inclusion/exclusion decisions
Validation and Refinement
- Pilot-test consent materials with representative individuals
- Assess comprehension and identify information gaps
- Revise disclosures based on feedback
- Secure IRB approval of final materiality determinations

Quality Control: Maintain detailed documentation of the materiality assessment process, including stakeholder input, decision rationales, and IRB feedback. This documentation demonstrates regulatory compliance and provides defensibility for disclosure decisions.

Objective: To implement a consent process that provides sufficient opportunity for consideration, minimizes coercion, and facilitates understanding.

Background: The Common Rule requires that investigators "seek informed consent only under circumstances that provide the prospective subject or the legally authorized representative sufficient opportunity to discuss and consider whether or not to participate" [9]. This protocol translates this requirement into operational procedures.

Procedure:

Pre-Consent Preparation
- Develop consent materials at ≤8th grade reading level
- Create supplementary visual aids for complex concepts
- Train research staff in communication techniques and ethical obligations
- Establish private, comfortable environments for consent discussions
Structured Consent Discussion
- Begin with "key information first" as required by §46.116(a)(5)(i)
- Present information in logical sequence: purpose, procedures, risks, benefits, alternatives
- Use teach-back method to verify understanding
- Encourage questions and provide thoughtful answers
- Include surrogate decision-makers when appropriate
Adequate Consideration Period
- Implement minimum 24-hour waiting period between consent discussion and documentation for non-emergency research
- Provide copies of consent materials for review during consideration period
- Offer opportunities to discuss with family, friends, or personal physicians
Documentation and Verification
- Obtain written signature unless IRB has waived documentation requirement
- Assess understanding through targeted questions rather than simple assent
- Provide copy of signed consent form to participant
- Document any unusual circumstances or concerns
Ongoing Consent Process
- Establish procedures for reconsent when protocol modifications occur
- Develop system for communicating significant new findings to participants
- Implement periodic consent reaffirmation for long-term studies
- Provide updated information that may affect willingness to continue

Quality Control: Record consent discussions when feasible and permitted, utilizing checklists to ensure comprehensive coverage. Monitor comprehension scores and identify areas needing improved communication.

Special Research Contexts

The reasonable person standard requires additional considerations when research involves vulnerable populations. The Common Rule contains specific subparts protecting pregnant women, human fetuses, prisoners, and children, recognizing that these groups may require enhanced protections [12]. For research involving vulnerable populations, the consent process must be adapted to address specific needs while maintaining the reasonable person framework.

Table 3: Adapting the Reasonable Person Standard for Vulnerable Populations

Population	Special Considerations	Consent Modifications	Regulatory References
Children	Requirement for parental permission and child assent	- Age-appropriate information disclosure- Document assent when appropriate- Dual parental permission typically required	45 CFR Subpart D
Prisoners	Vulnerability to coercion/undue influence	- Additional safeguards for voluntariness- Specific IRB member requirements- Limited allowable research categories	45 CFR Subpart C
Pregnant Women	Considerations for woman and fetus	- Clear description of risks to both- Father's consent typically not required	45 CFR Subpart B
Cognitively Impaired	Assessment of decision-making capacity	- Surrogate consent procedures- Capacity assessment protocols- Assent even when capacity impaired	45 CFR 46.116
Emergency Settings	Inability to consent due to condition	- Exception from informed consent requirements- Community consultation required- Public disclosure of study results	45 CFR 46.116(e)

For research in emergency settings where obtaining prospective consent is not feasible, the Common Rule provides for exception from informed consent requirements under specific conditions at §46.116(e) [9] [13]. The research must involve subjects in life-threatening situations, available treatments must be unproven or unsatisfactory, and the research must be unable to be practically carried out without the waiver [13]. Even under these circumstances, investigators must seek consent from legally authorized representatives when feasible and provide opportunities for survivors to consent to continued participation.

Biorepository and Genetic Research

The reasonable person standard applies particularly to biorepository research and studies involving genetic information. The Common Rule's broad consent provisions at §46.116(d) specifically address storage, maintenance, and secondary research use of identifiable private information and identifiable biospecimens [9]. When obtaining broad consent for such future research, investigators must provide:

A general description of the types of research that may be conducted
A description of the identifiable information/biospecimens that might be used
Information about the period of time that materials may be stored and used
A statement that subjects will not be informed about specific research studies
An explanation of whom to contact for answers about rights, storage, and use [9]

For research involving whole genome sequencing, §46.116(c)(9) requires specific disclosure when known, or potential use when not definitively planned [9]. This recognizes that genetic information carries special considerations regarding privacy, familial implications, and potential psychosocial impact that a reasonable person would likely consider material to participation decisions.

Table 4: Essential Research Tools for Studying and Implementing the Reasonable Person Standard

Tool Category	Specific Instrument	Application in Consent Research	Implementation Notes
Comprehension Assessment	DECISION (Dyadic Exchange & Common-Sense Model In ONcology) Scale	Measures objective understanding of key consent concepts	Validated in clinical trials context; adaptable to other research domains
Readability Metrics	Fry Graph Readability Formula	Evaluates reading level of consent documents	Prefer over Flesch-Kincaid for medical materials; target ≤8th grade level
Decision Aid Platforms	International Patient Decision Aid Standards (IPDAS)	Quality criteria for patient decision support tools	Certification process available; 116 studies show improved knowledge [10]
Materiality Assessment	Modified Delphi Consensus Methodology	Systematic approach to identifying material information	Engages multiple stakeholders; structured communication process
Process Evaluation	Informed Consent Process Quality Scale	Assesses quality of consent discussions and environment	Observer-rated; includes physical setting, interpersonal manner, information coverage
Understanding Verification	Teach-Back Method Assessment Tool	Evaluates effectiveness of comprehension verification	Participant explains in own words; identifies misunderstanding areas

These research tools enable systematic study and implementation of the reasonable person standard in informed consent processes. The DECISION Scale provides validated measurement of understanding across multiple domains, while readability metrics ensure materials meet literacy needs of diverse populations. Decision aids certified under IPDAS criteria have demonstrated significant improvements in patient knowledge, accurate risk perceptions, and participation in decision-making [10]. Implementation of these tools should be tailored to specific research contexts and populations, with appropriate validation for each application.

The reasonable person standard represents both a legal requirement and an ethical imperative for research conducted under the Common Rule. Operationalizing this standard requires systematic approaches to information disclosure, consent processes, and documentation practices. Based on the regulatory framework and empirical evidence, the following implementation guidelines are recommended:

First, information materiality assessments should be conducted during study design to identify what a reasonable person would want to know before participating. This assessment should incorporate multiple perspectives, including potential participants, advocacy groups, and content experts. Second, consent processes must provide sufficient opportunity for consideration, minimize possibility of coercion, and facilitate genuine understanding through clear communication and verification techniques. Third, documentation practices should transparently reflect the consent process and decisions, providing defensible evidence of regulatory compliance.

The reasonable person standard continues to evolve through regulatory interpretation and case law. Researchers should monitor developments in this area, particularly regarding broad consent for biospecimen research, electronic consent methodologies, and adaptations for vulnerable populations. By embracing both the letter and spirit of the reasonable person standard, researchers can ensure that informed consent truly respects participant autonomy while advancing scientific knowledge ethically and responsibly.

The Common Rule (45 CFR Part 46) establishes the foundational ethical framework for protecting human subjects in federally funded research. Within this framework, informed consent serves as a cornerstone, ensuring that individuals voluntarily agree to participate in research after being provided with comprehensive information about the study. The regulatory structure of informed consent under the Common Rule is organized into basic elements that must always be provided, and additional elements that must be included when applicable to the specific research study [9]. This protocol document delineates the mandatory core components required for legally and ethically valid informed consent documentation, with particular attention to the critical distinction between the eight basic elements and the essential ninth element concerning biospecimens and private information.

The following table summarizes the complete set of mandatory and conditional elements required for informed consent as specified in 45 CFR 46.116(b) and (c). These elements collectively form the minimum standard for adequate disclosure in most research involving human subjects.

Table 1: Core and Conditional Elements of Informed Consent Under 45 CFR 46.116

Element Category	Element Number	Description	Regulatory Citation
Basic Elements	1	Statement that study involves research, explanation of purposes, expected duration, procedures, and identification of experimental procedures	45 CFR 46.116(b)(1)
	2	Description of reasonably foreseeable risks or discomforts	45 CFR 46.116(b)(2)
	3	Description of any benefits to subject or others	45 CFR 46.116(b)(3)
	4	Disclosure of appropriate alternative procedures or courses of treatment	45 CFR 46.116(b)(4)
	5	Statement describing extent of confidentiality of records	45 CFR 46.116(b)(5)
	6	For research more than minimal risk: explanation of compensation/medical treatments if injury occurs	45 CFR 46.116(b)(6)
	7	Explanation of whom to contact for questions/rights/injuries	45 CFR 46.116(b)(7)
	8	Statement that participation is voluntary with no penalty for refusal/withdrawal	45 CFR 46.116(b)(8)
Additional Conditional Elements	9	Statement about use of identifiable private information/biospecimens	45 CFR 46.116(b)(9)
	10	Statement about unforeseeable risks to subject/embryo/fetus	45 CFR 46.116(c)(1)
	11	Circumstances for investigator-terminated participation	45 CFR 46.116(c)(2)
	12	Additional costs to subject resulting from participation	45 CFR 46.116(c)(3)
	13	Consequences of withdrawal and termination procedures	45 CFR 46.116(c)(4)
	14	Provision of significant new findings to subject	45 CFR 46.116(c)(5)
	15	Approximate number of subjects in study	45 CFR 46.116(c)(6)

The Critical Ninth Element: Biospecimens and Private Information

The evolution from eight to nine mandatory components reflects growing ethical considerations for research involving biospecimens and data privacy. When research involves the collection of identifiable private information or identifiable biospecimens, investigators must include one of two specific statements, creating what effectively functions as a ninth core element in contemporary research practice [9].

Regulatory Specification

The requirement states that for "research that involves the collection of identifiable private information or identifiable biospecimens," consent must include either:

A statement that identifiers might be removed from the identifiable private information or identifiable biospecimens and that, after such removal, the information or biospecimens could be used for future research studies or distributed to another investigator for future research studies without additional informed consent [9]; OR
A statement that the subject's information or biospecimens collected as part of the research, even if identifiers are removed, will not be used or distributed for future research studies [9].

Practical Implementation

This element requires researchers to make a deliberate determination about future research use of collected data and specimens during the study design phase. The selection between these two statements has significant implications for research reproducibility, specimen banking, and secondary research applications. Documentation must clearly reflect the chosen pathway, and this decision should align with the institution's policies on data sharing and retention [14].

Objective: To create a comprehensive, legally effective informed consent form that satisfies all mandatory Common Rule requirements while promoting genuine understanding by prospective research subjects.

Materials and Reagents:

Institutional Review Board (IRB) application forms
Protocol documentation describing all study procedures
Risk-benefit analysis documentation
Confidentiality safeguards plan
Source document for compensation structure (if applicable)
Contact information for research team and HRPP office

Procedural Steps:

Step 1: Foundational Element Incorporation

Integrate all eight basic elements specified in 45 CFR 46.116(b) as the foundation of the document [9].
Compose content using lay language appropriate to the population being asked to sign the form [14].
Organize information with short paragraphs, bullets, and subheadings to increase readability [14].

Step 2: Ninth Element Assessment and Implementation

Determine whether the research involves collection of "identifiable private information" or "identifiable biospecimens" [9].
Select the appropriate statement regarding future use based on study design and institutional policy.
For biospecimen research, include specific statements regarding commercial profit sharing and whole genome sequencing when applicable [9].

Step 3: Conditional Element Evaluation

Systematically evaluate the research protocol against the eight additional elements in 45 CFR 46.116(c).
Include all applicable conditional elements such as unforeseeable risks, additional costs, or withdrawal consequences [9].
For clinical trials, include specific statements regarding disclosure of clinically relevant research results [9].

Step 4: Organizational and Contact Information

Include study title and names/affiliations of investigators [14].
Provide contact information for the principal investigator and the Human Research Protection Program (HRPP) for questions about rights as a human subject [14].

Step 5: Comprehension and Voluntariness Assurance

Incorporate a clear statement that participation is voluntary and that subjects may refuse to answer questions or withdraw at any time without penalty [14] [9].
Include the subject consent statement with signature lines for documentation.
For FDA-regulated research, ensure additional FDA-specific requirements are met.

Troubleshooting:

If consent forms become unduly long, refine language to maintain clarity while including all required elements.
For complex studies, consider a layered consent approach with a summary of key information followed by detailed information.
When subjects have limited literacy or comprehension, utilize verbal explanation and comprehension assessment.

Table 2: Essential Materials for Informed Consent Documentation and Compliance

Reagent/Resource	Primary Function	Application Notes
IRB Application System	Electronic submission and tracking of research protocols for ethics review	Required for initial approval; maintain current certification for all study team members
Consent Form Template	Standardized structure ensuring regulatory compliance	Customize for specific study; include all required elements; use lay language appropriate to population
HRPP/IRB Contact Information	Resource for subject rights questions and regulatory guidance	Must be included in consent document; provides independent oversight contact
Documentation Log System	Tracks consent versioning and documentation	Critical for audit trails; maintain records for required retention period
Comprehension Assessment Tools	Verifies subject understanding of key study elements	Especially important for complex studies or vulnerable populations
Electronic Consent Platforms	Digital consent capture with multimedia enhancements	Must provide same information as paper consent; requires IRB approval
Translation Services	Accurate translation for non-English speaking populations	Required when enrolling subjects with limited English proficiency
Data Security Documentation	Describes confidentiality protections for subject data	Must align with actual study procedures; specify access controls and storage

Additional Considerations for Special Circumstances

The revised Common Rule permits use of broad consent as an alternative to standard informed consent for the storage, maintenance, and secondary research use of identifiable private information or identifiable biospecimens [9]. This approach allows subjects to provide a general consent for future unspecified research uses, provided specific regulatory requirements are met regarding the description of research types, information about storage periods, and statements about not being informed of specific research studies [9].

An IRB may approve a waiver or alteration of consent requirements under specific circumstances, particularly for research conducted by or subject to the approval of state or local government officials examining public benefit or service programs [9]. The IRB must find and document that the research could not practicably be carried out without the waiver or alteration [9].

Special Populations and Contexts

Additional consent provisions apply to specific research contexts, including focus groups (with special confidentiality statements) [14], research involving incomplete disclosure or deception (with required debriefing procedures) [14], studies covered by Certificates of Confidentiality [14], and research involving mandated reporting obligations [14]. Each circumstance requires tailored language to maintain ethical standards while complying with regulatory requirements.

New Requirements for Identifiable Private Information and Biospecimens

Research involving identifiable private information and biospecimens operates within a complex regulatory framework designed to protect participant rights while enabling scientific progress. The Common Rule (45 CFR Part 46) establishes the foundational requirements for federally funded human subjects research in the United States [15]. Recent regulatory developments, including the 2018 Revised Common Rule and new National Institutes of Health (NIH) security policies, have significantly altered compliance requirements for researchers working with biospecimens and associated data [15] [16] [17]. These changes impact how researchers obtain informed consent, manage data privacy, and share materials internationally, particularly with designated "Countries of Concern" [16] [17]. Understanding these evolving requirements is essential for maintaining ethical standards and regulatory compliance in biomedical research.

Table: Key Regulatory Documents Governing Biospecimen Research

Regulatory Document	Key Focus Areas	Enforcement Agency
Revised Common Rule (2018 Requirements) [15]	Informed consent requirements, broad consent, exemption categories	HHS Office for Human Research Protections (OHRP)
HIPAA Privacy Rule [15]	Protection of health information, de-identification standards	HHS Office for Civil Rights
NIH Genomic Data Sharing Policy [15]	Sharing of large-scale genomic data, data access committees	National Institutes of Health
NIH Biospecimen Security Policy (NOT-OD-25-160) [16] [17]	Restrictions on international sharing of biospecimens	National Institutes of Health

Core Ethical Principles

The ethical collection and use of human biospecimens in research is guided by the principle of respect for persons, which operationalizes through the informed consent process [15]. Several advisory commissions have contributed to the ethical framework governing biospecimen research. The President's Commission for the Study of Bioethical Issues addressed critical issues in genomic research, including recommendations for managing incidental findings and privacy protection in whole genome sequencing [15]. Similarly, the National Bioethics Advisory Commission's 1999 report initially identified many ethical controversies that remain relevant today, particularly regarding the secondary use of stored biological materials [15].

The fundamental regulatory requirement states that "before involving a human subject in research covered by this policy, an investigator shall obtain the legally effective informed consent of the subject or the subject's legally authorized representative" [15]. This requirement applies specifically to research with federally funded components, though many institutions apply these standards more broadly to ensure uniform ethical protections.

The revised Common Rule introduced specific consent requirements for research involving biospecimens. For studies that may include whole genome sequencing, the informed consent document must explicitly inform participants whether the research will or might include this analysis [15]. This requirement acknowledges the unique privacy considerations associated with genomic data, which carries potentially identifiable information and implications for relatives.

The regulations also authorize the use of a broad consent model for collecting and storing biospecimens for future research uses that are not precisely known or specified at the time of collection [15] [18]. This approach allows participants to consent to future research use of their biospecimens within defined parameters, balancing the practical needs of biobanking with the ethical requirement for informed choice.

Table: Scenarios Requiring IRB Review for Biospecimen Research

Research Activity	IRB Review Required?	Applicable Regulations
Prospective collection of biospecimens for a specific study	Yes [18]	Common Rule, HIPAA
Secondary use of identifiable biospecimens from a biobank	Yes [18]	Common Rule, HIPAA
Secondary use of coded biospecimens with investigator access to code	Yes [18]	Common Rule
Use of de-identified remnant specimens (not for FDA submission)	No [18]	Common Rule
Storage of biospecimens in repositories for future research	Yes [18]	Common Rule, NIH GDS Policy

Recent Regulatory Changes and Security Measures

On September 24, 2025, the NIH published a new policy entitled "Enhancing Security Measures for Human Biospecimens" that establishes significant restrictions on international sharing of biospecimens [16] [17]. This policy, which takes effect on October 24, 2025, prohibits the sharing of human biospecimens from U.S. persons with institutions or parties located in "Countries of Concern," including China, Russia, Iran, North Korea, Cuba, and Venezuela [16] [17]. Unlike the Department of Justice's Data Security Program which establishes bulk thresholds, the NIH policy applies to even a single biospecimen collected, obtained, stored, used, or distributed using ongoing or new NIH funds [16].

The policy applies broadly to all human clinical and research biospecimens obtained from U.S. persons, regardless of identifiability, that are supported by NIH funding mechanisms [17]. This includes tissues, blood, urine, gametes, embryos, fetal tissue, and derived cell lines not yet publicly available [17]. Notably, the policy does not apply to cell lines or derivative products that were commercially or publicly available prior to the effective date [16] [17].

The NIH policy outlines three limited exceptions that allow sharing of biospecimens with Countries of Concern [16] [17]:

Regulatory Compliance: Transactions required or authorized by federal law or international agreements
Rare and Compelling Circumstances: Situations where facilities and personnel in a Country of Concern possess unique capabilities or expertise not available elsewhere, the use cannot be delayed, and the donor has provided consent
Individual Patient Care: At the request of the individual whose biospecimen was collected, for purposes of diagnosis, prevention, or treatment of that individual

When researchers utilize these exceptions, they must maintain detailed documentation including the quantity and content of shared biospecimen material, and provide this documentation to NIH upon request [16] [17].

Compliance Protocols for Researchers

Objective: To ensure informed consent documents for biospecimen research comply with revised Common Rule requirements and new NIH security policies.

Materials Needed:

Institutional Review Board (IRB) approved consent template
Protocol-specific information about biospecimen collection, storage, and use
NIH Genomic Data Sharing Policy guidelines
Information about potential future research uses

Procedures:

Required Consent Elements:
- Clearly state whether whole genome sequencing may be performed [15]
- Specify the storage duration and storage conditions for biospecimens [18]
- Describe potential future research uses, including whether biospecimens may be used for commercial profit [18]
- Explain procedures for withdrawal, including whether already-collected specimens will be destroyed or de-identified [18]
- Detail privacy protection measures and risks of re-identification [15] [18]

Broad Consent for Future Research:
- When obtaining broad consent for unspecified future research, provide a general description of the types of research that might be conducted [15] [18]
- Specify whether identifiable information might be shared with other researchers [18]
- Explain how clinical relevant findings will be handled, including whether they will be returned to participants [18]
International Sharing Restrictions:
- For NIH-funded research, include information about restrictions on sharing with Countries of Concern [16] [17]
- Describe the limited circumstances under which sharing might occur [16]

Objective: To establish procedures for compliant sharing and transfer of biospecimens in accordance with new NIH security restrictions.

Materials Needed:

Documentation of biospecimen source and funding
Material Transfer Agreements (MTAs)
NIH policy compliance checklist
Donor consent documents

Procedures:

Funding Source Verification:
- Document the original funding source for biospecimen collection and storage
- Identify whether NIH funds were used in collection, obtaining, storage, use, or distribution
- Maintain chain of custody documentation for all biospecimens

International Transfer Assessment:
- Screen all potential recipient institutions against the Countries of Concern list [16] [17]
- For potential transfers to Countries of Concern, evaluate whether any exceptions apply [16]
- Obtain institutional approval prior to any transfers that might fall under exceptions
Exception Documentation:
- For transfers under the "rare and compelling circumstances" exception, document:
  - Unique capabilities not available elsewhere
  - Temporal urgency preventing delay
  - Donor consent for the specific transfer [16]
- Maintain all exception documentation for minimum required retention period

Research Reagent Solutions and Essential Materials

Table: Essential Materials for Compliant Biospecimen Research

Material/Reagent	Function in Research Protocol	Compliance Considerations
Coding System	Replaces direct identifiers with codes to protect participant privacy	Must maintain secure linkage document separate from research data [18]
Secure Storage Repository	Long-term preservation of biospecimens and associated data	Must implement physical and electronic security controls per NIH guidelines [15]
Material Transfer Agreements (MTAs)	Govern transfer of biospecimens between institutions	Must incorporate NIH security restrictions for international transfers [16] [17]
Informed Consent Templates	Standardize disclosure of research risks and benefits	Must include required elements for genomic research and broad consent [15] [18]
De-identification Protocols	Remove identifiers to create limited datasets	Must comply with both HIPAA (18 identifiers) and Common Rule standards [15]

The regulatory landscape for data derived from biospecimens involves overlapping requirements from multiple frameworks. The HIPAA Privacy Rule establishes standards for de-identification, requiring removal of 18 specified identifiers or formal determination by a qualified expert [15]. In contrast, the Common Rule standard for identifiability is based on whether individual identity is "readily ascertainable" [15]. This creates a complex compliance environment where research may satisfy one standard but not the other.

The NIH Genomic Data Sharing (GDS) Policy imposes additional requirements for research generating large-scale human genomic data [15]. This policy requires informed consent for new collections of biospecimens used to generate large-scale genomic data, even when the data is de-identified [15]. The GDS Policy also establishes a system of controlled-access data, requiring researcher approval by an NIH data access committee before accessing genomic data for secondary research [15].

Recent technological advances have increased privacy risks for research participants. The growing concern about re-identification from pooled databases and matched samples has led to enhanced security requirements [15]. In response, the NIH has modernized security standards under the GDS Policy and established minimum expectations for access to controlled-access data, with updates effective January 25, 2025 [15]. These changes reflect the ongoing tension between promoting data sharing for scientific progress and protecting participant privacy in an era of advanced data analytics.

The Common Rule (45 CFR 46) establishes the foundational framework for protecting human subjects in research, with Institutional Review Board (IRB) review and informed consent serving as its cornerstones. However, not all systematic activities involving people constitute "human subjects research" as legally defined. Understanding these boundaries is crucial for researchers, scientists, and drug development professionals to allocate resources efficiently, avoid unnecessary regulatory burdens, and ensure appropriate ethical oversight.

This application note delineates three key activity categories generally excluded from IRB review under the Common Rule: journalism, public health surveillance, and certain operational activities. It provides protocols for distinguishing these activities from regulated research, emphasizing how these exclusions connect to the broader regulatory context where informed consent is not mandated by the Common Rule, though other ethical guidelines may still apply.

Public Health Surveillance Activities

Definition and Regulatory Basis

Public health surveillance is systematically collected, analyzed, and interpreted data essential for planning, implementing, and evaluating public health practice [19]. The Revised Common Rule (2018) explicitly excludes these activities from the definition of "human subjects research," provided they meet specific criteria [19]. The core distinction from research lies in its immediate purpose: surveillance directly informs public health action or policy, whereas research aims to develop generalizable knowledge.

Table 1: Criteria for Public Health Surveillance Exclusion vs. Research

Feature	Public Health Surveillance (Excluded)	Human Subjects Research (Requires IRB Review)
Primary Purpose	To inform decisions/actions by a public health authority to protect health [19]	To develop or contribute to generalizable knowledge [20]
Direct Link to Action	Direct, timely link between data collection and public health action is a hallmark [19]	Conclusions may inform future research or policy, but no immediate public health action is required
Oversight & Authorization	Conducted, supported, requested, ordered, required, or authorized by a public health authority [19]	Initiated and designed by investigators; requires IRB approval
Informed Consent	Not required by Common Rule, but other ethical guidelines (e.g., WHO) may recommend providing information or consent where feasible [19]	Generally required from subjects, with limited exceptions granted by the IRB

Experimental Protocol: Distinguishing Public Health Surveillance from Research

Objective: To determine if a data collection activity qualifies as a public health surveillance activity excluded from IRB review.

Materials: Study protocol document, documentation of public health authority involvement (e.g., contract, grant, letter of authorization).

Methodology:

Identify the Public Health Authority: Confirm the agency or entity has an official mandate for public health matters. This can include federal, state, tribal, or foreign government agencies, or entities acting under contract with them [19].
Define the Public Health Objective: Document the specific public health signal, disease outbreak, condition of public health importance, or threat (e.g., natural disaster) the activity aims to address. The objective must be to enable the authority to "identify, monitor, assess, or investigate" the issue [19].
Establish the Link to Action: Describe how the collected data will be used for timely situational awareness, priority setting, or direct public health decision-making. The activity must be necessary for this action [19].
Document Authorization: Secure documentation proving the activity is conducted, supported, requested, ordered, required, or authorized by the identified public health authority [19].
Submit for Determination (If Required): Many institutions, like Johns Hopkins University, require investigators to submit the above information for an official "non-research" determination by the IRB or another administrative body [19].

Diagram 1: Public health surveillance decision pathway.

Journalism, Biographical, and Historical Activities

Definition and Regulatory Basis

Activities in journalism, biography, and history (including oral history) are typically excluded from IRB oversight because their intent is not to generate "generalizable knowledge" but rather to document specific events, experiences, or individuals [21] [20]. The Department of Health and Human Services (HHS) clarifies that such activities are not subject to the Common Rule [21].

Table 2: Key Characteristics of Excluded Documentary Activities

Activity Type	Primary Purpose	Common Methods	Distinction from Research
Journalism	To report on specific newsworthy events or issues for public information [21]	Interviews, observation, document review	Focus is on reporting facts or narratives, not testing hypotheses or drawing conclusions applicable to a wider category.
Oral History	To create a record of specific historical events and personal experiences [21] [20]	Recorded, open-ended interviews	Aims to preserve perspective; not designed to prove a hypothesis, inform policy, or generalize findings [20].
Biography	To document the life and experiences of a specific individual [21]	Archival research, interviews with associates	The focus is particular to the subject, not generalizable to a broader population or group.

Experimental Protocol: Assessing Projects Involving Interviews or Observations

Objective: To determine if an interview-based or observational project is journalism/history (excluded) or human subjects research (requires IRB review).

Materials: Project proposal, interview guides, data management plan.

Methodology:

Define the Project's Aim: Clearly state the primary goal. Is it to document a specific event, create a historical record of an individual's life, or report a news story? If yes, it likely points to an exclusion.
Assess Generalizability: Determine if the project is designed to draw conclusions that are applicable to a broader category, group, or field of knowledge. Archiving results for future research or comparing outcomes to other assessments indicates generalizable knowledge and constitutes research [20].
Review Methodology for Systematic Investigation: Even if the aim seems documentary, evaluate if the methods constitute a "systematic investigation." This involves a methodical procedure or plan to answer a research question. A retrospective review of records with data analysis to answer a research question requires IRB review, whereas a single case report typically does not [20].
Document the Determination: For projects at the boundary (e.g., ethnographic studies), it is a best practice to seek a formal determination from the IRB or research ethics office. Lehigh University's guidance emphasizes that activities intended to understand institutions or social processes are only excluded if they are not focused on the characteristics of the individuals providing the information [20].

Operational Activities: Quality Improvement and Classroom Exercises

Definition and Regulatory Basis

Many operational activities within institutions are not designed to contribute to generalizable knowledge and thus fall outside the Common Rule's purview. These include quality assurance (QA), quality improvement (QI), program evaluations, and classroom exercises for pedagogical purposes [20]. The critical factor is the intent behind the data collection.

Table 3: Common Operational Activities Not Considered Human Subjects Research

Activity Type	Description	Examples	When It Becomes Research
Quality Assurance/Improvement (QA/QI)	Measures effectiveness of internal programs/services to improve local outcomes [20].	Model curriculum evaluation, hospital readmission rate audit.	If results are compared to a control group, used to test a hypothesis, or intended to be published as generalizable findings.
Classroom Research Activities	Data collection for teaching research methodology within a course [21] [20].	Student-conducted surveys for a statistics class project.	If the instructor or student later uses the data for further analysis to contribute to scholarly knowledge (e.g., presentation, publication) [20].
Case Reports	Highlights a unique treatment, case, or outcome, typically from a single patient [20].	Retrospective review of a single patient's medical record.	A meta-analysis of multiple case reports to examine or compare interventions is considered research [20].

The Scientist's Toolkit: Research Reagent Solutions

For activities that do qualify as human subjects research, the following regulatory "reagents" are essential.

Table 4: Essential Materials for Human Subjects Research Compliance

Item	Function	Application Notes
IRB Protocol Template	Standardized form for submitting a research proposal for IRB review.	Ensures all necessary elements for ethical and regulatory review are addressed, including risks, benefits, and consent procedures.
Informed Consent Form (ICF) Template	Document providing potential subjects with all material information about the research.	Must be written in lay language and include: research purpose, procedures, risks, benefits, alternatives, confidentiality, and contact information [22].
Informed Consent Documentation	Process of obtaining and recording consent from subjects.	For minimal-risk research qualifying for exemption, the NU IRB still expects participants to be provided with key consent information, even if a signed form is not required [22].
Citiprogram.org or Equivalent Training	Online curriculum in ethical research practices (e.g., CITI Program) [21].	Mandatory certification for researchers and staff involved in human subjects research at most institutions.
Data Use/Transfer Agreement	Contract governing the sharing of identifiable data with third parties.	Critical for compliance with HIPAA when research involves Protected Health Information (PHI) under Exemption Category 4 [22].
eIRB+ or Equivalent System	Online submission and management system for IRB applications.	Used to submit protocols for exempt determinations and full board review; required even for studies that may qualify for exemption [22].

Diagram 2: Logical pathway for IRB review requirement.

Navigating the exclusions from IRB review is a critical skill for the modern researcher. Activities in journalism, public health surveillance, and operational functions like quality improvement are excluded not because they are unimportant, but because they fall outside the Common Rule's specific definition of "human subjects research." This exclusion is fundamentally tied to the absence of the core ingredient that triggers the Common Rule's informed consent requirements: a systematic investigation designed to develop generalizable knowledge.

Researchers must be proactive in making these determinations, using the protocols and tools provided. When in doubt, the most prudent protocol is to consult with the institution's IRB office for a formal determination, ensuring both regulatory compliance and the ethical protection of individuals.

Creating Compliant Consent Documents: Practical Strategies and Template Implementation

The revised Common Rule, effective from January 2019, introduced a pivotal requirement for informed consent documentation in federally funded clinical research: the inclusion of a "concise and focused presentation of the key information" at the beginning of the consent form [2]. This regulatory change was driven by a recognized need to enhance participant comprehension, as traditional consent forms were often lengthy, complex, and written at a reading level exceeding the recommended 8th grade level, thereby burying crucial details necessary for an informed decision [2]. This document provides detailed application notes and protocols for researchers, scientists, and drug development professionals to effectively structure and present this key information. The objective is to move beyond mere regulatory compliance and create a participant-centric document that truly empowers potential subjects to understand the research and make a voluntary, informed choice about their participation.

Core Principles and Regulatory Framework

The Purpose of the Key Information Section

The key information section is designed to facilitate a reasonable lay person's decision-making process. It serves as a primer, providing the most critical information upfront before the subject encounters the full, detailed consent form. The goal is to improve transparency and ensure that the fundamental nature of the research, its inherent risks, and potential benefits are clearly communicated from the outset [2].

Regulatory Scope and Flexibility

It is critical to note that this requirement, as of the 2019 update, is mandatory for federally funded studies governed by the Common Rule. For FDA-regulated trials that are not federally funded, the inclusion of a key information section is considered a best practice but is not yet required, as the FDA has not harmonized its regulations with the revised Common Rule [2]. The regulations allow for flexibility in the presentation of this section, and currently, there is no universal consensus on the exact list of information to be included, placing the onus on research teams and Institutional Review Boards (IRBs) to exercise informed judgment [2].

Experimental Protocol: Developing and Validating the Key Information Section

Phase 1: Content Identification and Scoping

Objective: To systematically identify and prioritize the core elements that must be included in the key information section. Methodology:

Conduct a Stakeholder Survey: Follow the methodology of Le et al. (2018) to survey key stakeholders, including IRB members, principal investigators, clinical research coordinators, and—critically—patient advocates or former research participants [2]. The survey should present a comprehensive list of potential risks, benefits, and procedural details, asking respondents to rank them by importance for inclusion in the key information section.
Facilitate a Multi-Disciplinary Workshop: Organize a structured workshop with the study team (e.g., PI, CRC, biostatistician) to define the "key message" of the study. A recommended technique is to use the "Conclusion-First" approach, where the core takeaway for a potential participant is defined before drafting the content [23]. This ensures the section is built around a single, clear message.
Drafting Principle: Employ the "Conclusion-Upfront" structural approach [23]. State the most critical information first, such as that the study is research (not standard treatment), its primary purpose, and the main commitment required from participants.

Phase 2: Content Structuring and Drafting

Objective: To translate the prioritized content into a logically structured, easy-to-read draft. Methodology:

Apply the "Five-Part Body Framework": Adapt the presentation structure used in financial communications to organize the key information [23]. This provides a logical flow from context to implications. The workflow for this phase is detailed in the diagram below.

Diagram: Logical workflow for structuring Key Information content, adapting a five-part framework [23] [2].

Adhere to Readability Standards: Draft all content with the goal of achieving an 8th-grade reading level [2]. Use short sentences, active voice, and avoid medical jargon. If technical terms are unavoidable, they must be defined in simple language within the section.
Incorporate Required Elements for Advanced Studies: For studies involving biospecimens, ensure the key information section explicitly states whether identifiers will be removed, if the research could lead to commercial profit, if it includes whole genome sequencing, and under what conditions clinically relevant results will be disclosed to participants [2].

Objective: To test and improve the draft key information section for clarity and comprehension. Methodology:

Implement the "3-Step Review Process":
- Alignment Check: Verify every sentence directly supports the core "key message" defined in Phase 1. Remove any information that is "nice to know" but not essential for the initial decision [23].
- Simplification Check: Assess the draft for "immediate visibility" of key insights. Use bullet points and concise phrasing. Ask a colleague unfamiliar with the study if the main takeaways are clear after a quick read [23].
- Feedback and Practice: Conduct a "Think-Aloud" session with 5-10 individuals from the study's target population or layperson proxies. Observe and note where they struggle to understand concepts or language. Use this feedback to refine the draft before submitting it for IRB review [23] [2].

Data Presentation and The Scientist's Toolkit

Quantitative Data: Core Content Elements

The following table synthesizes survey findings and regulatory requirements to provide a ranked list of elements for inclusion in the key information section [2].

Table 1: Prioritized Elements for the Key Information Section

Priority Tier	Content Element	Rationale for Inclusion	Regulatory Basis
Critical	Statement that this is research, not standard clinical care.	Establishes the fundamental nature of the interaction.	Common Rule Core
Critical	Explanation of the research purpose and duration of participation.	Provides context and scope of the commitment.	Common Rule Core
Critical	Clear description of the key procedures and which are experimental.	Informs the participant about what will be done to them.	Common Rule Core
Critical	Presentation of the most significant and serious risks.	Allows for a risk-benefit assessment.	Common Rule Core
Critical	Statement that participation is voluntary and that refusal or withdrawal has no penalty.	Protects the ethical principle of autonomy.	Common Rule Core
High	Description of any potential direct benefits to participants.	Completes the risk-benefit assessment.	Common Rule Core
High	Information on the handling of biospecimens and private information.	Addresses modern privacy and ethical concerns.	Common Rule Revision
Medium	Alternatives to participation that may be available.	Ensures informed clinical decision-making.	Common Rule Core
Medium	Key financial aspects, such as major costs to the participant.	Impacts the decision to participate.	Common Rule Core

The Scientist's Toolkit: Research Reagent Solutions

This table outlines essential resources for developing and validating effective key information sections.

Table 2: Essential Resources for Consent Design and Validation

Tool / Resource	Function/Brief Explanation	Application in Key Information Design
Readability Analyzers (e.g., Hemingway App, Flesch-Kincaid)	Software tools that calculate the approximate grade level and complexity of written text.	To objectively measure and ensure the draft meets the ≤8th grade reading level target [2].
Institutional Review Board (IRB) Templates	Pre-formatted consent templates provided by the local IRB, often including a section for key information.	To ensure compliance with institutional interpretations of the Common Rule and streamline the approval process [2].
Stakeholder Survey Instruments	Standardized questionnaires used to gather quantitative and qualitative data on content prioritization.	To empirically identify which elements are deemed most important by IRB members, researchers, and patient advocates [2].
Plain Language Thesaurus (e.g., NIH Plain Language Thesaurus)	A reference tool that suggests simple, everyday alternatives for complex medical and technical terms.	To replace jargon and improve comprehension during the drafting and simplification phases.

The following diagram illustrates the complete lifecycle and decision pathway for creating, reviewing, and administering the key information section within the broader informed consent process, as mandated by the Common Rule.

Diagram: End-to-end lifecycle for Key Information section development and deployment.

Within the framework of Common Rule research, informed consent is a cornerstone of ethical practice, requiring that prospective subjects provide voluntary informed consent before participating in research [6]. The revised Common Rule mandates that this consent is based on comprehension, stipulating that "informed consent must begin with a concise and focused presentation of the key information that is organized and presented in a way to facilitate understanding" [6]. This regulatory shift directly addresses a critical issue: the persistent gap between the reading level of most consent forms and the reading ability of the adult population.

Research indicates that nearly half of American adults have limited basic literacy skills, and 46% are functionally illiterate when dealing with the health care system [24]. Although the average adult reads between an 8th and 9th-grade level, most health care materials, including consent forms, are written at a 10th-grade level or higher [25]. This misalignment creates a significant barrier to genuine informed consent, as potential subjects may sign documents they have not fully understood, compromising the ethical foundation of research [25] [26]. The problem is exacerbated for older patients and those for whom English is not a primary language [25].

Impact of Inadequate Health Literacy

Poor Comprehension and Compliance: Patients with inadequate health literacy face difficulties following instructions, taking medication properly, and controlling chronic illnesses [25].
Increased Healthcare Utilization: They are more likely to be hospitalized than those with adequate skills, resulting in significantly higher health care costs [25].
Undermined Autonomy: In the research context, a failure to understand the consent form undermines the principle of respect for persons and the validity of the consent obtained [26] [6].

Assessing Readability: Methodologies and Tools

A critical first step in addressing health literacy is to objectively assess the reading level of existing informed consent documents. Relying on the highest grade of education completed is an unreliable method, as final grade completed is often higher than the actual level of literacy [25]. The following protocols provide a standardized approach for assessment.

Quantitative Readability Assessment Protocol

The goal of this protocol is to determine the grade level of written materials using validated mathematical formulas.

Primary Tool: The Flesch-Kincaid grade level formula. This is a valid and reliable language readability formula embedded within Microsoft Word, making it practical and widely available [24].
Procedure:
- Obtain the electronic version of the informed consent document.
- Within Microsoft Word, access the spelling and grammar check feature.
- Upon completion of the check, review the readability statistics pop-up window.
- Record the "Flesch-Kincaid Grade Level" result.
Acceptable Benchmark: The consensus target for health care materials is a 6th-grade reading level, which allows about 75-80% of adult Americans to read the materials easily [24]. The Common Rule's "reasonable person" standard reinforces the need for materials that are understandable to a broad audience [6].

Qualitative Formatting Assessment Protocol

This protocol evaluates the document's structure and visual presentation, which are crucial for comprehension.

Principles for Clear Health Communication: Use the following checklist [24]:
- Use of bullets and white space instead of dense narrative paragraphs.
- Appropriate headings to break up text and "chunk" information by topic.
- Replacement of complicated medical or technical words with plain language.
- Inclusion of pictures and diagrams that clarify written concepts.
- Focus on desired behavior and key decisions rather than on extensive medical facts.

The following table summarizes a real-world analysis of patient education materials, demonstrating the typical reading levels found in healthcare settings before and after revision.

Table 1: Readability Analysis of Rehabilitation Educational Materials by Discipline

Discipline	Number of Documents Reviewed	Average Initial Reading Level	Average Reading Level After Revision
Occupational Therapy (OT)	17	10th Grade	4th Grade
Physical Therapy (PT)	3	8th Grade	3rd Grade
Speech Language Pathology (SLP)	8	12th Grade	6th Grade
Nursing	55	15th Grade	5th Grade
Psychology (Psych)	7	8th Grade	5th Grade
TOTAL	90	11th Grade	5th Grade

Source: Adapted from J Allied Health. 2012;41(2):e33–e37 [24].

Protocol for Revision and Simplification

Based on the assessment, this protocol provides a systematic method for revising informed consent documents to meet the 8th-grade reading level target and the revised Common Rule's requirements for a "concise and focused presentation" of key information [6].

Core Revision Workflow

The following diagram illustrates the sequential and iterative process for revising consent documents.

Detailed Revision Techniques

Apply the "Ask Me 3" Framework: Structure the information around three core questions a reasonable person would ask [24]:
- What is my main problem? (The research's purpose and why they are being asked to participate.)
- What do I need to do? (A clear description of the procedures, including duration and experimental tasks.)
- Why is it important for me to do this? (The potential benefits to society and themselves, along with the risks and alternatives.)
Simplify Vocabulary and Sentence Structure:
- Replace complex, multi-syllable words with simple, common ones (e.g., "use" instead of "utilize," "help" instead of "facilitate") [25].
- Use the active voice and break long, complex sentences into shorter ones (aim for 10-15 words per sentence).
- Define unavoidable technical terms in plain language immediately following the term.
Implement "Chunking" and Formatting:
- Use bulleted lists to present key facts, procedures, and risks.
- Incorporate meaningful headings and subheadings (e.g., "About This Research," "What We Will Ask You to Do," "Possible Risks").
- Ensure ample white space to reduce visual crowding and improve readability.
Incorporate Visual Aids:
- Use simple pictures, icons, or diagrams to reinforce critical concepts, such as the flow of study visits or the randomization process [25].
- Ensure all visuals include descriptive captions in plain language.

Pre- and Post-Revision Example

The table below provides a concrete example of applying the revision techniques to a segment of a consent form.

Table 2: Example of Document Revision for Improved Readability

Element	Pre-Revision (Higher Reading Level)	Post-Revision (Lower Reading Level)
Sample Text	"Sodium (salt) causes your body to retain fluids, which can put extra strain on the heart and make the blood vessels narrow. For this reason, low-sodium diets are recommended to reduce the amount of retained water, which then helps to lower the blood pressure. Flesch-Kincaid: 11th Grade"	"Blood pressure can often be controlled by a low-salt diet, exercise, and weight loss: • Salt makes your body hold onto water. • When that happens, your blood vessels get smaller and your heart has to work harder. • If you eat food with less salt, your body will keep less water and you can lower your blood pressure. Flesch-Kincaid: 5th Grade"
Key Changes	• Complex sentence structure.• Passive voice.• Dense paragraph format.• Technical terms ("retain fluids").	• Simple, short sentences.• Active voice.• Bulleted list for clarity.• Common, everyday language.

Source: Adapted from J Allied Health. 2012;41(2):e33–e37 [24].

The Scientist's Toolkit: Research Reagent Solutions

This toolkit details essential resources for researchers committed to creating accessible, compliant informed consent documents.

Table 3: Essential Toolkit for Developing Low-Literacy Consent Forms

Tool / Resource	Function	Source / Example
Flesch-Kincaid Readability Statistic	Automatically calculates the U.S. grade level of a text document.	Built into Microsoft Word's spelling and grammar check.
"Ask Me 3" Framework	Provides a clear, patient-centered structure for organizing information to facilitate understanding.	National Patient Safety Foundation model [24].
Plain Language Thesaurus	Suggests simple, common words to replace complex medical and technical jargon.	Resources from the NIH and CDC "Plain Language" websites.
Institutional Consent Template	A pre-formatted template that incorporates Common Rule requirements and clear communication principles.	Ochsner Clinic Foundation Research Informed Consent template [6].
Health Literacy Advisor Tool	Software designed to analyze and suggest improvements for the readability of health documents.	Commercial and non-profit health literacy tools.

Compliance with the Revised Common Rule

The revision process directly supports compliance with specific elements of the revised Common Rule.

Key Information Section: The revised protocol mandates beginning the consent with a concise summary, fulfilling §46.116(a)(5) [6]. This section should be a standalone, easy-to-read document that answers the "Ask Me 3" questions.
Reasonable Person Standard: By lowering the reading level and improving organization, the revised documents provide "information that a reasonable person would want to know" in a form that is actually accessible to them, per §46.116(a)(4) [6].
New Required Elements: The revision process ensures that new required disclosures, such as those regarding the use of identifiable private information/biospecimens for future research (§46.116(b)(9)) and commercial profit (§46.116(c)(7)), are written in plain language [6].

A final evaluation with end-users, such as focus groups with former research participants, is recommended to validate the clarity, organization, and overall satisfaction with the revised documents, ensuring they truly meet the goal of facilitating informed decision-making [24].

The Revised Common Rule (45 CFR § 46), which took effect on January 21, 2019, introduced significant changes to informed consent requirements aimed at enhancing participant autonomy and transparency in human subjects research [27] [26]. These regulations apply to federally funded studies, though many institutions adopt them for all research [27]. A key impetus for these changes was addressing the increasingly complex research environment where investigators may have multiple roles (clinician, researcher, and businessperson) and where secondary use of data and biospecimens has become commonplace [26]. The revisions specifically added three new consent elements concerning commercial profit, return of clinically relevant research results, and whole genome sequencing, recognizing that these areas require explicit disclosure to ensure participants make truly informed decisions [28] [27].

The updated regulations also introduced two new general requirements for the consent process: (1) using a "reasonable person" standard to determine what information should be disclosed, and (2) beginning the consent document with a concise key information section that facilitates understanding of reasons why one might or might not want to participate [27] [26]. This represents a shift from merely providing facts to facilitating comprehension, acknowledging that consent forms had become too lengthy and complex for many participants to understand [26].

Regulatory Framework and Key Definitions

Table 1: New Consent Elements in the Revised Common Rule

Element Category	Specific Requirement	Applicability	Regulatory Citation
Commercial Profit	Statement whether biospecimens may be used for commercial profit and whether the subject will or will not share in this profit	Required when research involves collection of identifiable biospecimens	§46.116(c)(9)
Return of Research Results	Statement regarding whether clinically relevant research results will be disclosed to subjects, and if so, under what conditions	Required for both minimal risk and greater-than-minimal-risk research	§46.116(c)(9)
Whole Genome Sequencing	Statement regarding whether the research will or might include whole genome sequencing	Required when research involves collection of identifiable biospecimens	§46.116(c)(9)
Future Use of Data/Biospecimens	Statement about whether the research involves plans for future use of private information and/or specimens	Required basic element for all research collecting identifiable private information or biospecimens	§46.116(b)(9)

Key Regulatory Definitions

Identifiable Biospecimens: Biospecimens that are coded or directly identified [28]. The revised Common Rule specifies that biospecimens are considered identifiable even if identifiers have been removed, as technological advances have increased re-identification risks [29].
Commercial Profit: Financial gain that may result from the development of commercial products derived from research participants' biospecimens or data [28] [27]. This element addresses the business role that researchers or institutions may have alongside their research roles [26].
Clinically Relevant Research Results: Research findings that could impact a participant's health management or medical decision-making [28]. The regulations require transparency about if and how such results will be returned, acknowledging the potential psychological and health implications [26] [29].

Protocol for Commercial Profit Disclosure

Purpose: To ensure transparent communication about potential commercial applications of research and any potential for participant profit sharing.

Procedure:

Assessment: Determine if the research involves collection of identifiable biospecimens that could have commercial potential [28].
Language Development: Craft consent language that clearly states:
- Whether biospecimens may be used for commercial profit
- Whether subjects will or will not share in any commercial profit [28]
Institutional Approval: Utilize institution-approved template language when available. Example: "The biospecimens collected, even if identifiers are removed, may be used for commercial profit. You will not share in this profit." [28]
Discussion: Allocate time during the consent process to discuss what commercial profit means, how it might occur, and why participants will not share in profits if that is the case [27].

Considerations: Research has shown that participants generally want to know about profit potential even if they won't share in it, as it affects their decision-making about participation [27].

Protocol for Returning Research Results

Purpose: To establish clear policies and procedures for whether and how clinically relevant research results will be returned to participants.

Procedure:

Pre-Study Planning: Before IRB submission, determine the study's policy on returning research results, considering:
- Analytical validity of results
- Clinical utility of results
- Practical feasibility of returning results
- Resources needed for appropriate counseling [29]
Consent Language: Include a clear statement in the consent form regarding:
- Whether clinically relevant results will be disclosed
- Under what conditions results will be disclosed
- Potential implications of receiving results [28]
Process Documentation: Describe the mechanism for returning results, including:
- Who will communicate results (e.g., principal investigator, study physician)
- How results will be communicated (e.g., in person, with genetic counseling)
- Timing of result disclosure
- Follow-up procedures [29]
Participant Choice: When possible, offer participants the option to choose whether they want to receive results [29].

Considerations: Returning unvalidated research results can cause psychological harm and inappropriate medical decision-making. The protocol should distinguish between validated clinical findings and preliminary research results [29].

Protocol for Whole Genome Sequencing Disclosure

Purpose: To inform participants when their biospecimens will undergo whole genome sequencing, given the unique privacy and confidentiality considerations.

Procedure:

Technology Assessment: Determine if the research will or might include whole genome sequencing, including targeted genomic sequencing that covers significant portions of the genome [29].
Consent Language: Include explicit statement that the research will or might include whole genome sequencing [28].
Risk Communication: Discuss during consent process:
- Increased re-identification risks with genomic data
- Potential for incidental findings
- Data sharing requirements for NIH-funded genomic research [29]
Data Sharing Disclosures: For NIH-funded genomic research, include information about submission to controlled-access repositories [29].

Considerations: Genomic data poses higher re-identification risks compared to other health data. Even de-identified genomic data can be re-identified through technological advances and cross-referencing with other databases [29].

The following diagram illustrates the relationship between these new consent requirements and their implementation workflow:

Figure 1: Workflow for implementing new Common Rule consent requirements

For research involving genomic data, additional consent requirements apply under the NIH Genomic Data Sharing Policy [29]. The following table outlines key certification requirements for submitting genomic data to NIH-designated repositories:

Table 2: Genomic Data Sharing Certification Requirements

Requirement Category	Specific Expectations	Consent Implications
Informed Consent	Expectations for future research use and data sharing must be met	Consent must allow for broad data sharing and future research use
Data Limitations	Any limitations on research use must be delineated	Consent form should specify any restrictions on data use
De-identification	Data must be de-identified according to NIH GDS standards	18 HIPAA identifiers must be removed; random unique codes used
Risk Considerations	Risks to individuals, families, and populations must be considered	Consent should address privacy risks and protections
Results Return	Individual results generally not returned from secondary research	Consent should clarify that results from shared data won't be returned

Purpose: To ensure compliance with NIH Genomic Data Sharing Policy requirements when submitting genomic data to designated repositories.

Procedure:

Pre-Submission Assessment: Determine if the study involves genomic data that will be submitted to NIH-designated repositories [29].
Consent Review: Verify that informed consent allows for:
- Future research use
- Broad data sharing
- Submission to controlled-access databases [29]
Institutional Certification: Complete institutional certification procedures, which require IRB review of:
- Consistency with applicable laws and regulations
- Data limitations as expressed in consent
- Protections against re-identification
- Consideration of risks to individuals and groups [29]
De-identification Process: Implement procedures to remove all 18 HIPAA identifiers and use random, unique codes [29].

Considerations: Research with American Indian and Alaska Native populations must comply with tribal laws, which may impose additional restrictions on data sharing [29].

Documentation Templates and Institutional Implementation

Table 3: Template Language for New Consent Elements

Element	Recommended Template Language	Source
Commercial Profit	"The biospecimens (even if identifiers are removed) may be used for commercial profit and whether the subject will or will not share in this profit."	[28]
Future Use/Data Sharing	"The information [and samples] may be shared with other researchers within Penn, or other research institutions, as well as pharmaceutical, device, or biotechnology companies."	[28]
Future Use (Basic Element)	"We may use or share your research information and/or biospecimen for future research studies, but it will be deidentified, which means that it will not contain your name or other information that can directly identify you."	[27]
Whole Genome Sequencing	Include explicit statement that the research will or might include whole genome sequencing (institution-specific language recommended)	[28]

Implementation Toolkit for Research Teams

Research Reagent Solutions for Consent Implementation:

Table 4: Essential Resources for Implementing New Consent Requirements

Resource Type	Specific Tool/Resource	Function/Purpose
Institutional Templates	Penn Informed Consent Template (post-4/2021)	Provides pre-approved language incorporating all new Common Rule requirements [28]
Guidance Documents	Penn Medicine Guidance on Sharing Data and Biological Samples with Third Parties	outlines institutional requirements for data and biospecimen sharing with external entities [28]
Certification Tools	Genomic Data Sharing Supplement and Worksheet	Facilitates NIH GDS policy compliance and institutional certification [29]
Assessment Tool	Consent Form Comparison Checklist	Helps research teams perform gap analysis between existing consents and new requirements [28]
Implementation Option	Consent Addendum Template	Enables updating consent for existing studies without revising entire consent document [28]

Institutional Implementation Timeline and Requirements

The following diagram outlines the decision process for implementing new consent requirements based on study characteristics:

Figure 2: Decision pathway for implementing revised Common Rule consent elements in existing studies

Based on institutional implementation experiences, studies approved before January 21, 2019, that remain open to enrollment or have active participants must incorporate the new consent elements [28]. The IRB expects existing enrolled subjects to be re-consented on these new elements, particularly future use, return of research results, commercial profit, and whole genome sequencing [28]. For studies closed to enrollment but with active participants, consent addenda may be used instead of revising the main consent form [28].

The new consent requirements relating to commercial profit, return of research results, and whole genome sequencing represent a significant advancement in research ethics and participant transparency. These changes acknowledge the evolving research landscape where data and biospecimens have long-term value beyond their initial collection purpose, and where participants have a right to understand the full scope of how their contributions will be used [27] [26].

Successful implementation requires careful planning, utilization of institutional resources, and thoughtful communication with research participants. By addressing these elements explicitly during the consent process, researchers can build trust, enhance participant understanding, and ensure ethical conduct in line with both regulatory requirements and the fundamental principle of respect for persons that underpins human subjects research protections [26].

The 2018 revisions to the Common Rule introduced significant changes to informed consent requirements, aiming to enhance participant understanding and autonomy through improved consent processes and documentation [27]. These regulatory changes mandated that informed consent begin with a concise key information section and added new required elements concerning the future use of identifiable private information and biospecimens [27]. Institutional Review Boards (IRBs) at leading research institutions have responded by developing standardized consent templates that incorporate these updated regulatory requirements while addressing the documented problem of consent forms becoming increasingly lengthy and complex [27]. This document analyzes the template approaches from Johns Hopkins Medicine, Ochsner Clinic Foundation, and Penn State University, providing researchers with practical guidance for implementing Common Rule-compliant consent documentation.

Template Structures and Implementation Approaches

The reviewed institutions have developed distinct yet comprehensive template systems to guide researchers in creating compliant consent documents, each incorporating the revised Common Rule mandates while maintaining institutional specificity.

Table 1: Institutional Informed Consent Template Profiles

Institution	Template Scope & Availability	Key Regulatory Alignment Features	Unique Implementation Characteristics
Johns Hopkins Medicine	Comprehensive system including signed consent, oral consent scripts, parental permission, and assent forms [30].	Explicitly incorporates requirements of 45 CFR 46.116, including key information presentation [31].	Integrated HIPAA authorization within primary consent template; distinct templates for different participant populations [30].
Ochsner Clinic Foundation	Detailed template incorporating all Common Rule revisions with specific language for new required elements [27].	Includes mandatory statements on future use of identifiable information/biospecimens; key information section [27].	Provides specific example language for biospecimen use: "We may use or share your deidentified information/biospecimen for future research..." [27].
Penn State University	System includes HRP-580 template series, with specialized versions for emergency use, screening, and pregnant partners [32].	Aligns with Belmont Report principles; emphasizes plain language at 8th-grade reading level [32].	Offers structured guidance for waiver of documentation scenarios; emphasizes readability through formatting recommendations [32].

Quantitative Comparison of Template Requirements and Features

The institutional templates share common foundational elements while exhibiting variations in specific requirements and organizational approaches.

Table 2: Comparative Analysis of Template Components and Requirements

Template Component	Johns Hopkins	Ochsner Clinic	Penn State
Key Information Section	Required: Concise, focused presentation first in document [31].	Required: Facilitates understanding of participation decisions [27].	Required: Organized to assist understanding per 45 CFR 46.116 [32].
Future Use of Identifiable Data/Biospecimens	Addressed through template language for genes, cell lines, repositories [30].	Explicit required element with sample opt-in/opt-out language [27].	Incorporated through standardized data management sections [32].
Commercial Profit Disclosure	Included in template when applicable [30].	Addressed as additional element when relevant [27].	Covered through standard benefit/risk sections [32].
Reading Level Guidance	Recommended 8th-grade level with short sentences, clear formatting [30].	Emphasizes understandable language for participant comprehension [27].	Explicit plain language requirement with tailoring to subject population [32].
Documentation Alternatives	Oral consent scripts for minimal risk research [30].	Primarily focused on written documentation [27].	Explicit waiver of documentation options for minimal risk research [32].

A 2021 randomized controlled trial conducted across six ongoing clinical trials provides an evidence-based protocol for evaluating consent process interventions [33]. This methodology offers a robust approach for testing template effectiveness in actual research settings.

Objective: To rigorously test two novel consent interventions (fact sheet and interview-style video) against standard consent processes to determine their effect on participant understanding and satisfaction [33].

Materials and Research Reagent Solutions:

Table 3: Essential Materials for Consent Intervention Research

Material/Resource	Function/Application in Consent Research
Parent Study Consent Forms	Serves as foundational content for intervention development; provides standard against which to compare new approaches [33].
Fact Sheet Intervention	Condensed, focused presentation of key consent information derived from full consent form [33].
Interview-Style Video	Dynamic visual presentation of consent information using familiar communication format to enhance engagement [33].
Assessment of Understanding	Validated instrument to quantitatively measure participant comprehension of consent information; primary outcome measure [33].
Satisfaction Survey	Instrument to assess participant perceptions of consent process experience; secondary outcome measure [33].

Methodology:

Intervention Development: For each of the six parent studies, develop two interventions: (1) a fact sheet containing key information from the approved consent form, and (2) an interview-style video presenting the same consent information [33].
Participant Randomization: Randomize eligible participants to one of three arms: standard consent process, fact sheet intervention, or video intervention [33].
Intervention Administration: Implement the assigned consent process with participants prior to enrollment in the parent study.
Assessment: Administer the understanding assessment and satisfaction survey immediately following the consent process.
Data Analysis: Compare understanding scores and satisfaction ratings across the three arms using appropriate statistical methods, with particular focus on differences between intervention groups and standard consent [33].

Outcomes and Applicability: This protocol demonstrated that participants exposed to the video intervention had significantly better understanding scores compared to those exposed to the standard consent process (p=0.020) and reported higher satisfaction [33]. The fact sheet intervention did not significantly improve understanding over standard consent [33]. This experimental approach provides a validated methodology for institutions to test the effectiveness of their own consent templates and interventions.

Protocol for Implementing Key Information Sections

The revised Common Rule mandates that consent begins with "a concise and focused presentation of the key information" to facilitate decision-making [27] [31]. The following workflow outlines the systematic development of this critical section:

Implementation Protocol:

Content Identification: Extract the information most relevant to a potential subject's decision to participate, including: purpose of the research; expected study duration; key procedures; reasonably foreseeable risks and benefits; and meaningful alternatives to participation [27] [31].
Language Simplification: Transform technical research terminology into plain language accessible to the average adult reader, targeting an 8th-grade reading level [32] [30].
Structural Organization: Present information in a logical flow that connects related concepts, moving from the study's purpose through procedures to risks and benefits, rather than as isolated facts [31].
Formatting Optimization: Utilize white space, bullet points, and clear headings to enhance readability and comprehension [32].
Validation: Conduct comprehension testing with individuals representative of the potential participant population to identify areas needing clarification.

The revised Common Rule introduced broad consent as a new option for obtaining prospective consent for the storage, maintenance, and secondary research use of identifiable private information or identifiable biospecimens [34]. This represents a third pathway alongside traditional study-specific consent and consent waivers.

Key Implementation Considerations:

Scope Limitations: Broad consent may only be used for storage, maintenance, and secondary research use of identifiable private information or biospecimens—not for the primary research intervention itself [34].
Unique Required Elements: Broad consent must include specific elements not required for standard consent, including: a general description of the types of research that may be conducted; information about how long information/biospecimens may be stored and used; whether subjects will be informed about the details of subsequent research; and whether research results will be disclosed to subjects [34].
Institutional Variation: While Johns Hopkins Medicine has indicated it will not approve broad consent processes, other institutions may offer this option, requiring researchers to consult their local IRB policies [31] [34].

Documentation Alternatives and Waivers

In certain limited circumstances, institutional templates provide mechanisms for alternatives to traditional signed consent documentation:

Waiver of Documentation: Permissible for minimal risk research where the signed consent form would be the only record linking the subject to the research and the primary risk would be a breach of confidentiality, or when the research presents no more than minimal risk and involves no procedures for which written consent is normally required outside the research context [31] [32].
Oral Consent Processes: Implemented using IRB-approved scripts that contain all required consent elements, with documentation in the research record that consent was obtained [31] [30].
Electronic Consent: Emerging approach that utilizes electronic platforms to present consent information and obtain legally effective signatures, often incorporating multimedia elements to enhance understanding [32].

Institutional templates from leading research organizations provide essential frameworks for implementing the revised Common Rule's informed consent requirements. While structural variations exist across institutions, common principles emerge: the mandatory inclusion of concise key information, transparent communication about future data and biospecimen use, and commitment to accessible language and formatting. The experimental evidence supporting video interventions to enhance understanding offers promising directions for future template development. By strategically utilizing these institutional templates and incorporating evidence-based enhancements, researchers can create consent documents that not only satisfy regulatory requirements but truly fulfill the ethical goal of enabling autonomous decision-making by research participants.

Electronic consent (e-consent) represents a transformative approach to obtaining informed consent in human subjects research, authorized under the Common Rule (45 CFR Part 46) and relevant FDA regulations [35] [12]. The Common Rule establishes the foundational ethical standards for federally conducted or funded research, with §46.116 delineating the general requirements for informed consent [9]. E-consent refers to the use of electronic systems and processes that employ various digital media—including text, graphics, audio, video, podcasts, and interactive websites—to convey study information and obtain documented consent [36]. This shift from paper-based methods accelerated significantly during the COVID-19 pandemic when many research protocols were redesigned to facilitate offsite data collection [35].

The regulatory framework for e-consent is both flexible and rigorous, allowing researchers to implement innovative consent processes while maintaining strict ethical standards. The FDA and Department of Health and Human Services (DHHS) have authorized electronic media for both presenting consent information and capturing consent documentation [35]. For FDA-regulated research, electronic signatures must comply with 21 CFR Part 11, which mandates specific system controls, identity verification, and certification that electronic signatures are legally binding equivalents of handwritten signatures [36]. This application note details the multimedia capabilities, interactive formats, and digital best practices that constitute compliant and effective e-consent solutions within this regulatory context.

Multimedia and Interactive Formats for Enhanced Understanding

Multimedia Content Delivery

Multimedia elements in e-consent transform complex information into accessible formats, addressing varied literacy levels and learning preferences. Effective implementations include:

Animated Explanatory Videos: Short, focused animations that explain study procedures, risks, and benefits. A 2023 study found that a three-minute animated film effectively conveyed core study information to participants from diverse socio-economic and ethnic backgrounds [37].
Interactive Information Layers: Modular content structures with expandable sections, hyperlinks to definitions, and embedded graphics that allow participants to control information depth based on individual comprehension needs [38].
Audio Narration and Podcast-style Content: Alternative presentation formats for participants with visual preferences or lower literacy levels, providing accessibility alongside text-based information [36].

Research demonstrates that these multimedia approaches can improve participant understanding compared to traditional paper documents. A study of a digital informed consent app found participants generally considered the app well-designed, informative, and easy to use, with most choosing to watch the animated film to learn about the study [37].

Interactive Comprehension Assessment

Interactive e-consent platforms incorporate features that verify and enhance participant understanding:

Embedded Comprehension Checks: Knowledge-testing questions throughout the consent process that flag areas requiring further clarification [38].
Question Flagging Systems: Digital tools allowing participants to mark specific content for discussion with research staff, ensuring all concerns are addressed before consent confirmation [38].
Branching Logic: Adaptive content pathways that provide additional explanation when comprehension checks indicate misunderstanding, creating personalized consent experiences [38].

These interactive elements facilitate the Common Rule requirement that investigators seek informed consent "only under circumstances that provide the prospective subject sufficient opportunity to discuss and consider whether or not to participate" [9]. The structured interactivity ensures participants demonstrate understanding before proceeding through consent documentation.

Technical Implementation and Workflow Protocols

Implementing compliant e-consent requires integrated technical systems that address both regulatory requirements and user experience. The core architecture typically involves:

Figure 1: E-Consent System Architecture and Data Flow

Identity Verification and Signature Protocols

Compliant e-consent implementation requires rigorous identity verification and legally valid electronic signatures:

Identity Verification Methods: For remote consent, researchers must verify participant identity through:
- Unique identification codes or security questions provided prior to consenting [35]
- Submission of identity documents during the consent process [35]
- Video conferencing where participants show identification to research staff [35]
- Governmental identification tools (e.g., DigiD in the Netherlands) [37]
Electronic Signature Standards: FDA 21 CFR Part 11 describes two signature types:
- Electronic signatures: Computer data compilations of symbols executed by an individual as legally binding equivalents of handwritten signatures [36]
- Handwritten signatures executed to electronic records: Scripted signatures applied with stylus, finger, or cursor drawing [36]

Valid electronic signatures must (1) prove the actual signer is the intended signer, (2) prevent the signer from denying the signature, and (3) ensure neither record nor signature has been altered since signing [36].

Regulatory Compliance Table

Table 1: E-Consent Compliance Requirements Across Regulatory Frameworks

Requirement Area	Common Rule (45 CFR 46)	FDA Regulations (21 CFR 11)	Implementation Considerations
Information Presentation	"Concise and focused presentation of key information" in understandable language [9]	Not specifically addressed for content, but applies to electronic records	Use multimedia to enhance understanding; ensure accessibility across devices [35]
Signature Standards	Permits electronic signatures if legally valid within jurisdiction [36]	Requires specific system controls, identity verification, and legal equivalence to handwritten signatures [36]	Implement two-factor authentication; maintain audit trails; ensure signature integrity [36]
Documentation	Must provide copy of signed consent to participant [9]	Electronic records must be maintained with accurate copies for reference [35]	Provide PDF copies via email or secure links; include all hyperlinked content in documentation [35]
Version Control	IRB must approve consent documents [9]	Systems must ensure correct version usage and prevent unauthorized changes [38]	Automated version control in e-consent platforms; real-time monitoring of ICF versions [38]

Experimental Protocols and Case Studies

Objective: To implement a compliant e-consent process that enhances participant understanding through multimedia and interactive elements while meeting regulatory requirements.

Materials:

E-consent platform (REDCap, Signant SmartSignals, or equivalent compliant system)
Multimedia content (animated videos, graphics, audio narration)
Identity verification system
Secure document storage with version control
Communication channels for participant questions (video conferencing, live chat)

Procedure:

Pre-Consent Preparation:
- Develop multimedia content explaining study procedures, risks, benefits, and alternatives
- Create layered information structure with core content and expandable detailed sections
- Program comprehension check questions and question flagging system
- Obtain IRB approval for all consent materials and processes

Participant Engagement:
- Provide participant access to e-consent platform via secure link
- Present introductory multimedia content (animated video overview)
- Guide participant through interactive information modules with embedded comprehension checks
- Enable question flagging and provide real-time access to research staff for clarification
Identity Verification:
- For remote consent: Implement two-factor authentication or video verification
- For onsite consent: Use secondary identification with electronic signature capture
- Document verification method in audit trail
Consent Documentation:
- Present electronic consent form with required elements per §46.116(b)
- Capture electronic signature with timestamp and linked audit trail
- Provide immediate copy of signed consent to participant via email or secure download
- Store completed consent in secure, encrypted database with access controls
Post-Consent Follow-up:
- Conduct information retention assessment where appropriate
- Provide mechanism for ongoing questions and consent withdrawal
- Implement re-consenting protocols for study amendments

Validation: A 2023 study implementing a digital consent app found participants used the app between 4-15 minutes to provide consent, with overall positive feedback on usability and information clarity [37]. However, information retention questions revealed fewer than half of participants answered all questions satisfactorily, highlighting the need for complementary face-to-face discussion in some populations [37].

Case Studies in Pragmatic Clinical Trials

Recent implementations demonstrate tailored e-consent approaches across diverse trial designs:

Table 2: E-Consent Applications in Pragmatic Clinical Trials

Trial/Study	Design & Population	E-Consent Model	Outcomes & Lessons Learned
TIPAL [39]	Placebo-controlled RCT; idiopathic pulmonary fibrosis patients	Remote e-consent with paper alternative; REDCap platform with video consultation	Successful remote recruitment; participant choice enhanced engagement
Quit Sense [39]	Feasibility RCT; adult smokers	Fully remote e-consent as sole method; entirely online trial delivery	Demonstrated feasibility of completely remote consent and trial participation
COSTED [39]	RCT; emergency department smokers	Onsite e-consent with paper alternative; tailored to urgent care setting	Increased efficiency in time-sensitive environment; maintained participant understanding
Sarphati Cohort [37]	Population cohort; multicultural parents	Digital app with animated video and multilingual support	High usability ratings; identified trust barriers with identification procedures

Research Reagent Solutions

Table 3: Essential E-Consent Platform Components and Functions

Platform Component	Function	Implementation Examples
Multimedia Content Library	Stores and delivers video, audio, and graphical content	Animated study explanations; interactive risk visualizations; audio narration of complex concepts [38] [37]
Identity Verification Module	Authenticates participant identity remotely	DigiD integration; two-factor authentication; video identification sessions; document upload with validation [35] [37]
Electronic Signature System	Captures legally binding consent documentation	FDA 21 CFR Part 11-compliant signatures; biometric verification; signature pads; cryptographic digital signatures [36]
Version Control System	Manages approved consent form versions	Automated version tracking; real-time monitoring; prevention of outdated form usage [38]
Audit Trail Generator	Creates timestamped record of all consent activities	Detailed logs of information access, questions asked, comprehension checks, and signature process [38] [36]
Comprehension Assessment Tool	Evaluates participant understanding	Embedded knowledge checks; branching explanations for incorrect answers; question flagging for staff review [38]

Compliance and Ethical Considerations

Common Rule Alignment

E-consent solutions must align with core Common Rule requirements, particularly §46.116, which mandates:

Key Information Presentation: Consent must begin with "a concise and focused presentation of the key information that is most likely to assist a prospective subject in understanding the reasons why one might or might not want to participate" [9]. Multimedia formats are particularly effective for this requirement, using video to highlight critical decision-point information.
Comprehension Facilitation: The consent process as a whole must "facilitate the prospective subject's understanding of the reasons why one might or might not want to participate" [9]. Interactive e-consent supports this through layered information, embedded definitions, and comprehension verification.
Voluntariness Assurance: The process must minimize possibility of coercion or undue influence [9]. Remote e-consent options can reduce perceived pressure that might occur in clinical settings.

Accessibility and Equity

A fundamental ethical consideration in e-consent implementation is ensuring equitable access across diverse populations:

Technology Access: Researchers must consider whether populations have adequate technology to complete e-consent remotely. When needed, e-consent can be conducted onsite using study-provided devices [35].
Digital Literacy: For populations unfamiliar with technology or with disabilities affecting device use, e-consent may still be appropriate with onsite guidance from research staff [35].
Alternative Options: Ethical e-consent protocols should always include an option for potential participants to complete the consent process using paper-based methods [35].

The 2023 digital consent app study highlighted these challenges, noting that while the app was generally well-received, some participants expressed concerns about the identification process, and information retention varied, suggesting the need for complementary traditional approaches in some cases [37].

Electronic consent solutions represent a significant advancement in ethical research practices, offering enhanced comprehension through multimedia and interactive formats while maintaining rigorous compliance with Common Rule requirements. When implemented with attention to regulatory standards, technical robustness, and ethical considerations, e-consent processes can improve participant understanding, streamline documentation, and create more accessible research participation opportunities.

The case studies and protocols outlined demonstrate that effective e-consent is not a one-size-fits-all solution but rather should be tailored to specific study designs, populations, and settings. As research methodologies continue to evolve, e-consent stands as a critical tool for maintaining the fundamental ethical principle of informed consent in an increasingly digital research landscape.

Overcoming Common Consent Challenges: Health Literacy, Waivers, and Complex Scenarios

The Common Rule establishes the foundational ethical standards for protecting human subjects in federally funded research within the United States [12]. A core tenet of these regulations is the requirement for informed consent, which must be obtained under circumstances that provide the prospective subject sufficient opportunity to consider whether to participate and that minimize the possibility of coercion or undue influence [9]. The information presented must be in language understandable to the subject or their legally authorized representative [9].

Health literacy—the capacity to obtain, process, and understand basic health information to make appropriate health decisions—is therefore central to the ethical conduct of research [40]. Research indicates that nearly 90% of U.S. adults struggle with health literacy, which can complicate their ability to follow medical instructions or understand research protocols [41]. This challenge is not confined to specific demographics; even highly educated individuals may face comprehension difficulties during times of stress or illness [41]. Within the context of Common Rule research, this widespread limitation directly impacts the validity of the informed consent process. The teach-back method emerges as a critical, evidence-based intervention to verify comprehension, thereby ensuring that consent is not merely obtained, but is truly informed and meaningful.

The Teach-Back Method: A Verification Tool for Research Comprehension

Definition and Rationale

The teach-back method is an evidence-based health literacy intervention that promotes engagement, safety, and adherence [42]. In practice, it involves asking a patient or research participant to explain in their own words the information they have just received regarding their care or the research study [42]. This technique moves beyond the ineffective question, "Do you understand?" which often prompts an affirmative response regardless of actual comprehension [42]. Instead, teach-back provides a direct method for the investigator or study coordinator to confirm that explanations about the research protocol, risks, benefits, and procedures have been communicated clearly.

The utility of this method is underscored by studies showing that a majority of patients remain confused about their health care plans after discharge, and most do not recognize their own lack of comprehension [40]. This gap in understanding poses a significant risk in the research context, where misunderstanding a protocol can lead to non-adherence, adverse events, and invalid research data. By confirming understanding through teach-back, researchers can fulfill the Common Rule's mandate that consent information is presented in a manner that facilitates the prospective subject's understanding of the reasons why one might or might not want to participate [9].

Evidence of Effectiveness

Systematic reviews of the literature suggest that the teach-back technique is beneficial in reinforcing education and can improve health outcomes [40]. The following table summarizes key quantitative findings from the literature on the effectiveness of the teach-back method.

Table 1: Quantitative Evidence for the Teach-Back Method

Outcome Category	Specific Findings	Context/Study Population
Patient Satisfaction	Improved satisfaction with medication education, discharge information, and health management [40].	Multiple settings, including hospital discharge.
Post-Discharge Readmission	Statistically significant improvement at 12 months for heart failure patients (59% vs 44%, P = .005) and 30-day readmission for CABG patients (25% pre-intervention vs 12% post-intervention, P = .02) [40].	Patients with heart failure and coronary artery bypass grafting (CABG).
Disease Knowledge	Significantly higher knowledge scores for diagnosis (P < .001), return symptoms (P < .001), and follow-up instructions (P = .03) [40].	Emergency department patients receiving discharge instructions.
Patient Perception	96% of participants rated teach-back as effective or highly effective [40].	Patients with CABG.

Application Notes & Protocols for Common Rule Research

Integrating teach-back into the research informed consent process requires a structured protocol to ensure consistency and thoroughness. The following workflow diagram outlines a standardized procedure for its application.

Protocol: Implementing Teach-Back for Research Consent

Preparation and Environment:
- Shame-Free Environment: Conduct the consent discussion in a private setting. Frame the teach-back process as a check on the clarity of your explanation, not the participant's intelligence. Use phrases like, "I want to be sure I explained that clearly. Can you please tell me back in your own words what this part involves?" [41].
- Use of Plain Language: Prepare explanations for key study elements (e.g., randomization, blinding, risks, voluntary participation) using plain language, avoiding scientific jargon [41].
Sequential Explanation and Verification:
- Segment Information: Break down the consent form into manageable sections (e.g., study purpose, procedures, risks, benefits, alternatives, rights) [41]. Do not provide all information at once.
- Explain a Single Concept: Clearly explain one key concept at a time.
- Request Teach-Back: Ask the participant to state their understanding of that concept in their own words.
- Assess and Clarify:
  - If the explanation is correct, acknowledge the understanding and proceed to the next concept.
  - If the explanation is incorrect, incomplete, or unclear, re-explain the information using different, simpler language. Avoid simply repeating the original phrasing.
- Repeat: Continue this process of explain → ask → assess → clarify until all critical aspects of the research study have been covered and understood.
Documentation:
- Document in the research record that the teach-back method was used to verify comprehension of the informed consent. Note any concepts that required re-explanation. This documentation provides evidence that efforts were made to ensure the consent was truly informed, aligning with the spirit of the Common Rule.

The Researcher's Toolkit: Essential Reagents for Effective Comprehension

Table 2: Research Reagent Solutions for Implementing Teach-Back

Tool/Resource	Function & Application in Research Consent
Plain Language Consent Form	The foundational document, stripped of complex jargon, that serves as the primary source for segmented explanations. It fulfills the Common Rule requirement for "key information" presented in an understandable manner [9].
Segmenting Guide/Checklist	A protocol aid that breaks the consent form into logical, sequential parts (e.g., Purpose, Procedures, Risks, Benefits, Rights) to prevent information overload and facilitate step-by-step verification [41].
Pre-Scripted Teach-Back Prompts	Standardized, open-ended questions for the researcher to use (e.g., "Just to be sure I was clear, what will you need to do if you experience that side effect?") to ensure consistent application of the method.
Visual Aids/Diagrams	Flowcharts or simple diagrams to illustrate complex study designs (e.g., randomization paths, visit schedules), supporting verbal explanations and aiding comprehension for visual learners.
Interpreter Services	Essential for non-English speaking participants or those with limited English proficiency. The teach-back method should be used with an interpreter to correct any missed communication and verify understanding across languages [42].

Within the framework of the Common Rule, the informed consent process is a cornerstone of ethical research, demanding more than a participant's signature on a form. It requires a good-faith effort to ensure genuine understanding. The teach-back method provides a structured, evidence-based strategy to meet this ethical and regulatory obligation. By integrating this verification tool into the consent process, researchers and drug development professionals can proactively address the pervasive challenge of limited health literacy. This practice enhances participant autonomy, strengthens the integrity of the research protocol, and ultimately fosters a more ethical and robust research environment. Adopting teach-back is a pragmatic and powerful step toward ensuring that consent is not just documented, but truly comprehended.

The 21st Century Cures Act directed the U.S. Food and Drug Administration (FDA) to harmonize its human subject regulations with the Federal Policy for the Protection of Human Subjects (the "Common Rule") to the extent practicable and consistent with statutory provisions [43]. In response, the FDA published a final rule effective January 22, 2024, that amends its regulations to permit Institutional Review Boards (IRBs) to waive or alter informed consent requirements for certain minimal-risk clinical investigations [44] [43]. This regulatory change establishes a consistent framework across federal agencies and creates new opportunities for research that would not otherwise be practicable to conduct.

This application note details the five regulatory criteria IRBs must apply when evaluating requests for waiver or alteration of informed consent for minimal risk investigations. The guidance is essential for researchers, scientists, and drug development professionals designing studies that may qualify for these regulatory flexibilities while maintaining rigorous protection of human subjects.

Table 1: Economic Impact Analysis of the FDA Final Rule on Informed Consent Waivers

Cost Category	Net Present Value (3% discount rate)	Annualized Value (3% discount rate)	Net Present Value (7% discount rate)	Annualized Value (7% discount rate)
Total Estimated Costs	$10.1 million($8.1M - $14.0M range)	$1.2 million($0.9M - $1.6M range)	$9.1 million($7.5M - $12.4M range)	$1.3 million($1.1M - $1.8M range)
Total Estimated Cost Savings	$1.7 million($0.9M - $3.5M range)	$0.2 million($0.1M - $0.4M range)	$1.4 million($0.7M - $2.8M range)	$0.2 million($0.1M - $0.4M range)

Source: FDA Regulatory Impact Analysis [45]

The economic analysis conducted by the FDA estimates the rule will generate net costs of approximately $10.1 million over 10 years, primarily associated with IRBs, investigators, and sponsors reading and learning the new rule, drafting waiver or alteration requests, and additional recordkeeping burdens [45]. These costs are partially offset by an estimated $1.7 million in cost savings from harmonization of FDA's informed consent regulations with the Common Rule [45]. The rule is expected to yield significant unquantifiable benefits through healthcare advances from minimal risk clinical investigations that would not be performed without a waiver or alteration of informed consent [43].

Defining Key Regulatory Concepts

Minimal Risk

The foundational concept for applying the waiver criteria is understanding the regulatory definition of minimal risk. According to FDA and HHS regulations, minimal risk means that "the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests" [46]. This definition references the risks encountered by healthy persons in the general population, rather than being specific to the condition or environment of the potential research subjects [47].

Regulatory Authority

The FDA's final rule implements section 3024 of the 21st Century Cures Act, which amended the Federal Food, Drug, and Cosmetic Act to allow an exception from informed consent requirements for minimal risk clinical investigations [43]. Prior to this rule, FDA regulations only allowed exceptions from informed consent in certain life-threatening situations or by Presidential waiver for certain military operations [44]. This change brings FDA regulations into closer alignment with the Common Rule, which has contained provisions for waiver or alteration of consent for minimal risk research since 1981 [9].

The Five Regulatory Criteria for Waiver or Alteration

For an IRB to approve a waiver or alteration of informed consent for minimal risk clinical investigations, the IRB must find and document that all five of the following criteria are satisfied [44] [43]:

Criterion 1: Minimal Risk Nature

The clinical investigation involves no more than minimal risk to subjects [44].

Application Notes: The research team must provide a detailed risk assessment comparing all research procedures to the "daily life" experiences of a healthy person in the general population. This assessment should address both the probability and magnitude of potential harms [47].
Documentation Requirements: Protocol must include a systematic analysis of each procedure's risk profile, referencing established risk categories for common research interventions.

The research could not practicably be carried out without the requested waiver or alteration [44].

Application Notes: "Practicably" refers to whether the study would be methodologically or scientifically feasible without the waiver, not merely more convenient or less expensive [48]. Researchers must demonstrate that requiring informed consent would compromise scientific validity, raise ethical concerns, or make the research impossible to conduct.
Documentation Requirements: Provide a detailed justification explaining why alternative approaches requiring consent are not feasible, with specific methodological or scientific rationales.

Criterion 3: Necessity of Identifiable Data

If the clinical investigation involves identifiable private information or identifiable biospecimens, it could not practicably be carried out without using such information or biospecimens in an identifiable format [44].

Application Notes: This criterion applies specifically to research involving protected health information or biospecimens. Researchers must justify why de-identified data cannot be used and why identifiability is essential to the research objectives.
Documentation Requirements: Explain the technical or methodological requirements necessitating identifiability, such as need for data linkage, longitudinal follow-up, or specific analyses requiring identifying information.

Criterion 4: Protection of Rights and Welfare

The waiver or alteration will not adversely affect the rights and welfare of the subjects [44].

Application Notes: The IRB must consider whether the subject population would consider their rights violated if they knew of the waiver, and whether the waiver has potential to cause adverse consequences to their welfare [48]. Consider applicable state and local laws that may provide additional protections.
Documentation Requirements: Analysis of potential impacts on subject rights and welfare, including confidentiality protections and assessment of whether the waiver would be acceptable to a reasonable person in the subject population.

Criterion 5: Post-Participation Information

Whenever appropriate, the subjects or legally authorized representatives will be provided with additional pertinent information after participation [44].

Application Notes: This criterion requires debriefing procedures for studies involving deception or when withholding information during the research participation. The IRB determines when such disclosure is appropriate based on the study design and potential impact on subjects [48].
Documentation Requirements: Detailed debriefing protocol outlining what information will be provided to subjects, when, and how, including procedures for handling subject questions or concerns post-disclosure.

Experimental Protocol for Implementing Waiver Criteria

Purpose: To provide researchers with a systematic methodology for preparing and submitting requests for waiver or alteration of informed consent for minimal risk clinical investigations.

Materials:

Complete study protocol document
IRB waiver request form (institution-specific)
Risk-benefit analysis matrix
Documentation of confidentiality protections
Debriefing script (if applicable)

Procedure:

Preliminary Assessment Phase
- Conduct systematic risk assessment using the "minimal risk" standard
- Document why research could not practicably be carried out without waiver
- Consult with IRB during study development phase if uncertainty exists

Criterion-Specific Justification Phase
- For Criterion 1: Map all study procedures against ordinary daily life risks
- For Criterion 2: Document methodological reasons why consent is not practicable
- For Criterion 3: Justify needs for identifiable data with specific technical reasons
- For Criterion 4: Analyze rights and welfare impacts through ethical framework
- For Criterion 5: Develop comprehensive debriefing plan if applicable
Documentation Preparation Phase
- Complete all required IRB forms and supporting documents
- Prepare protocol-specific justifications for each criterion
- Develop monitoring plan for ongoing evaluation of waiver conditions
IRB Review and Response Phase
- Submit complete application package to IRB
- Respond promptly to IRB requests for additional information
- Implement approved waiver conditions precisely as authorized

Validation:

Successful IRB approval of waiver request
Documentation of all five criteria satisfied
Establishment of ongoing monitoring procedures

Regulatory Workflow and Decision Pathway

Figure 1: IRB Decision Pathway for Waiver or Alteration of Informed Consent. This workflow illustrates the sequential evaluation of the five regulatory criteria that must be satisfied for approval of a waiver or alteration of informed consent for minimal risk clinical investigations. NA = Not Applicable.

Research Reagent Solutions: Essential Regulatory Tools

Table 2: Essential Materials for Implementing Informed Consent Waivers

Research Reagent	Regulatory Function	Application Context
FDA 21 CFR 50.23 Exception	Provides waiver authority for life-threatening situations	Emergency research where subject cannot communicate and no alternative therapy exists [48]
Common Rule 45 CFR 46.116(f)	Establishes waiver/alteration criteria for non-FDA research	Minimal risk research not regulated by FDA [9]
HIPAA Authorization Waiver	Permits use of PHI without individual authorization	Research involving protected health information when consent waiver granted [48]
Expedited Review Categories	Allows efficient IRB review for minimal risk studies	Research that is minimal risk and fits defined categories [46]
Minimal Risk Assessment Tool	Systematically evaluates risks against daily life standard	Justifying Criterion 1 for waiver requests [46] [47]
Debriefing Protocol Template	Standardizes post-participation information disclosure	Satisfying Criterion 5 when additional information is appropriate [48]

The FDA's final rule establishing criteria for waiver or alteration of informed consent for minimal risk clinical investigations represents a significant harmonization with the Common Rule that expands opportunities for valuable research while maintaining rigorous human subject protections. Successful implementation requires researchers to systematically address all five regulatory criteria through comprehensive documentation and methodological justification. By following the protocols and guidance contained in this application note, researchers and IRBs can navigate this new regulatory landscape to facilitate important minimal risk research that would not otherwise be practicable, advancing public health and scientific knowledge while safeguarding the rights and welfare of research participants.

The initial phases of participant recruitment in human subjects research present a complex ethical landscape, particularly regarding activities conducted prior to obtaining formal informed consent. Pre-enrollment activities, often termed screening and recruitment, serve as the gateway to research participation yet operate outside the formal consent documentation process. These activities are governed by a nuanced framework within the Common Rule (45 CFR Part 46), which permits certain limited interactions without full consent under specific conditions. The ethical justification for these activities stems from their role in determining initial eligibility for research participation without yet involving experimental interventions or procedures that would require comprehensive informed consent.

The 2024 revision to the Declaration of Helsinki significantly reframes the ethical approach to research participants, replacing the term "human subjects" with "research participants" to emphasize active engagement rather than passive submission to research procedures. This linguistic shift underscores the declaration's strengthened position that individuals in the pre-enrollment phase deserve respect and ethical consideration, even when full consent protocols have not yet been initiated. The declaration further mandates meaningful engagement with potential and enrolled participants and their communities throughout the research process, including during these preliminary stages [49].

Regulatory Framework and Ethical Boundaries

Common Rule Provisions for Screening and Recruitment

The Common Rule establishes specific conditions under which researchers may perform pre-enrollment activities without obtaining full informed consent. These activities are generally limited to procedures that would be performed as part of routine clinical care or involve minimal risk to potential participants. The regulatory framework distinguishes between activities aimed at identifying eligible candidates and those that constitute research interventions themselves.

According to the Common Rule's provisions, screening and recruitment activities without consent are permissible when:

The activities involve only review of medical records or existing specimens
The procedures are not scientifically invalid without additional private information
The research could not practicably be carried out without the screening access
The activities involve minimal risk to potential participants
Appropriate confidentiality safeguards are implemented

Ethical Principles Governing Pre-Enrollment Activities

The Belmont Report's foundational principles of respect for persons, beneficence, and justice provide the ethical underpinnings for pre-enrollment activities. Respect for persons requires that even preliminary screening activities acknowledge the autonomy and dignity of potential participants. The 2024 Declaration of Helsinki reinforces this by emphasizing that researchers must interact meaningfully with potential participants throughout the research continuum, beginning with these early stages [49].

The principle of beneficence necessitates that the risks of pre-enrollment activities are minimized and justified by potential benefits to science or society. Justice requires fair distribution of both the burdens and benefits of research, preventing the exploitation of vulnerable populations even in preliminary screening activities. The 2024 Declaration of Helsinki specifically addresses the need to responsibly include vulnerable populations by weighing the "harms of exclusion" against the "harms of inclusion" [49].

Table: Regulatory and Ethical Framework for Pre-Enrollment Activities

Component	Common Rule Requirements	Declaration of Helsinki 2024 Updates
Terminology	Refers to "human subjects"	Uses "research participants" to include patients and healthy volunteers [49]
Risk Assessment	Focus on minimal risk activities	Expands to consider participant "well-being" beyond just health [49]
Vulnerable Populations	Requires additional protections	Emphasizes responsible inclusion and balancing exclusion/inclusion harms [49]
Participant Engagement	Not explicitly addressed	Mandates meaningful engagement throughout research process [49]

Permissible Pre-Enrollment Activities: Protocols and Procedures

Medical Record Review and Data Screening

The review of existing medical records represents one of the most common pre-enrollment activities conducted without consent. This protocol enables researchers to identify potentially eligible participants based on predefined inclusion and exclusion criteria before making initial contact.

Experimental Protocol: Medical Record Screening

Objective: To identify potential research participants who meet preliminary eligibility criteria through review of existing health information without prior consent.
Materials:
- Electronic health record system with research access permissions
- Predefined eligibility criteria checklist
- Secure data collection form
- IRB-approved screening protocol documentation
Methods:
- Obtain IRB approval for the screening plan with a waiver of consent
- Define specific data elements necessary for eligibility determination
- Implement privacy safeguards including data encryption and secure storage
- Limit access to minimum necessary information for screening purposes
- Establish audit trail for all record accesses
Quality Control:
- Regular monitoring of screening procedures
- Verification of eligibility criteria application
- Documentation of screening outcomes

Preliminary Contact and Recruitment Communication

Initial contact with potential participants identified through screening represents a critical transition point in the recruitment process. These communications must balance informational value with respect for individual autonomy and privacy.

Experimental Protocol: Preliminary Recruitment Contact

Objective: To establish initial contact with potential participants identified through screening to assess interest in research participation.
Materials:
- IRB-approved contact script
- Study information sheet (if applicable)
- Response tracking system
- Privacy notice documentation
Methods:
- Utilize approved contact method (letter, phone call, or clinician referral)
- Provide basic study information without overwhelming detail
- Clearly state that participation is voluntary
- Explain how the individual was identified (e.g., "through your clinic")
- Offer opportunity to decline further contact
- Document responses and interest level
Quality Control:
- Monitor adherence to approved scripts
- Track response rates and opt-out requests
- Assess representativeness of interested participants

Quantitative Assessment of Pre-Enrollment Activities

Risk-Benefit Analysis of Screening Procedures

The implementation of pre-enrollment activities requires careful quantitative assessment of both risks and benefits. The following table summarizes common screening methods with their associated risk profiles and regulatory considerations.

Table: Quantitative Analysis of Pre-Enrollment Screening Methods

Screening Method	Risk Level	Privacy Impact	Regulatory Requirements	Participant Burden
Medical Record Review	Minimal	Medium	IRB Waiver of Consent	None
Existing Specimen Analysis	Minimal	Low	IRB Waiver of Consent	None
Preliminary Health Questionnaire	Low	Low	Limited IRB Review	Low (5-10 minutes)
Brief Physical Measurements	Low	Low	Full IRB Review	Low (15-20 minutes)
Clinical Data Abstraction	Minimal	Medium	IRB Waiver of Consent	None

Statistical Considerations for Screening Populations

Sample size calculations for screening activities must account for expected eligibility rates and recruitment yields. The predictive value of screening criteria directly impacts recruitment efficiency and resource allocation. Quantitative research methods provide the framework for measuring these relationships through descriptive statistics and inferential analyses [50].

Key statistical measures for screening optimization include:

Eligibility prevalence: Proportion of screened individuals meeting inclusion criteria
Recruitment yield: Proportion of eligible individuals who consent to participate
Screening efficiency: Ratio of resources expended to participants enrolled
Selection bias assessment: Demographic comparison between screened and enrolled populations

Research Reagent Solutions for Pre-Enrollment Activities

The effective implementation of pre-enrollment screening protocols requires specific methodological tools and documentation systems. The following table outlines essential research reagents and their applications in permissible pre-enrollment activities.

Table: Research Reagent Solutions for Pre-Enrollment Screening

Reagent/Tool	Primary Function	Application in Pre-Enrollment	Regulatory Considerations
IRB Waiver Request Template	Documents justification for consent waiver	Medical record screening protocols	Must address Common Rule criteria
Eligibility Criteria Checklist	Standardizes screening decisions	Consistent application of inclusion/exclusion criteria	Requires IRB approval before use
Secure Data Collection Form	Captures screening data	Limited data collection during pre-enrollment	Must include privacy protections
Pre-Screening Contact Script	Standardizes initial participant contact	Ensures consistent communication	IRB approval required for content
Screening Log Template	Tracks screening outcomes	Documents screening workflow and results	Must protect potential participant privacy

Special Considerations for Vulnerable Populations

The 2024 Declaration of Helsinki emphasizes responsible inclusion of vulnerable populations rather than blanket exclusion. For pre-enrollment activities, this requires careful consideration of how screening protocols might either disproportionately burden or unfairly exclude vulnerable groups. Researchers must weigh the "harms of exclusion" (potential perpetuation of health disparities) against the "harms of inclusion" (potential exploitation or undue influence) when designing screening approaches for vulnerable populations [49].

Special safeguards for vulnerable populations in pre-enrollment activities include:

Enhanced confidentiality protections for identifiable information
Consultation with community representatives during screening design
Cultural adaptation of preliminary contact methods
Assessment of comprehension during initial interactions
Additional IRB oversight specifically for screening procedures

Documentation and Compliance Monitoring

Essential Documentation for Pre-Enrollment Activities

Comprehensive documentation practices provide the foundation for regulatory compliance and ethical oversight of pre-enrollment activities. Essential documentation includes:

IRB approval of the screening and recruitment plan
Waiver of consent documentation if applicable
Screening protocols with eligibility criteria
Data security safeguards implementation records
Participant tracking system with privacy protections
Communication logs for all preliminary contacts

Compliance Monitoring Framework

Ongoing monitoring and auditing of pre-enrollment activities ensures adherence to both regulatory requirements and ethical principles. The monitoring framework should include:

Regular review of screening yields and demographic patterns
Privacy breach detection and reporting systems
Participant feedback mechanisms regarding recruitment experience
Protocol deviation tracking and corrective actions
Stakeholder engagement in process evaluation

Pre-enrollment screening and recruitment activities represent a critical interface between research objectives and participant protections. While the Common Rule provides regulatory permission for limited activities without formal consent, the 2024 Declaration of Helsinki establishes higher ethical expectations for meaningful engagement and participant welfare throughout the research continuum [49]. The evolving ethical landscape emphasizes that pre-enrollment activities must balance scientific necessity with profound respect for potential participants' autonomy, privacy, and well-being.

Successful implementation of these protocols requires researchers to view pre-enrollment activities not as exceptions to ethical requirements, but as integral components of their participant protection responsibilities. By adopting the frameworks, protocols, and documentation practices outlined in this application note, researchers can navigate the complex terrain of screening and recruitment while maintaining the highest standards of research ethics and regulatory compliance.

The 2018 revisions to the Federal Policy for the Protection of Human Subjects (the Common Rule) introduced broad consent as a new category of informed consent, creating a third regulatory pathway alongside traditional study-specific consent and consent waivers [51] [34]. This provision addresses the growing need for secondary research with biospecimens and data stored in biobanks and repositories, where obtaining specific consent for each future study is often impractical [52]. Broad consent is defined specifically as consent for the storage, maintenance, and secondary research use of identifiable private information or identifiable biospecimens [51] [34]. For researchers and institutional review boards (IRBs) operating under the Common Rule, understanding the implementation requirements, challenges, and ethical considerations of broad consent has become essential for compliant biobank-based research.

The diagram below illustrates the decision pathway for implementing broad consent under the revised Common Rule.

Definition and Scope under the Revised Common Rule

Broad consent represents a significant regulatory shift, specifically authorized under 45 CFR §46.116(d) [51] [34]. Its application is deliberately limited to secondary research contexts—it can only be used to obtain consent for future unspecified research use of identifiable private information or identifiable biospecimens [34]. This distinguishes it fundamentally from "blanket consent," as it requires establishing clear ethical and legal boundaries for secondary use, including limitations on research types and procedural safeguards [53].

The implementation of broad consent is not mandatory under the revised Common Rule. Researchers maintain the flexibility to choose between study-specific informed consent, broad consent, or requesting an IRB waiver of consent based on their specific research context and requirements [51] [34].

The Common Rule specifies essential elements that must be included in broad consent documentation, none of which may be omitted or altered as each is considered essential [51] [34]. These requirements blend standard informed consent components with unique elements specific to broad consent.

Table 1: Essential Elements of Broad Consent Documentation

Element Category	Specific Requirement	Regulatory Citation
Standard Consent Elements	Description of reasonably foreseeable risks	45 CFR §46.116(d)(1)
	Description of benefits to subject or others	45 CFR §46.116(d)(2)
	Statement on confidentiality protections	45 CFR §46.116(d)(3)
	Statement that participation is voluntary	45 CFR §46.116(d)(4)
Conditional Elements	Statement on commercial profit potential	45 CFR §46.116(b)(9)
	Statement on whole genome sequencing	45 CFR §46.116(b)(10)
Unique Broad Consent Elements	General description of types of future research	45 CFR §46.116(d)(5)
	Description of information/biospecimens to be used	45 CFR §46.116(d)(6)
	Duration of storage and use (may be indefinite)	45 CFR §46.116(d)(7)
	Statement that subjects may not be informed of subsequent research details	45 CFR §46.116(d)(8)
	Statement that results may not be disclosed	45 CFR §46.116(d)(9)
	Contact information for subject questions	45 CFR §46.116(d)(10)

For the unique elements, several require particular attention in implementation. The general description of research types must be sufficient for a reasonable person to understand what they are consenting to, particularly highlighting potentially sensitive areas like genetic research or controversial methodologies [34]. The duration of storage may be indefinite under current regulations, but this approach has drawn ethical criticism regarding long-term privacy implications [52]. The statements about not providing subsequent research details or research results must be explicit to manage participant expectations [54].

Implementation Challenges and Ethical Considerations

Practical and Ethical Limitations

Despite its regulatory approval, broad consent faces significant practical and ethical challenges that impact implementation. Recent empirical research with patient organizations reveals that while there is general recognition of the efficiency benefits of broad consent, stakeholders express substantial reservations about its limitations [53]. These concerns particularly focus on reduced information flow, the absence of concrete research objectives, and coverage of excessively long time periods that extend beyond what participants can reasonably comprehend [53].

A critical vulnerability of one-time broad consent emerges when considering how participants' health status and personal values may evolve over time. A 25-year-old participant in good health might perceive minimal privacy risk when consenting to indefinite access to their health records, but may develop serious reservations years later if their records accumulate sensitive information about mental health conditions, substance use, sexually transmitted infections, or other stigmatizing health information [52]. This creates a significant ethical tension between the scientific value of longitudinal data access and respect for participants' potentially changing autonomy and privacy preferences.

Governance and Withdrawal Mechanisms

International ethics codes, including the Nuremberg Code, Declaration of Helsinki, and specifically for biobanking the Declaration of Taipei, affirm the right of research participants to withdraw consent at any time without reprisal [52]. However, in practice, this right functions as an individually initiated opt-out mechanism that provides insufficient protection unless participants receive periodic reminders about their ongoing participation and withdrawal rights [52].

The implementation of withdrawal mechanisms presents technical and operational challenges, particularly regarding irreversibly de-identified biospecimens and data, where actual withdrawal becomes impossible [52] [54]. Research repositories must establish clear protocols specifying whether participants can have their data/specimens destroyed or identifiers removed upon withdrawal, and should explicitly address the limitations of withdrawal for materials that have been distributed to secondary researchers or irreversibly anonymized [54].

Repository Establishment and Management Protocol

Establishing a compliant biorepository for broad consent-based research requires meticulous planning and documentation. The following protocol outlines key steps for repository setup and management:

IRB Approval Pathway: Submit either a stand-alone repository application or incorporate repository intentions into a specific research protocol. Clearly specify whether collection occurs alongside a primary research study or as an independent initiative [54].
Data Security Specifications: Implement and document robust security protections including encryption standards, access controls, and audit trails. Describe whether data/biospecimens will be stored with direct identifiers, coded, or anonymized [54].
Withdrawal Procedures: Establish transparent procedures for participant withdrawal. Specify whether destruction of specimens/records is possible or if the approach will focus on removing identifiers. Document limitations, particularly for distributed or anonymized materials [54].
Usage Limitations: Define the scope of permitted research, including any categorical exclusions (e.g., commercial use, genetic studies, reproductive research) [53] [54].
Sustainability Planning: Address repository longevity, including plans for eventual dismantling, data/specimen disposal, or transfer protocols in cases of funding loss or principal investigator departure [54].

Table 2: Research Reagent Solutions for Broad Consent Implementation

Tool/Resource	Function/Purpose	Implementation Notes
Broad Consent Documentation Template	Standardized format including all required regulatory elements	Institutions must develop customized templates; none provided in regulations [51]
Participant Tracking System	Database to record consent status, track withdrawals, and manage recontact permissions	Essential for complying with exclusion requirements for non-consenting individuals [54]
Certificate of Confidentiality	Additional protection against compelled disclosure of sensitive data	Particularly recommended for genetic materials or sensitive health information [54]
Data Use Agreements	Governance documents specifying conditions for secondary researcher access	Should incorporate limitations specified in original broad consent [54]
Limited IRB Review Protocol	Expedited review process for secondary research under broad consent	Required to determine if proposed research is within scope of original consent [51]
Periodic Recontact Framework	System for updating consent or providing ongoing participation information	Addresses ethical concerns about changing values over time; electronic methods make this feasible [52]

Special Considerations and Cross-Border Implications

Researchers operating in international contexts or collaborating across jurisdictions must navigate varying regulatory interpretations of broad consent. The European Union's General Data Protection Regulation (GDPR) permits a form of broad consent for scientific research but requires greater specificity than U.S. regulations, particularly regarding the narrowing of research purposes to specific areas and questions [52]. The European Data Protection Board has clarified that broad consent under GDPR cannot cover "unspecified future research purposes" without additional safeguards [52].

Additional special considerations include:

Pediatric Transition Protocols: Establish procedures for reconsenting participants who were enrolled as minors but reach the legal age of consent during the research period [54].
Commercialization Disclosures: Clearly state policies regarding potential commercial applications and profit-sharing, particularly for biospecimens that may retain value even after identifier removal [34].
Multi-institutional Governance: For collaborative research, implement centralized IRB review mechanisms to reduce administrative burdens while maintaining consistent consent interpretation [12].

Broad consent represents a pragmatic regulatory response to the evolving needs of modern biomedical research, offering efficiency benefits for secondary research with biospecimens and health data. However, its implementation requires careful attention to both regulatory requirements and the ethical imperative to respect participant autonomy over time. Successful broad consent frameworks incorporate transparent documentation, robust governance mechanisms, and practical withdrawal procedures that acknowledge the limitations of one-time consent for long-term research participation. As research becomes increasingly global and data-intensive, the continued evolution of broad consent practices will demand ongoing dialogue between researchers, regulators, and research participants to maintain the crucial balance between scientific progress and participant protection.

The Single Institutional Review Board (sIRB) model represents a fundamental shift in the ethical oversight of multi-site research. It involves using one IRB to review the human research protections for all participating sites in a multisite study, replacing the traditional model where each site's local IRB conducted its own review [55] [56]. This approach is now mandated for most federally-funded cooperative research in the United States under the Revised Common Rule (effective January 21, 2019) and the NIH Policy (effective January 25, 2018) [55] [56] [57]. The primary objectives of these mandates are to enhance review efficiency, reduce administrative burdens and delays, and ensure consistent application of ethical standards and participant protections across all research sites [55] [56]. For researchers operating within the framework of the Common Rule, understanding sIRB requirements is particularly crucial for ensuring that informed consent documentation is reviewed consistently and meets all regulatory standards.

Regulatory Framework and Compliance Timelines

The regulatory landscape for sIRB use has evolved significantly, moving from a recommended practice to a mandatory requirement for most multi-site studies. The key policies establish a coordinated framework with overlapping jurisdictions.

Table 1: Key Single IRB Mandates and Compliance Dates

Regulatory Body	Policy Name	Effective Date	Key Scope Requirements	Notable Exceptions
National Institutes of Health (NIH)	NIH Policy on Use of a Single IRB [56]	January 25, 2018 [56]	All domestic sites in NIH-funded multi-site studies [56] [57]	Research conducted at foreign sites [55]
Department of Health & Human Services (HHS)	Revised Common Rule (45 CFR 46) [56] [57]	January 21, 2019 [56] [57]	Federally-funded cooperative research (multi-site) in the U.S. [55] [57]	Studies initially approved before Jan 21, 2019; research determined to be exempt [55] [57]
Food and Drug Administration (FDA)	Proposed Rule (Institutional Review Boards; Cooperative Research) [55] [56]	Expected 2024 (Finalization) [56]	FDA-regulated cooperative research within the U.S. [56]	Rule not yet finalized

The FDA's proposed rule, published in September 2022, aims to harmonize its regulations with the NIH and HHS requirements, creating a uniform expectation for sIRB use across major federal research agencies [55] [56]. The definition of cooperative research central to these mandates is projects covered by the Common Rule that involve more than one institution [55]. It is critical to note that the sIRB requirement applies only to the portion of the research conducted within the U.S. and only to sites engaged in nonexempt human subjects research activities [55] [57]. Furthermore, specific state, federal, or tribal laws may require local IRB review, which would serve as an exception to the federal sIRB mandate [57].

sIRB Workflow and Reliance Agreements

Implementing the sIRB model requires a formalized process of ceding review authority from participating sites to a single IRB of record. This process is governed by IRB Authorization Agreements (IAAs), which are legal documents that establish the responsibilities of the reviewing IRB and the relying institutions [57]. The workflow for establishing these agreements is methodical and requires careful planning and communication between all parties.

Diagram 1: sIRB Implementation and Reliance Agreement Workflow. This diagram outlines the key steps for establishing a single IRB of record for a multi-site study, from identification through to ongoing review.

The process begins with determining which IRB will serve as the sIRB of record. The federal sponsor supporting the research may sometimes designate a specific IRB [57]. If not, the lead institution typically assumes this responsibility [57]. Once identified, the lead investigator must formally request that their local IRB cede authority to the designated sIRB. As per Lehigh University's protocol, this involves submitting a "Request to Rely on External IRB" form, the sIRB's approval letter, approved consent form(s), and human subjects protection training certificates for all study personnel [57]. The IRB signatory officials from the sIRB and the relying institution must then sign an IAA before any research activities can commence [57]. Post-approval, the relying sites are responsible for following the sIRB's determinations and submitting continuing review approval letters to their local institutional officials to maintain compliance [57].

Within the sIRB framework, the management of informed consent documents must adhere to both the standard Common Rule requirements and the specific mandates for multi-site studies. A critical, often overlooked requirement of the Revised Common Rule is the public posting of consent forms for federally-funded clinical trials [58]. This requirement directly enhances transparency and creates a repository of sample documents for the research community.

The consent form posting mandate applies to all federally-funded clinical trials, including behavioral and social science research that meets the definition of a clinical trial (prospective assignment of subjects to interventions to evaluate health-related outcomes) [58]. Adherence to this protocol involves several key steps:

Determine Responsibility: For single-awardee projects, the Principal Investigator (PI) is responsible for posting. For multi-site research, the prime awardee is generally the responsible party [58].
Select Approved Website: The consent form must be posted on a publicly available federal website. The two identified options are:
- ClinicalTrials.gov: Required for studies already registered on this platform [58].
- Regulations.gov: Specifically, the docket folder (ID: HHS-OPHS-2018-0021) can be used for posting [58].
Establish Timing: The posting must occur after the trial is closed to recruitment and no later than 60 days after the last study visit by any subject, as required by the protocol. For studies on ClinicalTrials.gov, the consent form should be uploaded when the trial status is updated to "closed to recruitment" [58].
Identify Correct Version: The posted version must be the most recent IRB-approved consent form that was actually used to enroll a participant [58].
Prepare Document for Posting:
- For ClinicalTrials.gov, the consent form must have a cover page with the Study Title, Document Date (IRB approval date), and NCT number, and be saved in PDF/A format [58].
- For Regulations.gov, the consent form is submitted as a comment to the designated docket folder [58].
Manage Redactions: Any request to redact information from the consent form prior to posting must be submitted to and approved by the specific federal agency supporting the clinical trial [58].

The Scientist's Toolkit: Essential Materials for sIRB Compliance

Table 2: Key Research Reagent Solutions for sIRB Implementation

Item	Function & Purpose	Protocol for Use
IRB Authorization Agreement (IAA) Template	Legal document that formalizes the reliance relationship between the sIRB and participating institutions, outlining roles and responsibilities [57].	Draft and execute the IAA prior to study initiation. Ensure it is signed by the signatory officials of both the sIRB and the relying institution [57].
"Request to Rely on External IRB" Form	Internal institutional form used by a researcher to formally request that their local IRB cede review authority to an external sIRB [57].	Submit this form via the institution's designated portal (e.g., IRBNet) along with the sIRB's approval letter and approved study documents [57].
Federal Website Account (ClinicalTrials.gov/Regulations.gov)	Platform for fulfilling the federal requirement to publicly post the IRB-approved informed consent form after a clinical trial is closed to recruitment [58].	After study closure, upload the consent form with required metadata (e.g., IRB approval date, NCT number) in the specified file format (PDF/A) to the appropriate website [58].
sIRB-Compliant Informed Consent Form	The human subjects consent document reviewed and approved by the single IRB of record, ensuring consistency in participant protections and information across all sites [55].	Use only the version of the consent document approved by the sIRB for all enrolling sites. Any amendments must be submitted to and approved by the sIRB before implementation [55] [57].
Centralized Submission Portal	Online system (e.g., IRBNet) used for managing all IRB submissions, communications, and document storage between the participating sites and the sIRB [57].	All study personnel must be trained on the portal. All correspondence, continuing reviews, amendments, and event reports must be submitted through this centralized system [56] [57].

The mandatory use of a single IRB for multi-site research fundamentally streamlines the ethical review process, reducing administrative burdens and promoting consistent human subject protections. Successful implementation hinges on a clear understanding of the overlapping regulatory mandates from the NIH, Revised Common Rule, and forthcoming FDA rule. Researchers must master the protocols for establishing IRB Authorization Agreements and diligently adhere to the specific requirements for informed consent documentation, including its public posting. By systematically applying these application notes and protocols, the research community can achieve compliance more efficiently, ultimately accelerating the initiation of important multi-site trials while robustly safeguarding participant rights and welfare.

Regulatory Harmonization and Recent Updates: FDA Alignment and Future Directions

The FDA's 2023 Final Rule represents a significant milestone in regulatory harmonization, establishing a unified pathway for Institutional Review Boards (IRBs) to waive or alter informed consent for certain minimal-risk clinical investigations. This rule, which took effect on January 22, 2024, amends FDA regulations at 21 CFR § 50.22 to align with the Common Rule's standards (45 CFR § 46.116(f)) for waiving consent requirements in minimal risk research [43] [44]. Prior to this rule, FDA regulations permitted exceptions from informed consent only in specific life-threatening situations or for emergency research, creating a regulatory gap between FDA-regulated research and Common Rule-governed studies [59]. This divergence caused confusion and inefficiency, particularly for research subject to both regulatory frameworks [59].

The 21st Century Cures Act, enacted in 2016, mandated that FDA harmonize its human subject regulations with the Common Rule to the extent practicable and consistent with statutory provisions [43]. The 2023 Final Rule fulfills this mandate for informed consent waivers, adopting the same five criteria the revised Common Rule established in 2017 [59]. This alignment reduces administrative burdens for researchers and IRBs overseeing FDA-regulated clinical investigations that pose minimal risk to participants [45].

Rule Specifications and Criteria

The Five Criteria for IRB Waiver or Alteration

For an IRB to waive or alter informed consent requirements under the Final Rule, it must find and document that the clinical investigation satisfies five specific criteria [43] [44] [59]:

The clinical investigation involves no more than minimal risk to subjects
The clinical investigation could not practicably be carried out without the requested waiver or alteration
If the clinical investigation involves using identifiable private information or identifiable biospecimens, the clinical investigation could not practicably be carried out without using such information or biospecimens in an identifiable format
The waiver or alteration will not adversely affect the rights and welfare of the subjects
Whenever appropriate, the subjects or legally authorized representatives will be provided with additional pertinent information after participation

The third criterion represents a significant addition from the revised Common Rule that was not included in FDA's 2018 proposed rule [59]. This requirement mirrors a similar provision in the HIPAA Privacy Rule for waivers of authorization, which states that research could not practicably be conducted without access to and use of protected health information [59].

Economic Impact Analysis

The FDA has quantified the economic impacts of this regulatory change, estimating both implementation costs and anticipated cost savings from harmonization [43] [45]. The following table summarizes these economic projections:

Table 1: Economic Impact Analysis of FDA's 2023 Final Rule on Informed Consent Waivers

Impact Category	Net Present Value (3% discount rate)	Net Present Value (7% discount rate)	Annualized Value (3% discount rate)	Annualized Value (7% discount rate)
Estimated Costs	$10.1 million (Range: $8.1M - $14.0M)	$9.1 million (Range: $7.5M - $12.4M)	$1.2 million (Range: $0.9M - $1.6M)	$1.3 million (Range: $1.1M - $1.8M)
Estimated Cost Savings	$1.7 million (Range: $0.9M - $3.5M)	$1.4 million (Range: $0.7M - $2.8M)	$0.2 million (Range: $0.1M - $0.4M)	$0.2 million (Range: $0.1M - $0.4M)

These costs primarily stem from IRBs, investigators, and sponsors reading and learning the new rule, drafting waiver or alteration requests, and additional recordkeeping burdens [45]. Cost savings are expected from reduced administrative burdens and harmonization with existing Common Rule procedures [43]. Additional unquantified benefits include healthcare advances from minimal risk clinical investigations that would not be performed without a waiver or alteration of informed consent [43].

Application Notes for Researchers

Implementing the "Practicability" Standard

A critical implementation challenge involves interpreting the "practicably be carried out" standard referenced in the second and third criteria [59]. FDA has clarified that practicability must be determined based on more than just considerations of convenience, cost, or speed [59]. The agency cites SACHRP guidance, noting that obtaining consent may be impracticable if the research would be "unduly delayed" – defined as "a delay in the initiation of a clinical investigation that is so lengthy as to raise ethical or scientific concerns given the benefit, or value, potentially gained by the research" [59].

For secondary research using leftover biospecimens, FDA has acknowledged the potential overlap between this Final Rule and its existing guidance on IVD device studies using non-identifiable leftover biospecimens [59]. While the agency believes most IVD investigations falling within that guidance would also satisfy the new waiver criteria, it has stated the IVD guidance will remain in place during the transition period to avoid disruption [59].

Documentation and IRB Workflow Requirements

The following workflow diagram illustrates the decision process IRBs must follow when evaluating requests for waiver or alteration of informed consent:

Diagram 1: IRB Decision Workflow for Consent Waiver Requests

IRBs must maintain comprehensive documentation of their findings for all five criteria, including the scientific and ethical rationales supporting each determination [43] [44]. This documentation should be sufficiently detailed to demonstrate careful consideration of each criterion and withstand potential regulatory scrutiny.

Experimental Protocols

Protocol for Secondary Use of Identifiable Biospecimens

This protocol provides a methodology for implementing the FDA Final Rule when conducting secondary research using identifiable biospecimens, a common scenario where consent waivers may be appropriate.

Table 2: Research Reagent Solutions for Biospecimen Research

Item/Category	Function/Application	Implementation Notes
Coded Biospecimens	Enables tracking of specimens while maintaining privacy through a coding system	Replace direct identifiers with a code; maintain linkage in secure, separate location
IRB-Approved Protocol	Provides regulatory compliance framework for waiver and specimen use	Must include justification why research cannot use non-identifiable specimens
Secure Data Repository	Protected electronic system for storing identifiable specimen information	Must include access controls, audit trails, and encryption meeting institutional standards
Data Use Agreement	Governs appropriate handling and use of identifiable data/specimens	Required when multiple institutions collaborate; specifies privacy protections

Procedure:

Study Design Phase: Develop a research protocol that specifically addresses all five waiver criteria, with particular emphasis on Criterion 3 (justifying why the research cannot use non-identifiable biospecimens).
IRB Submission: Submit to the IRB a detailed waiver request that includes:
- Risk Assessment: Documentation that the research involves no more than minimal risk to subjects
- Practicability Analysis: Explanation why the research could not practicably be conducted without both the waiver and using identifiable biospecimens
- Welfare Impact Statement: Analysis of how the waiver will not adversely affect rights and welfare
- Debriefing Plan: Procedure for providing additional pertinent information to subjects after participation, when appropriate
Data Management: Implement a data security plan that includes:
- Access controls limiting identifiable information to essential personnel only
- Encryption of electronic files containing identifiers
- Secure physical storage for any paper records with identifiers
- Audit trails tracking access to identifiable information
Post-Research Considerations: Determine if subjects should receive additional information about the research after their participation, particularly if findings have potential clinical relevance.

Protocol for Real-World Data Analysis Studies

This protocol applies the FDA Final Rule to retrospective analyses of real-world data (RWD), such as electronic health records or claims data, where obtaining individual consent is often impracticable.

Procedure:

Data Identification: Identify specific datasets containing the information needed to address the research question while minimizing unnecessary collection of identifiable data elements.
Waiver Justification Development: Create a comprehensive justification addressing:
- Why obtaining consent would be impracticable (e.g., sample size, geographical distribution of subjects, or potential introduction of bias)
- How the analysis plan incorporates appropriate safeguards to protect privacy and confidentiality
- Why the research could not be conducted without access to identifiable information
Privacy Safeguards Implementation: Institute technical and procedural safeguards including:
- Data de-identification to the maximum extent possible while maintaining scientific validity
- Limited dataset creation with removal of direct identifiers
- Secure data analytic environments with restricted output review
IRB Review and Documentation: Work with the IRB throughout the review process to address questions about the waiver request and ensure all five criteria are properly documented in the approval.

The following diagram illustrates the comparative analysis workflow for real-world data studies conducted under a consent waiver:

Diagram 2: Real-World Data Analysis Workflow with Consent Waiver

Regulatory Context and Harmonization Benefits

Pre- and Post-Rule Comparative Analysis

The following table compares the regulatory landscape before and after implementation of the FDA Final Rule, highlighting key changes and harmonization benefits:

Table 3: Regulatory Comparison Before and After FDA's 2023 Final Rule

Aspect	Pre-Rule Framework	Post-Rule Framework
FDA Waiver Authority	Limited to life-threatening situations and emergency research [59]	Expanded to include minimal risk clinical investigations with appropriate safeguards [43]
Common Rule Alignment	Divergent standards creating confusion for dual-regulated research [59]	Harmonized criteria allowing consistent application across regulatory frameworks [44]
IRB Review Criteria	Varied depending on applicable regulations [60]	Standardized five criteria matching revised Common Rule [43] [59]
Biospecimen Research	Relied on FDA enforcement discretion for certain IVD studies [59]	Clear regulatory pathway with specific identifiability criterion [44] [59]
Documentation Requirements	Inconsistent documentation standards between agencies	Uniform documentation expectations for waiver justifications

Ongoing Harmonization Efforts

While the 2023 Final Rule represents significant progress, FDA continues to work on additional harmonization initiatives as required by the 21st Century Cures Act [59]. These include:

Potential future harmonization of provisions on posting of informed consent forms, broad consent, limited IRB review, exempt research, and public health surveillance activities [59]
Finalization of proposed rules from September 2022 to harmonize FDA regulations pertaining to human subjects research and review of cooperative research by a single IRB with the Common Rule [59]

Researchers should note that FDA continues to require annual continuing review for FDA-regulated studies, even those involving only minimal risk, unlike the Common Rule which eliminated continuing review requirements for certain minimal risk research [60]. This represents an area where regulatory divergence persists despite harmonization efforts.

The FDA's 2023 Final Rule on IRB waiver or alteration of informed consent for minimal risk clinical investigations represents a substantial step toward reducing regulatory burdens while maintaining rigorous human subject protections. By fully aligning with the Common Rule's five criteria for consent waiver, FDA has created a consistent framework for researchers and IRBs overseeing minimal risk studies across multiple regulatory domains.

Successful implementation requires researchers to develop robust justifications addressing all five criteria, with particular attention to the "practicability" standard and the specific requirements for research involving identifiable private information or biospecimens. IRBs must establish clear procedures for evaluating waiver requests and maintain comprehensive documentation of their findings.

As FDA continues its harmonization efforts, researchers should monitor for additional regulatory updates that may further align FDA requirements with the Common Rule. The research community now has an opportunity to leverage this unified approach to facilitate valuable minimal risk research, including real-world data analyses and secondary biospecimen studies, that can advance public health while appropriately protecting research participants.

Informed consent represents a cornerstone of ethical clinical research, yet sponsors, investigators, and institutional review boards (IRBs) operating in the United States must navigate a complex regulatory landscape with distinct requirements under the U.S. Food and Drug Administration (FDA) regulations and the Federal Policy for the Protection of Human Subjects (Common Rule). While both frameworks share the common goal of protecting human subjects, significant regulatory divergence has historically created compliance challenges for multi-site clinical investigations [61].

The 21st Century Cures Act (2016) mandated that FDA harmonize its informed consent regulations with the Common Rule "to the extent practicable" [62] [44]. Although progress has been incremental, recent FDA regulatory actions demonstrate a clear path toward increased alignment, particularly regarding minimal-risk investigations [44]. This application note analyzes the current areas of divergence and convergence to provide stakeholders with clear protocols for compliant informed consent documentation within the context of a broader thesis on Common Rule research requirements.

Current Regulatory Divergence: A Comparative Analysis

Despite harmonization efforts, key differences remain between FDA regulations and the Common Rule. The table below summarizes the most consequential divergences affecting informed consent documentation and IRB procedures.

Table 1: Key Differences Between FDA Regulations and the Common Rule for Informed Consent

Regulatory Aspect	FDA Requirements	Common Rule (45 CFR 46)	Practical Implications for Researchers
Minimal Risk Waiver	Final rule effective Jan 2024 permits IRB waiver/alteration under 5 specific criteria [44].	Long-standing provision for waiver/alteration under §46.116(f) [9].	FDA now aligned with Common Rule, allowing consistent approach for minimal-risk studies [44].
Key Information	FDA guidance references differences but does not yet include key information mandate [61].	§46.116(a)(5)(i) requires consent to begin with concise key information presentation [9].	Researchers must add a key information section for HHS-funded studies, even if not required for FDA portion.
Broad Consent	Does not include broad consent provisions for secondary research [61].	§46.116(d) permits broad consent for storage/maintenance/secondary research use [9].	Different consent pathways for biospecimens depending on funding source and regulatory oversight.
Post-Consent Documentation	Permits photographic image of signed form as documentation in specific scenarios (e.g., isolation) [61].	No specific provision for photographic documentation mentioned.	Flexibility for FDA-regulated studies when traditional or electronic signature is not feasible.
Continuing Review	Generally requires continuing review for all approved research [61].	Eliminates continuing review requirement for studies that have completed interventions [12].	Administrative burden differs; Common Rule studies may have fewer ongoing review requirements.

The Minimal Risk Waiver: A Converged Pathway

The most significant recent harmonization achievement involves the waiver or alteration of informed consent for minimal-risk clinical investigations. The FDA's final rule of December 2023, effective January 2024, brings the agency into alignment with the Common Rule by adopting identical criteria [44]. An IRB may now approve a waiver under both regulatory frameworks if it finds and documents all of the following criteria are met:

The investigation involves no more than minimal risk to the subjects
The waiver or alteration will not adversely affect the rights and welfare of the subjects
The investigation could not practicably be carried out without the waiver or alteration
Whenever appropriate, the subjects will be provided with additional pertinent information after participation
If the investigation involves identifiable private information or biospecimens, it could not practicably be carried out without using such information in an identifiable format [44]

This convergence creates a streamlined pathway for certain types of minimal-risk research, such as analyses of identifiable data or residual biospecimens where obtaining individual consent is impracticable.

The following protocol provides a detailed methodology for implementing a compliant informed consent process that addresses both FDA and Common Rule requirements, particularly for research falling under both jurisdictions.

Purpose: To establish a standardized procedure for creating and administering informed consent documents that satisfy both FDA regulations (21 CFR Parts 50 and 56) and the revised Common Rule (45 CFR 46) requirements.

Scope: Applies to all clinical investigators, research coordinators, and IRB personnel involved in human subjects research that is subject to both FDA and Common Rule regulations.

Materials and Reagents:

Electronic Consent System: FDA-compliant electronic system capable of capturing electronic signature and presenting information in accessible format [61]
Document Version Control System: System to track and manage revisions of informed consent documents
Multi-lingual Resources: Translated short forms and access to qualified interpreters for subjects with limited English proficiency [61]

Procedure:

Step 1: Determination of Applicable Regulations

Classify the research according to funding source (federal/non-federal), involvement of FDA-regulated products (drugs, devices, biologics), and institutional policies
Document which regulatory frameworks apply (Common Rule only, FDA only, or both) in the study protocol and IRB application

Step 2: Core Consent Document Development

Incorporate all basic elements required by both FDA (21 CFR 50.25) and Common Rule (§46.116(b))
Draft a "Key Information" section at the beginning, as required by the Common Rule, that provides a concise and focused presentation to assist prospective subjects in understanding reasons for or against participation [9]
Include additional elements from §46.116(c) when appropriate, even for FDA-regulated research, to create a single comprehensive document [61]

Step 3: Special Provision Assessment

For studies involving storage of identifiable data or biospecimens:
- For Common Rule-covered research: Implement broad consent procedure per §46.116(d) if applicable [9]
- For FDA-regulated research: Use specific consent for each research use [61]
Assess eligibility for minimal risk waiver using the harmonized five criteria if the study involves no more than minimal risk [44]

Step 4: IRB Review and Approval

Submit the complete consent document(s) and study protocol to the IRB of record
For multi-site studies using a single IRB: Ensure local context issues are addressed, particularly when using a centralized IRB model [12] [61]
Document the IRB's determination regarding the consent process and any waivers granted

Step 5: Consent Administration and Documentation

Conduct the consent discussion in a setting with sufficient opportunity for questions and consideration
For FDA-regulated research: Document consent using a method acceptable under 21 CFR 56.109(c), which may include photographic documentation of the signed form when standard methods are not feasible [61]
Provide a copy of the signed consent form to the subject

Step 6: Ongoing Consent Management

Implement procedures to provide subjects with significant new findings that may affect their willingness to continue participation [61]
For Common Rule-covered research: Adhere to revised continuing review requirements, which may eliminate continuing review for some studies [12]

Diagram 1: Dual-Compliant Informed Consent Development Workflow

Table 2: Research Reagent Solutions for Informed Consent Documentation

Tool/Resource	Function	Regulatory Consideration
eConsent Platform	Electronic system for presenting consent information and capturing signatures	Must comply with FDA 21 CFR Part 11 for electronic records and signatures [61]
Certificate of Confidentiality (CoC)	Protects identifiable research information from compelled disclosure	Broadened under 21st Century Cures Act; can be requested for FDA-regulated research [61]
Multi-lingual Short Form	Consent documentation for subjects with limited English proficiency	Requires IRB-approved written summary; witness presence needed [61]
Visual Aids/Diagrams	Supplemental materials to enhance subject comprehension	Recommended by FDA guidance to improve understanding of complex trials [61]
Centralized IRB Platform	Streamlined review process for multi-site trials	Aligns with Common Rule requirement for use of single IRB for multi-site research [12]

Convergence Efforts and Future Directions

Harmonization between FDA regulations and the Common Rule remains a work in progress. The FDA has publicly acknowledged areas where differences still exist and has expressed commitment to updating its regulations [61]. Key convergence initiatives include:

FDA's Minimal Risk Waiver Rule: The December 2023 final rule represents the most significant recent harmonization achievement, directly implementing Common Rule standards for minimal risk investigations [44]
Pending Key Information Requirement: While current FDA guidance does not mandate the "key information" first element, the agency has indicated plans to update its regulations in the future [62] [61]
Guidance Document Alignment: The FDA's August 2023 final guidance on informed consent, while not incorporating all Common Rule changes, explicitly references differences and provides pathways for navigating them [61]

Diagram 2: Regulatory Harmonization Timeline and Future Directions

The regulatory landscape governing informed consent is evolving toward greater alignment between FDA and Common Rule requirements. The recent harmonization of minimal risk waiver criteria provides a template for future convergence efforts. For researchers and IRBs, adopting a proactive approach to consent documentation—one that incorporates the most protective elements of both frameworks—creates a efficient path to compliance while maintaining rigorous ethical standards for human subjects protection.

Successful navigation of this landscape requires ongoing vigilance to regulatory updates and a commitment to implementing consent processes that prioritize subject understanding and autonomy while satisfying complex, and sometimes divergent, regulatory requirements.

Within the framework of Common Rule research, the institutional review board (IRB) serves as the critical safeguard for protecting the rights and welfare of human subjects. A properly constituted IRB is formally designated to review and monitor biomedical research, possessing the authority to approve, require modifications in, or disapprove research [63]. Central to this protective role is the IRB's rigorous assessment of informed consent procedures. The informed consent process is designed to assure that subjects enter research voluntarily with sufficient understanding of the risks and benefits [9]. Under specific limited conditions, however, regulations permit IRBs to waive or alter standard informed consent requirements. This application note details the five-criteria assessment framework that IRBs must document when approving such waivers or alterations for minimal risk clinical investigations.

Regulatory Foundation and the Five-Criteria Assessment

The Food and Drug Administration (FDA) has amended its regulations to implement provisions of the 21st Century Cures Act, creating harmony with the revised Common Rule (45 CFR 46) [43]. This final rule, effective January 22, 2024, permits an IRB to waive or alter certain informed consent elements, or to waive the requirement to obtain informed consent entirely, for certain FDA-regulated minimal risk clinical investigations [43]. For an IRB to approve such a waiver or alteration, it must find and document that the investigation satisfies five specific criteria established in the regulations.

Table 1: The Five-Criteria Assessment for IRB Waiver or Alteration of Informed Consent

Criterion Number	Regulatory Requirement	Documentation Focus for IRB
1	The research involves no more than minimal risk to the subjects [43].	Document the IRB's risk assessment and justification for determining the investigation poses no more than minimal risk to subjects.
2	The waiver or alteration will not adversely affect the rights and welfare of the subjects [43].	Provide analysis of how subjects' rights and welfare remain protected despite the waiver or alteration of consent.
3	The research could not practicably be carried out without the waiver or alteration [43].	Justify the impracticability of conducting the research with standard informed consent.
4	Whenever appropriate, the subjects will be provided with additional pertinent information after participation [43].	Describe plans, if appropriate, for debriefing subjects or providing additional information post-participation.
5	The research is not subject to an independent requirement for consent under other regulations or laws [43].	Confirm that no other applicable laws or regulations mandate informed consent for the specific research context.

The diagram below illustrates the logical workflow an IRB must follow when reviewing a request for a waiver or alteration of informed consent.

IRB Waiver Approval Workflow

Experimental Protocol for IRB Assessment Documentation

The following protocol provides a detailed methodology for IRB administrators and members to consistently execute and document the five-criteria assessment.

Scope and Application

This protocol applies to the initial review of any FDA-regulated clinical investigation or research covered by the Common Rule where the investigator has requested a waiver or alteration of informed consent requirements on the basis that the study poses no more than minimal risk.

Pre-Review Submission Requirements

The investigator must submit a complete research protocol. For investigator-initiated studies, using a standardized protocol template, such as the HRP-503-TEMPLATE PROTOCOL -Biomedical, is recommended to ensure all necessary information is included [64]. The submission must contain a specific section justifying the waiver request against each of the five regulatory criteria.

IRB Review Procedure

Conducted Review: The review must be conducted at a convened meeting with a quorum of members present, including at least one member whose primary concerns are non-scientific [63]. Members with conflicting interests must abstain from deliberation and voting [63].
Criterion-by-Criterion Assessment: The IRB shall discuss and make a finding for each of the five criteria as outlined in Table 1.
Documentation in Minutes: The IRB's findings for each criterion, along with the rationale for these findings, must be documented in the meeting minutes. The minutes must reflect the members' awareness of the study details and context [63].

Key Deliberative Considerations by Criterion

Criterion 1 (Minimal Risk): The IRB must assess whether the probability and magnitude of harm or discomfort anticipated in the research are not greater than those encountered in daily life or during routine physical or psychological examinations [43].
Criterion 2 (Rights and Welfare): The IRB must evaluate how a waiver impacts the subject's autonomy and well-being. This includes considering the protocol's provisions for protecting privacy and maintaining data confidentiality [65].
Criterion 3 (Impracticability): The investigator's justification must be scrutinized. "Impracticable" means that it is not feasible to conduct the research without the waiver; mere inconvenience or increased cost is typically insufficient.
Criterion 4 (Post-Participation Information): The IRB must determine if providing subjects with additional information after their participation is appropriate for the scientific design and risk profile of the study. If deemed appropriate, the protocol must detail the nature and timing of this information.
Criterion 5 (No Independent Requirement): The IRB must verify that the research is not subject to other consent mandates, such as those that might be imposed by state or local laws for certain types of research.

Post-Review Actions

Approval: If all five criteria are met, the IRB can approve the waiver or alteration. The approval and the documented findings for each criterion must be communicated to the investigator in writing.
Disapproval or Modifications Required: If any single criterion is not met, the IRB must not approve the waiver. The IRB may provide the investigator with the rationale and an opportunity to address deficiencies, requiring a subsequent re-review.

Table 2: Key Research Reagent Solutions for IRB Applications and Waiver Justifications

Tool Name	Function	Application in Waiver Submissions
Biomedical Protocol Template (e.g., HRP-503) [64]	Standardized structure for drafting a research protocol.	Ensures the research plan is clearly defined and contains all information necessary for the IRB to assess the five waiver criteria.
Registry/Repository Protocol Template (e.g., HRP-503a) [64]	Template specifically for studies involving the collection of data or biospecimens.	Critical for waiver requests in minimal risk secondary research using identifiable information or biospecimens, as it helps structure the required information for regulatory determinations.
Checklists for Vulnerable Populations [64]	Guides for addressing additional regulatory requirements.	If a waiver is sought for research that may involve vulnerable subjects, these checklists ensure the protocol includes necessary additional safeguards, supporting Criterion 2.
FDA IRB Guidance Documents [63]	Agency interpretations of regulations on IRB functions and informed consent.	Provides authoritative reference for IRB members and investigators to ensure the waiver assessment aligns with current FDA thinking and regulatory requirements.
Electronic Code of Federal Regulations (eCFR) [9]	Direct access to the official text of federal regulations, including 45 CFR 46.116.	The primary source for verifying the exact regulatory language governing waivers and alterations of informed consent.

The implementation of the five-criteria assessment framework represents a significant harmonization between FDA regulations and the Common Rule, facilitating ethical minimal risk research that would otherwise be impracticable. For researchers and drug development professionals, a thorough understanding of these criteria is paramount when designing studies that may qualify for a waiver or alteration. For IRB members and administrators, meticulous application and documentation of this assessment are non-negotiable responsibilities. Rigorous documentation not only ensures regulatory compliance but also creates a transparent audit trail that demonstrates the IRB's unwavering commitment to its primary mission: protecting the rights and welfare of human subjects.

The Revised Common Rule, effective January 21, 2019, introduced a pivotal new mandate aimed at enhancing transparency in clinical research: the public posting of informed consent forms used for certain clinical trials [3]. This requirement, outlined in 45 CFR 46.116(h), represents a significant shift toward greater accountability and patient-centricity in the research ecosystem [58]. It creates a public repository of consent documents that can serve as educational resources for potential research participants, ethicists, and study designers, while also providing a mechanism for verifying that trials are conducted with proper informed consent [58].

This provision operates alongside other clinical trial transparency mandates, such as those specified in Section 801 of the Food and Drug Administration Amendments Act (FDAAA 801), which governs the registration and results reporting of applicable clinical trials on ClinicalTrials.gov [66]. Understanding the interplay between these regulatory frameworks is essential for research compliance. These mandates collectively address growing calls for transparency in trial communications and reflect an evolving ethical landscape where participant rights and public accountability are paramount [66].

Regulatory Framework and Scope

Definition of a Clinical Trial

The consent form posting requirement applies specifically to studies meeting the Revised Common Rule's definition of a clinical trial: "a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of the interventions on biomedical or behavioral health-related outcomes" [58] [67]. This broad definition encompasses not only traditional drug and device trials but also behavioral and social intervention studies that assess health-related outcomes.

Applicability Criteria

The mandate applies to federally-funded clinical trials conducted or supported by any of the 20 departments and agencies that have adopted the Revised Common Rule [67]. Importantly, the requirement does not currently apply to studies regulated exclusively by the FDA or funded by the Department of Justice, as these entities have not yet adopted the Revised Common Rule [3]. For multi-site research, the prime awardee typically bears responsibility for compliance, though another participating institution may post the form with written agreement from the awardee [67].

Table: Regulatory Frameworks Governing Consent Form Posting

Regulatory Framework	Key Requirements	Applicable Studies
Revised Common Rule [45 CFR 46.116(h)]	Post consent form on federal website after trial closed to recruitment	Federally-funded clinical trials (excluding FDA-regulated and DOJ-funded)
FDAAA 801 [66]	Register trials, report results, and (proposed) post consent forms	Applicable Clinical Trials (ACTs) of drugs, biologics, and devices

Detailed Posting Requirements

Posting Timeline and Version Control

The consent form posting mandate specifies precise timing requirements. The informed consent document must be posted on a designated federal website after the clinical trial is closed to recruitment, and no later than 60 days after the last study visit by any subject as required by the protocol [58]. For studies registered on ClinicalTrials.gov, the informed consent form should be uploaded simultaneously when the Overall Status is updated to reflect that the trial is closed to recruitment [58].

Regarding version control, the posted document must be an IRB-approved version that was actually used to enroll participants in the clinical trial [58]. Specifically, researchers must post "the most recent IRB-approved version that was used to enroll a participant" [58]. This ensures that the publicly available document accurately reflects what participants consented to during the enrollment process.

Approved Posting Venues

The Revised Common Rule requires posting on "a publicly available federal website" [58]. The Office for Human Research Protections has identified two specific platforms that satisfy this requirement:

ClinicalTrials.gov: For studies that are already registered on this platform, the consent form must be posted here [58]
Regulations.gov: Specifically, the docket folder with Docket ID: HHS-OPHS-2018-0021 serves as an alternative posting venue [58]

Each platform has specific technical requirements. For ClinicalTrials.gov, the consent form must include a cover page with the study title, document date (matching the IRB approval date), and NCT number, and the complete document must be saved in PDF/A format for upload [58]. For Regulations.gov, the consent form is submitted as a comment to the specified docket folder following OHRP instructions [58].

Formatting and Redaction Protocols

The posting requirement specifies that researchers must post an unsigned, IRB-approved stamped copy of the consent form [67]. This protects participant privacy while ensuring document authenticity. Regarding redactions, the regulations state that "any requests to redact certain information prior to posting must be submitted to the Federal department or agency supporting the clinical trial" [58]. Only the supporting federal agency may permit or require redactions; researchers cannot make independent determinations about removing content from the posted documents.

Compliance Protocol and Workflow

Implementing a systematic approach to consent form posting ensures consistent compliance with regulatory requirements. The following workflow outlines key decision points and actions from study initiation through posting completion.

Compliance Monitoring and Documentation

The prime awardee bears ultimate responsibility for ensuring adherence to posting requirements, particularly in multi-site trials [67]. Institutions should implement tracking mechanisms that monitor two critical milestones: when a study closes to recruitment, and when the final study visit occurs. The 60-day posting deadline is calculated from the latter milestone [58].

Documentation of compliance should include:

The specific version of the consent form posted
Date of posting
URL where the document is accessible
Confirmation that the posted document matches an IRB-approved version used for enrollment

This documentation may be subject to audit by funding agencies and institutional compliance offices.

Integration with Broader Regulatory Obligations

Relationship with FDAAA 801 Requirements

The consent form posting requirement under the Common Rule intersects with broader clinical trial transparency mandates, particularly FDAAA 801, which governs the registration and results reporting of Applicable Clinical Trials (ACTs) on ClinicalTrials.gov [66]. While these are distinct regulatory frameworks, they share overlapping compliance mechanisms.

Recent updates to FDAAA 801 implementation have introduced similar consent form posting requirements for a broader range of clinical trials [66]. The 2025 FDAAA 801 Final Rule changes include "mandatory posting of informed consent documents" for all Applicable Clinical Trials, expanding beyond the federally-funded trials covered by the Common Rule [66]. This regulatory convergence means many trials will need to comply with both sets of requirements.

Table: Comparison of Consent Form Posting Requirements

Aspect	Common Rule Requirement	FDAAA 801 Requirement
Applicable Studies	Federally-funded clinical trials [58]	Applicable Clinical Trials (ACTs) of drugs, biologics, devices [66]
Posting Timeline	After closure to recruitment, ≤60 days after last study visit [58]	Specific timeline integrated with results reporting [66]
Posting Venue	ClinicalTrials.gov or Regulations.gov [58]	ClinicalTrials.gov [66]
Enforcement	Agency-specific compliance mechanisms	Civil monetary penalties up to $15,000 per day [66]

Beyond posting requirements, the Revised Common Rule introduced significant changes to informed consent content and process. These include:

Key Information Requirement: A concise presentation of key information that would help a prospective subject understand why they might or might not want to participate must appear at the beginning of the consent document [3]
New Basic Elements: Additional required elements include statements about possible commercial profit from biospecimens, disclosure of clinically relevant research results, and whether the research will include whole genome sequencing [3]
Broad Consent Option: For storage and maintenance of identifiable private information or biospecimens for secondary research use, the rules allow for "broad" consent for future, unspecified research [12]

These enhancements to consent content work in tandem with the posting requirement to improve transparency and participant understanding.

Research Reagent Solutions for Compliance

Table: Essential Materials for Consent Form Posting Compliance

Tool Category	Specific Solutions	Function in Compliance Process
Document Management	IRB-approved stamped consent forms (PDF/A)	Ensures posting of correct, verifiable documents with institutional approval [58]
Regulatory Platforms	ClinicalTrials.gov PRS, Regulations.gov	Official federal websites mandated for consent form posting [58]
Version Control Systems	Electronic trial master files (eTMF)	Tracks IRB-approved consent form versions used for participant enrollment [58]
Formatting Tools	PDF/A conversion software	Creates archivable digital formats required for ClinicalTrials.gov uploads [58]
Cover Page Templates	Standardized cover sheets with NCT number	Provides required header information for ClinicalTrials.gov submissions [58]

The public posting of informed consent forms represents a significant advancement in clinical trial transparency, aligning with broader ethical imperatives for openness in human subjects research. Successful implementation requires researchers to develop robust systems for tracking study milestones, managing document versions, and executing timely submissions to designated federal websites.

As regulatory frameworks continue to evolve, with FDAAA 801 incorporating similar requirements for a broader range of trials, researchers and institutions must maintain vigilance in adapting their compliance approaches [66]. The convergence of these mandates signals an enduring trend toward greater transparency that serves the interests of research participants, the scientific community, and the public. Proper implementation not only fulfills regulatory obligations but also demonstrates institutional commitment to ethical research practices and respect for participant autonomy.

Informed consent is a foundational ethical requirement for human subjects research governed by the Common Rule (45 CFR Part 46), which mandates that prospective participants receive adequate information about research studies to make voluntary, informed decisions [68]. However, research consistently demonstrates that traditional Informed Consent Forms (ICFs) often fail to achieve their purpose due to excessive complexity and poor readability [68] [69]. Most ICFs are written at reading grade levels far exceeding the recommended 8th-grade level and participants' actual reading abilities, creating significant barriers to comprehension and voluntary participation [69] [70]. The 2018 updates to the Common Rule specifically addressed this concern by requiring that consent forms begin with a "concise and focused presentation of the key information" most likely to assist prospective subjects in understanding reasons for or against participation [68]. This regulatory evolution creates both an obligation and an opportunity for researchers to adopt emerging technologies, particularly Artificial Intelligence (AI), to enhance the consent process while maintaining compliance.

Natural Language Processing for Readability Enhancement

Advanced AI, particularly Large Language Models (LLMs) like GPT-4, demonstrate remarkable capability in transforming complex consent language into more accessible formats. Research reveals two primary methodological approaches for AI-assisted simplification, each with distinct advantages as quantified in Table 1 [70].

Table 1: Performance Comparison of AI Summarization Techniques for Informed Consent Forms

Performance Metric	Direct Summarization	Sequential Summarization	Original ICF
Flesch-Kincaid Grade Level	9.1 (average)	8.2 (average)	12.3 (average)
Readability Improvement	~3 grade levels	~4 grade levels	Baseline
Accuracy/Completeness	Moderate	Higher	Complete but inaccessible
Technical Jargon	Significantly reduced	Maximally reduced	High frequency
Patient Comprehension	Substantially improved	Maximally improved	Limited

The sequential summarization approach employs a multi-stage refinement process where the LLM first extracts key sections from ICFs (study objectives, procedures, risks, benefits), then systematically restructures and simplifies complex medical terminology while preserving essential information [70]. This method has proven particularly effective for oncology trials where complexity and emotional burden can overwhelm patients [70]. Empirical studies demonstrate that summaries generated through this process reduce readability scores from grade 12.3 to 8.2, moving from college-level to the recommended 8th-grade reading level [70].

Validation Through Comprehension Assessment

Beyond simplification, LLMs can generate multiple-choice question-answer pairs (MCQAs) to assess participant understanding of consent materials [70]. When evaluated against human-annotated responses, AI-generated comprehension questions demonstrated high concordance rates, providing researchers with efficient tools to identify areas of persistent confusion and tailor consent discussions accordingly [70]. In survey responses, over 80% of participants reported enhanced understanding of clinical trials when using AI-simplified materials compared to traditional consent documents [70].

Objective: To transform technically complex ICFs into accessible, patient-friendly summaries using a structured AI approach while preserving accuracy and essential information.

Materials:

Source ICF (typically from ClinicalTrials.gov or institutional repository)
LLM platform with API access (e.g., GPT-4)
Readability assessment tool (e.g., Flesch-Kincaid integrated in Microsoft Word)
Validation questionnaire template

Methodology:

Content Extraction Phase: Prompt the LLM to identify and extract key ICF sections: study objectives, procedures/alternatives, risks, costs, potential benefits, and confidentiality provisions [70].
Progressive Simplification Phase: Process extracted content through sequential refinement stages:
- Stage 1: Replace medical terminology with plain language equivalents (e.g., "myocardial infarction" → "heart attack")
- Stage 2: Restructure complex sentence syntax to active voice and shorter constructions (<15-20 words)
- Stage 3: Reorganize content to prioritize information most relevant to decision-making
Validation Phase:
- Assess readability using Flesch-Kincaid and similar metrics [71]
- Generate MCQAs to test comprehension of key concepts
- Submit to expert review (clinicians, ethicists, IRB members) for accuracy verification
- Conduct patient testing with target population representatives

Quality Control: Implement human oversight at each phase to identify and correct AI "hallucinations" or inaccurate simplifications. Document all modifications for IRB review [70].

Protocol 2: RUAKI Indicator Tool Development and Validation

Objective: To develop and validate a reliable tool for evaluating and improving readability, understandability, and actionability of key information sections in research ICFs [68].

Materials:

Candidate ICFs for testing (minimum of 10 recommended)
Pool of raters familiar with informed consent process (minimum 20 recommended)
Statistical analysis software (e.g., R, SPSS)
Focus group participants from target populations (minimum 15 recommended)

Methodology:

Item Generation: Conduct comprehensive literature review to identify candidate measures (87 items initially identified) [68].
Expert Review: Convene multidisciplinary advisory group (health literacy specialists, plain language writers, clinical investigators, IRB representatives, community advocates) to assess face and content validity [68].
Reliability Testing:
- Conduct multiple rounds of testing with rater groups
- Calculate inter-rater agreement using Fleiss' Kappa and Gwet's AC1
- Calculate intra-rater agreement using Cohen's Kappa
- Refine or eliminate items to improve agreement between rounds
Validation Phase:
- Convene focus groups with potential research participants
- Compare tool ratings with participant comprehension metrics
- Establish construct validity through statistical analysis

Outcome Measures: The final Readability, Understandability and Actionability of Key Information (RUAKI) Indicator comprises 18 items demonstrating substantial inter-rater agreement (Fleiss' Kappa = 0.73, Gwet's AC1 = 0.77) and intra-rater agreement (Cohen's Kappa = 0.74, Gwet's AC1 = 0.84) [68].

Regulatory and Ethical Considerations

The integration of AI into the informed consent process requires careful attention to regulatory compliance and ethical safeguards, particularly within Common Rule research. Key considerations include:

Transparency Requirements: Investigators must disclose AI usage in consent documents, explaining in lay terms the AI's role, data access, and limitations [72]. Participants should understand what AI tools will access their data and how it will be used [72] [73].

Consent Process Integrity: AI tools should not obtain consent autonomously; a trained human investigator must oversee the process to ensure meaningful understanding [72]. The University of Tennessee's Human Research Protection Program explicitly prohibits AI tools from obtaining "automatic informed consent" without human presence [72].

Data Privacy Protections: When AI processes participant data, investigators must implement safeguards including encryption, access controls, and minimal data collection [72] [73]. Special restrictions apply to sensitive data (e.g., biospecimens, genomic data, mental health records) [72] [73].

Bias Mitigation: Researchers should develop plans to continuously evaluate AI tools for potential biases and ensure equitable treatment across diverse populations [72].

Table 2: Research Reagent Solutions for AI-Enhanced Consent Processes

Tool Category	Specific Solution	Function/Application	Regulatory Status
Readability Assessment	Flesch-Kincaid Grade Level	Quantifies reading difficulty; integrated in Microsoft Word	Widely accepted by IRBs [71]
Validation Instrument	RUAKI Indicator	18-item tool evaluating readability, understandability, actionability	Validated with evidence of reliability [68]
Plain Language Framework	PRISM (Program for Readability in Science and Medicine)	Provides principles and strategies for clear communication	Recommended by NIH and CDC [71]
LLM Platforms	GPT-4 (with appropriate safeguards)	Sequential summarization of complex ICFs	Requires IRB review and human oversight [72] [70]
Comprehension Assessment	AI-generated MCQAs	Validates participant understanding of key concepts	Demonstrates high concordance with human annotation [70]

AI technologies offer transformative potential for addressing longstanding challenges in informed consent documentation and process optimization within Common Rule research. Through systematic language simplification, comprehension assessment, and process enhancement, AI can help bridge the gap between regulatory requirements and genuine participant understanding. However, successful implementation requires a balanced approach that leverages AI efficiencies while maintaining essential human oversight and ethical safeguards. The emerging paradigm positions AI as a powerful tool to augment—not replace—researcher judgment, creating consent processes that truly respect participant autonomy while advancing scientific progress. As these technologies evolve, continued attention to validation, regulation, and ethical implementation will be essential to realizing their full potential for improving human subjects research.

Conclusion

The revised Common Rule's informed consent requirements represent a significant evolution toward more transparent, participant-centered research practices. By implementing the key information presentation, addressing health literacy challenges, and adapting to regulatory harmonization between Common Rule and FDA standards, researchers can enhance participant comprehension and ethical safeguards. Future directions will likely see increased technological integration through electronic consent platforms and AI-assisted simplification tools, continued regulatory alignment, and greater emphasis on practical implementation strategies for complex consent scenarios involving biospecimens and genomic data. Mastering these requirements not only ensures regulatory compliance but fundamentally strengthens the trust and ethical foundation essential to advancing biomedical research.

Common Rule Informed Consent: Complete Guide to Documentation Requirements for Researchers

Common Rule Informed Consent: Complete Guide to Documentation Requirements for Researchers

Abstract

Understanding the Revised Common Rule: Core Principles and Mandatory Consent Elements

Major Regulatory Changes and Implementation Timeline

Detailed Analysis of Informed Consent Documentation Changes

New General Requirements for the Consent Process

New and Modified Consent Form Elements

Protocol for Implementing Revised Informed Consent Documents

Workflow for Consent Form Development and IRB Review

The Researcher's Toolkit for Common Rule Compliance

Additional Significant Regulatory Modifications

Exemption Categories and Limited IRB Review

Changes to Continuing Review and sIRB Requirements

Transition Provisions and Legacy Studies

Regulatory Framework and the Common Rule

Core Regulatory Requirements

Documentation Requirements Under the Common Rule

Operationalizing the Standard: Practical Protocols

Protocol 1: Information Materiality Assessment

Protocol 2: Consent Process Optimization

Special Research Contexts

Vulnerable Populations and Consent Modifications

Biorepository and Genetic Research

Research Reagent Solutions for Consent Research

The Critical Ninth Element: Biospecimens and Private Information

Regulatory Specification

Practical Implementation

Experimental Protocol for Informed Consent Documentation

Protocol: Development of Common Rule-Compliant Consent Documents

Visualization: Informed Consent Decision Pathway

Research Reagent Solutions for Consent Documentation

Additional Considerations for Special Circumstances

Broad Consent as an Alternative

Waiver of Consent Requirements

Special Populations and Contexts

New Requirements for Identifiable Private Information and Biospecimens

Ethical Foundations and Consent Requirements

Core Ethical Principles

Special Consent Considerations for Biospecimen Research

Recent Regulatory Changes and Security Measures

New NIH Restrictions on International Sharing

Exceptions to Sharing Restrictions

Compliance Protocols for Researchers

Informed Consent Documentation Protocol

Biospecimen Sharing and Transfer Protocol

Research Reagent Solutions and Essential Materials

Data Sharing and Privacy Considerations

Public Health Surveillance Activities

Definition and Regulatory Basis

Experimental Protocol: Distinguishing Public Health Surveillance from Research

Journalism, Biographical, and Historical Activities

Definition and Regulatory Basis

Experimental Protocol: Assessing Projects Involving Interviews or Observations

Operational Activities: Quality Improvement and Classroom Exercises

Definition and Regulatory Basis

The Scientist's Toolkit: Research Reagent Solutions

Creating Compliant Consent Documents: Practical Strategies and Template Implementation

Core Principles and Regulatory Framework

The Purpose of the Key Information Section

Regulatory Scope and Flexibility

Experimental Protocol: Developing and Validating the Key Information Section

Phase 1: Content Identification and Scoping

Phase 2: Content Structuring and Drafting

Phase 3: Validation and Refinement

Data Presentation and The Scientist's Toolkit

Quantitative Data: Core Content Elements

The Scientist's Toolkit: Research Reagent Solutions

Visualization Protocol: Logical Pathway for Consent Documentation

The Health Literacy Problem in Informed Consent

Impact of Inadequate Health Literacy

Assessing Readability: Methodologies and Tools

Quantitative Readability Assessment Protocol

Qualitative Formatting Assessment Protocol

Protocol for Revision and Simplification

Core Revision Workflow

Detailed Revision Techniques

Pre- and Post-Revision Example

The Scientist's Toolkit: Research Reagent Solutions

Compliance with the Revised Common Rule