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2 INFORMED CONSENT FORM AND PROCESS: GUIDANCE DOCUMENT 3

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DIVISION OF AIDS (DAIDS) 6

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VERSION XXX 11

SEPTEMBER 2018 12

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1. INTRODUCTION15

The Division of AIDS (DAIDS) has established an informed consent (IC) manual to provide guidance to 16 relevant stakeholders regarding the requirements for the development and implementation of informed 17 consent forms (ICFs), Informed Consent (IC) documentation, and the informed consent process to ensure 18 that all clinical research supported and/or sponsored by National Institute of Allergy and Infectious 19 Diseases (NIAID) (DAIDS) is in compliance with the U.S. Department of Health and Human Services (HHS) 20 regulations; the International Conference on Harmonisation (ICH), Guidance for Industry, E6 R2 Good 21 Clinical Practice; DAIDS Clinical Research Policies; and when applicable, the U.S. Food and Drug 22 Administration (FDA) regulations. The manual identifies required content areas for ICFs and provides 23 guidance as to the level of detail required. It references regulations, guidance documents, NIH, NIAID, 24 and DAIDS policies and standard procedures, and current best practices that should be consulted during 25 the development of ICF(s) and related documents, and during the implementation of these documents. 26 All DAIDS policies, standard procedures, guidance documents, and manuals referenced in this guidance 27 document/manual can be accessed at the NIAID website: DAIDS Clinical Research Policies and Standard 28 Procedures Documents. 29

Along with the Informed Consent Process Policy and the Informed Consent Process Guidance, there are 30 tools such as the DAIDS Informed Consent Templates and Informed Consent SOP Examples to assist 31 protocol teams, protocol chairs/co-chairs, DAIDS networks, staff, and other relevant stakeholders with 32 the development of protocol sample ICFs and site-specific ICFs. There are also informed consent 33 companion documents such as the Protocol Documents Policy and Manual, the Essential Documents 34 Policy and Guidance Document, and the Protocol Registration Policy and Manual. 35

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TABLE OF CONTENTS 36

1. INTRODUCTION ......................................................................................................................... 2 37

2. DEFINITIONS .............................................................................................................................. 6 38

3. LIST OF ABBREVIATION ............................................................................................................ 10 39

4. GUIDANCE FOR DEVELOPING PROTOCOL INFORMED CONSENT FORMS .................................... 12 40

4.1. ETHICAL FOUNDATION – THE BELMONT REPORT ........................................................................... 12 41 4.2. HHS, FDA, AND ICH E6 (R2) INFORMED CONSENT REGULATORY REQUIREMENTS ................................ 12 42 4.3. BASIC ELEMENTS OF INFORMED CONSENT ................................................................................... 13 43

4.3.1. PURPOSE AND PROCEDURES ..................................................................................................... 13 44 4.3.2. RISKS AND DISCOMFORTS ........................................................................................................ 14 45

4.3.2.1. RISK INFORMATION ASSOCIATED WITH THE STUDY PRODUCT(S)/INTERVENTION(S)/STRATEGY(IES) TO BE46 INCORPORATED INTO IC DOCUMENTS INCLUDES: ...................................................................................... 14 47 4.3.2.2. ADDITIONAL RISK INFORMATION CONSIDERATIONS TO BE ADDRESSED: .......................................... 15 48

4.3.3. BENEFITS .............................................................................................................................. 16 49 4.3.4. ALTERNATIVE TREATMENT AND PROCEDURES .............................................................................. 16 50 4.3.5. CONFIDENTIALITY ................................................................................................................... 17 51 4.3.6. COMPENSATION, TREATMENT OF INJURY .................................................................................... 18 52 4.3.7. PROBLEMS AND QUESTIONS ..................................................................................................... 19 53 4.3.8. VOLUNTARY PARTICIPATION STATEMENT .................................................................................... 19 54

4.4. ADDITIONAL ELEMENTS OF INFORMED CONSENT AS PER §46.116(B) AND §50.25(B) ............................ 20 55 4.4.1. RISKS TO PARTICIPANT/RISKS TO FETUS DURING PREGNANCY ......................................................... 20 56 4.4.2. INVOLUNTARY TERMINATION OF STUDY PARTICIPATION ................................................................. 21 57 4.4.3. ADDITIONAL COSTS ................................................................................................................ 21 58 4.4.4. EARLY WITHDRAWAL FROM STUDY/ ORDERLY TERMINATION ......................................................... 22 59 4.4.5. NEW FINDINGS ...................................................................................................................... 22 60 4.4.6. NUMBER OF PARTICIPANTS ...................................................................................................... 23 61

4.5. ADDITIONAL PREGNANCY-RELATED INFORMED CONSENT FORM REQUIREMENTS AND CONSIDERATIONS ...... 23 62 4.5.1. PREGNANCY PREVENTION CONSIDERATIONS ................................................................................ 23 63 4.5.2. SUBSEQUENT PREGNANCY CONSIDERATIONS ............................................................................... 23 64 4.5.3. PREGNANCY OUTCOME MONITORING CONSIDERATIONS ................................................................ 24 65 4.5.4. REPLACEMENT FEEDING/BREASTFEEDING ICF CONSIDERATIONS ..................................................... 24 66

4.6. ADDITIONAL REGULATORY, POLICY, AND MISCELLANEOUS IC DOCUMENT REQUIREMENTS AND67 CONSIDERATIONS ............................................................................................................................. 25 68

4.6.1. U.S. CERTIFICATES OF CONFIDENTIALITY ..................................................................................... 25 69 4.6.2. U.S. CLINICALTRIALS.GOV CONSIDERATIONS ............................................................................... 26 70 4.6.3. EUROPEAN GENERAL DATA PROTECTION REGULATION (GDPR) ...................................................... 26 71 4.6.4. U.S. GENETIC INFORMATION NONDISCRIMINATION ACT (GINA) .................................................... 27 72 4.6.5. U.S. HEALTH INSURANCE PORTABILITY AND ACCOUNTABILITY ACT OF 1996 (HIPAA PRIVACY RULE) .... 27 73 4.6.6. INTERNATIONAL COMMITTEE OF MEDICAL JOURNAL EDITORS (ICMJE) REQUIREMENTS ...................... 27 74 4.6.7. U.S. NIH DATA-SHARING POLICY ............................................................................................. 28 75 4.6.8. U.S. NIH GENOMIC DATA-SHARING (GDS) POLICY ..................................................................... 28 76 4.6.9. U.S. NIH POLICY ON DISSEMINATION OF NIH-FUNDED CLINICAL TRIAL INFORMATION ....................... 29 77

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4.6.10. POST-TRIAL ACCESS CONSIDERATIONS ....................................................................................... 29 78 4.6.11. STORED SAMPLES AND ASSOCIATED DATA CONSIDERATIONS .......................................................... 30 79 4.6.12. INCIDENTAL FINDINGS (IFS) CONSIDERATIONS ............................................................................. 31 80 4.6.13. INDIVIDUAL RESEARCH RESULTS (IRRS) CONSIDERATIONS .............................................................. 32 81

5. GUIDANCE FOR SITE-SPECIFIC INFORMED CONSENT DOCUMENTS ............................................ 32 82

5.1. SITE-SPECIFIC ICF(S) .............................................................................................................. 32 83 5.2. ADDITIONAL REGULATIONS AND NIH POLICIES ............................................................................. 33 84 5.3. IRB/EC/RE CONSIDERATIONS ................................................................................................. 34 85 5.4. KEY CONCEPTS/ISSUES ........................................................................................................... 34 86

6. THE INFORMED CONSENT PROCESS ......................................................................................... 35 87

6.1. RECRUITMENT ...................................................................................................................... 35 88 6.2. ELIGIBILITY .......................................................................................................................... 35 89 6.3. ONGOING CONSENT PROCESS .................................................................................................. 36 90 6.4. STUDY CLOSURE ................................................................................................................... 36 91 6.5. DAIDS INFORMED CONSENT PROCESS REQUIREMENTS................................................................... 37 92

6.5.1. INFORMED CONSENT PROCESS SOP AND DOCUMENTATION ........................................................... 37 93 6.5.2. FDA FORM 1572/DAIDS IOR FORM – DELEGATION OF DUTIES INCLUDING INFORMED CONSENT ....... 38 94 6.5.3. DOCUMENT MAINTENANCE ..................................................................................................... 38 95 6.5.4. CLINICAL QUALITY MANAGEMENT PLANS AND THE INFORMED CONSENT PROCESS (CQMP) ................ 39 96

6.6. NOTIFYING PARTICIPANTS OF NEW FINDINGS OR CHANGES TO THE STUDY ........................................... 39 97 6.6.1. NEW FINDINGS ...................................................................................................................... 40 98

6.6.2. STUDY AMENDMENTS FULL VERSION PROTOCOL AMENDMENT OR LETTERS OF AMENDMENT (LOA) ... 40 99 6.6.3. DAIDS DEAR PARTICIPANT LETTERS OR PARTICIPANT NOTIFICATIONS .............................................. 41 100 6.6.4. ADDENDA ............................................................................................................................. 41 101 6.6.5. SCRIPTS ................................................................................................................................ 42 102

6.7. VULNERABLE POPULATIONS ..................................................................................................... 42 103 6.7.1. CHILDREN IN RESEARCH ........................................................................................................... 43 104

6.7.1.1. ASSENT OF A MINOR ........................................................................................................... 44 105 6.7.1.2. PARENTAL/GUARDIAN PERMISSION ....................................................................................... 45 106 6.7.1.3. WARDS ............................................................................................................................ 46 107

6.7.2. PREGNANT WOMEN, FETUSES, AND NEONATES IN RESEARCH ......................................................... 46 108 6.7.2.1. PREGNANT WOMEN AND FETUSES ........................................................................................ 47 109 6.7.2.2. NEONATES ........................................................................................................................ 47 110

6.7.3. PRISONERS IN RESEARCH ......................................................................................................... 48 111 6.7.4. DIMINISHED CAPACITY/IMPAIRED CONSENT CAPACITY/DECISIONALLY IMPAIRED PERSONS IN RESEARCH . 49 112 6.7.5. LOCAL LANGUAGE SPEAKERS .................................................................................................... 50 113 6.7.6. ILLITERATE PERSONS ................................................................................................................ 51 114

7. DOCUMENTATION OF INFORMED CONSENT ............................................................................ 52 115

7.1. LEGAL SIGNATURE/THUMBPRINT/MARK/ELECTRONIC SIGNATURE ...................................................... 52 116 7.2. LEGALLY AUTHORIZED REPRESENTATIVE (LAR) ............................................................................. 53 117 7.3. IMPARTIAL WITNESS .............................................................................................................. 53 118

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7.4. SHORT FORM ICF/INFORMED CONSENT SUMMARY/LONG FORM ICF ................................................ 54 119 7.5. WAIVER AND ALTERATION OF SOME ELEMENTS OF INFORMED CONSENT OR PARENTAL PERMISSION FOR NON-120 FDA REGULATED STUDIES .................................................................................................................. 55 121 7.6. WAIVER OF DOCUMENTATION OF INFORMED CONSENT OR PARENTAL PERMISSION ................................ 55 122 7.7. ELECTRONIC INFORMED CONSENT GUIDANCE ............................................................................... 56 123

7.7.1. EIC PROCESS ......................................................................................................................... 56 124 7.7.2. DOCUMENTING EIC ................................................................................................................ 56 125 7.7.3. EIC CONFIDENTIALITY .............................................................................................................. 57 126 7.7.4. EIC ASSENT ........................................................................................................................... 57 127 7.7.5. EIC IRB/EC APPROVAL ........................................................................................................... 57 128

8. INFORMED CONSENT CONSIDERATIONS UNDER THE REVISED COMMON RULE ........................ 58 129

8.1. NEW REQUIREMENTS UPON IMPLEMENTATION OF THE REVISED FINAL RULE/COMMON RULE (45 CFR 46) .. 58 130 8.1.1. EXPANDED DEFINITION OF “LEGALLY AUTHORIZED REPRESENTATIVE” (LAR) ..................................... 58 131 8.1.2. CONCISE SUMMARY WITH “KEY INFORMATION” ........................................................................... 58 132 8.1.3. NEW REQUIRED ELEMENTS OF CONSENT .................................................................................... 58 133 8.1.4. BROAD CONSENT AND SECONDARY RESEARCH ............................................................................. 59 134 8.1.5. INCIDENTAL FINDINGS AND INDIVIDUAL RESEARCH RESULTS DISCLOSURE FROM SECONDARY RESEARCH135 WITH STORED BIOSPECIMENS ................................................................................................................... 60 136

9. OTHER ..................................................................................................................................... 61 137

9.1. DAIDS INFORMED CONSENT TEMPLATES .................................................................................... 61 138 9.2. DAIDS THERAPEUTICS RESEARCH PROGRAM (TRP) GUIDANCE FOR THE DEVELOPMENT OF PROTOCOL139 PROCEDURES TO ADDRESS REPRODUCTIVE RISK ....................................................................................... 61 140 9.3. INFORMED CONSENT PROCESS SOP EXAMPLES ............................................................................. 61 141

10. REFERENCES ............................................................................................................................ 62 142

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2. DEFINITIONS144

Children: Persons who have not attained the legal age for consent to treatments or procedures involved 145 in research, under the applicable law of the jurisdiction in which the research will be conducted. [45 CFR 146 §46.402(a) and 21 CFR §50.3(o)]147

Clinical Research: Research conducted on participants, material, or data of human origin with an 148 identifiable person as the source. Clinical research includes exploratory, behavioral, and observational 149 studies. All clinical trials are a subset of clinical research. (DAIDS) 150

Clinical Research Site (CRS): Distinct locations (e.g., hospitals, outpatient clinics, health maintenance 151 organizations, community health centers, private practices, clinics) supported and/or sponsored by 152 NIAID (DAIDS) where qualified professionals conduct clinical research in accordance with good clinical 153 practice (GCP) and applicable regulations. (DAIDS) 154

Clinical Research Site (CRS) Leader: The onsite senior research scientist responsible for the 155 administrative and scientific components of the CRS. The CRS leader is responsible for overall site 156 activities, including day-to-day operations, performance, and compliance at the site level. (DAIDS) 157

Clinical Trial: A research study in which one or more human subjects are prospectively assigned to one 158 or more interventions (which may include placebo or other control) to evaluate the effects of those 159 interventions on health-related biomedical or behavioral outcomes. (NIH) 160

Clinical Trial Insurance (CTI): Clinical trial liability insurance is a form of professional liability insurance 161 that protects clinical trial sponsors, investigators, institutions and administrators from risks they assume 162 when conducting clinical trials. The coverages of a policy are tailored to the policyholder’s specific needs 163 (i.e. trial protocol, informed consent, site locations, in country regulatory requirements, local ethics 164 committee requirements, etc.) and will vary in each instance. The policy may include coverage against 165 any bodily injury or property damage that a drug, device, or treatment may causes, as well as liability 166 coverage for any professional duties that an organization or its employees may have in the conduct of 167 performing the clinical trials. (DAIDS) 168

DAIDS Protocol Registration Office (PRO): An office within the DAIDS Regulatory Support Contract (RSC) 169 that receives and processes all protocol registration materials for DAIDS. (DAIDS) 170

DAIDS sponsored: NIAID (DAIDS) is responsible for the management (including submission of the 171 Investigational New Drug Application (IND) to the Food and Drug Administration (FDA) and the initiation 172 of the study) and oversight for the clinical trial or study. (DAIDS) 173

DAIDS supported: Clinical research activities would be considered to be supported by NIAID (DAIDS) 174 under one or more of the following circumstances: 175

• NIAID (DAIDS) provides direct funding to an institution via a grant, contract or cooperative agreement176 for the clinical research activities; or (b) indirect funding via a subcontract executed under a NIAID177 (DAIDS)-supported award to another institution; and/or178

• NIAID (DAIDS) provides other tangible support for the clinical research activities which includes, but179 is not limited to, regulatory support, site monitoring services, study product supply, management180 and distribution services; and/or181

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• NIAID (DAIDS)-supported central laboratory or data management center receives from other182 organization specimens or data for processing or analysis and the results or analyses will be used to183 direct involvement of some or all subjects in the conduct of the clinical research activities. (DAIDS)184

Fetus: The product of conception from implantation until delivery [45 CFR part 46.202(c)]. 185

Informed Consent Form (ICF): A document that provides the elements of informed consent as found in 186 21 CFR 50.25 and 45 CFR 46.116 (DAIDS) 187

Informed Consent (IC) Process: A process by which a participant voluntarily confirms his or her 188 willingness to participate in a particular study after having been informed of all aspects of the trial that 189 are relevant to the participant’s decision to participate. (ICH E6) 190

Incidental finding (IF): A finding concerning an individual research participant that has potential health 191 or reproductive importance and is discovered in the course of conducting research but is beyond the 192 aims of the study. (DAIDS) 193

Institutional Review Board/Ethics Committee (IRB/EC): The board, committee, or other group formally 194 designated by an institution to review, to approve the initiation of, and to conduct periodic review of 195 research involving human subjects. The primary purpose of such review is to assure the protection of the 196 rights and welfare of participants in research. IRB/EC reviewing DHHS sponsored research must be 197 registered with OHRP and identified on the institute FWA. (DAIDS) 198

Interventions: Physical procedures by which data are gathered and manipulations of the participant or 199 the participant's environment that are performed for research purposes. (DAIDS, modified from 45 CFR 200 46.102) 201

Investigational device exemption (IDE): An approved investigational device exemption permits a device 202 that otherwise would be required to comply with a performance standard or to have premarket approval 203 to be shipped lawfully for the purpose of conducting investigations of that device. (FDA) 204

Investigator of Record (IoR): The individual at the CRS responsible for ensuring that a clinical trial is 205 conducted in accordance with the protocol, applicable U.S. federal regulations, in-country regulations 206 and any provisions imposed by the reviewing IRB/EC/other regulatory entity. This person is the signatory 207 for the Form FDA 1572 for studies conducted under an IND or the DAIDS Investigator of Record 208 Agreement for non-IND studies. (DAIDS) 209

Letter of Amendment (LoA): A revision to a protocol made by the Protocol Team/Chair/Awardee through 210 a letter that requires DAIDS final approval/sign-off before implementation. Changes described in a LoA 211 are listed in a document that is separate from the protocol document itself and will NOT result in the 212 change to the DAIDS protocol version number. (DAIDS) 213

Minimal Risk: The probability and magnitude of harm or discomfort anticipated in the research are not 214 greater in and of themselves than those ordinarily encountered in daily life or during the performance 215 of routine physical or psychological examinations or tests. [45 CFR §46.102(i) and 21 CFR §50.3(k)] 216

Neonate: A newborn [45 CFR part 46.202(d)] 217

Nonviable neonate: A neonate after delivery that, although living, is not viable [45 CFR part 46.202(e)] 218

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Pregnancy: The period of time from implantation until delivery. A woman shall be assumed to be 219 pregnant if she exhibits any of the pertinent presumptive signs of pregnancy, such as missed menses, 220 until the results of a pregnancy test are negative or until delivery [45 CFR part 46.202(f)]. 221

Protection of Participants, Evaluation, and Policy Branch (ProPEP): A branch of DAIDS within the Office 222 of Clinical Research Policy and Resources (OPCRO). ProPEP provides consultation and expertise to 223 address complex human subjects protection regulatory issues. (DAIDS) 224

Protocol Chair/Co-Chair: Individual(s) who is/are responsible for developing and conducting the study. 225 (DAIDS) 226

Protocol Informed Consent Form (ICF): An informed consent form developed by the protocol team for a 227 specific protocol. See also Sample Informed Consent Form. (DAIDS) 228

Protocol Registration: The process established by DAIDS to ensure that all sites participating in NIAID 229 (DAIDS) supported and/or sponsored clinical research that is reviewed by a DAIDS Scientific Review 230 Committee conduct the research in accordance with requirements for human subjects protection and 231 the use of investigational new drugs (where applicable). The process includes initial protocol registration, 232 amendment registration, continuing review documentation, deregistration and submission of other 233 required documents. (DAIDS) 234

Protocol Registration Team (PRT): A Team within OPCRO responsible for managing the Protocol 235 Registration (PR) System, which includes oversight of the DAIDS PRO. (DAIDS) 236

Protocol Team: A team of individuals comprised of grantees, investigators, statisticians, and other 237 protocol support personnel who work to develop concepts into NIAID (DAIDS)supported and/or 238 sponsored research studies. DAIDS medical officers may be involved as members of this team. (DAIDS) 239

Regulatory Entity (RE)/Approving Entity: Any group other than the reviewing IRB/EC responsible, for 240 reviewing and/or approving a clinical research protocol and site-specific ICFs prior to implementation at 241 a site. For example, in some states within the U.S., institutional approvals are required since these states 242 have research regulations in addition to the federal human subjects protection regulations detailed in 243 U.S. federal regulations (45 CFR §46).In addition, at many non-U.S. sites, other approvals may be required 244 in addition to the reviewing IRB/EC approval, which include but are not limited to approvals from ministry 245 of health, national regulatory agency, in-country drug control council, national IRB/EC, or other 246 government agency). (DAIDS) 247

Sample Informed Consent Form (ICF): An informed consent form developed by the protocol team for a 248 specific protocol that will help guide participating sites in the development of their site-specific 249 informed consent. This term is mainly used for multi-site studies. See also Protocol Informed Consent 250 Form. (DAIDS) 251

Scientific Review Committee (SRC): A reviewing body within DAIDS to review the concepts and protocols 252 developed by various programs within DAIDS (e.g., CSRC and PSRC). (DAIDS) 253

Site-Specific Informed Consent Form (ICF): An informed consent form developed by a participating site 254 based upon the sample informed consent form which is reviewed and approved by the site’s designated 255 IRB/IEC and is used to consent subjects at the site for a specific clinical trial. (DAIDS) 256

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Study products: Any drug, biologic, vaccine, radiopharmaceutical, item or device that are either provided 257 for the study or identified in the protocol as being a study product. (DAIDS) 258

Vulnerable participants: Individuals whose willingness to volunteer in a clinical trial may be unduly 259 influenced by the expectation, whether justified or not, of benefits associated with participation, or of a 260 retaliatory response from senior members of a hierarchy in case of refusal to participate. (ICH E6). 261

For additional definitions, SEE the DAIDS Glossary. 262

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3. LIST OF ABBREVIATION 263

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ARV Antiretroviral CDRH Center for Devices and Radiological Health CFR Code of Federal Regulations CIOMS Council for International Organizations of Medical Sciences CoC Certificates of Confidentiality CQMP Clinical Quality Management Plan CRS Clinical Research Site CTA Clinical Trials Agreement CTI Clinical Trials Insurance DAIDS Division of AIDS dbGaP Database of Genotypes and Phenotypes DoD Delegation of Duties EC Ethics Committee eIC Electronic Informed Consent FDA (U.S.) Food and Drug Administration FDAAA (U.S.) Food and Drug Administration Amendments Act FWA (U.S.) Federalwide Assurance GCP Good Clinical Practice GDPR (European) General Data Protection Regulation GDS Genomic Data Sharing GINA Genetic Information Nondiscrimination Act GWAS Genome-Wide Association Studies HHS (U.S.) Department of Health and Human Services HIPAA (U.S.) Health Insurance Portability and Accountability Act HIV Human Immunodeficiency Virus HSP Human Subjects Protections IB Investigator's Brochure IC Informed Consent ICF Informed Consent Form ICH International Conference on Harmonisation ICMJE International Committee of Medical Journal Editors IDE Investigational Device Exemption IF Incidental Finding IND Investigational New Drug Application IoR Investigator of Record IRB Institutional Review Board IRR Individual Research Result LAR Legally Authorized Representative LoA Letter of Amendment MO Medical Officer NIAID (U.S.) National Institute of Allergy and Infectious Diseases NIH (U.S.) National Institutes of Health

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NLM (U.S.) National Library of Medicine OHRP (U.S.) Office for Human Research Protections PI Package Insert PRO Protocol Registration Office QA/QC Quality Assurance/Quality Control RE/AE Regulatory Entity/Approving Entity RSC Regulatory Support Center SACHRP (U.S.) Secretary’s Advisory Committee on Human Research Protections SAHPRA South African Health Products Regulatory Authority SIC Sample Informed Consent SOP Standard Operating Procedure SRC Scientific Review Committee STI Sexually Transmitted Infection WHO World Health Organization

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4. GUIDANCE FOR DEVELOPING PROTOCOL INFORMED CONSENT FORMS 266

Informed consent is a process that includes ongoing communication and information exchange between 267 the participant and an investigator/research team. This process often includes a written informed 268 consent form (ICF), Institutional Review Board (IRB)/Ethics Committee (EC) -approved participant 269 recruitment materials, verbal instructions, question/answer sessions and tools to measure participant 270 understanding. Often, an informed consent form (ICF) is used to inform participants about the study 271 and to document the informed consent process. The informed consent form must provide sufficient 272 information for a potential participant to make an informed decision about participating in a study. 273

4.1. Ethical Foundation – The Belmont Report 274

The Belmont Report describes three fundamental ethical principles for involving individuals in 275 clinical research: respect for persons, beneficence, and justice. These three principles are the 276 basis for the United States Department of Health and Human Services (HHS) human subjects 277 protection regulations. 278

• “Respect for Persons” is centered on the participant’s right to autonomy and the ability to279 make a choice, and the requirement to protect those participants with diminished autonomy.280 This principle underlies the requirement to obtain legally effective informed consent.281

• “Beneficence” is related to protecting research participants from harm and making efforts to282 safeguard their well-being. This principle is centered on the perspective of “do no harm” by283 minimizing risks to participants and maximizing benefits to society.284

• “Justice” is focused on the distribution of the burdens and benefits of research. This principle285 is related to the equitable selection of research participants and the prevention of286 exploitation of vulnerable populations.287

Three fundamental elements of informed consent—The Belmont Report 288

• “Information” needed to make an informed decision about study participation;289

• “Comprehension” or participant’s understanding of the information; and290

• “Voluntariness” or the participant’s capacity to decide whether or not to participate in the291 research, free of coercion and/or undue influence.292

4.2. HHS, FDA, and ICH E6 (R2) Informed Consent Regulatory Requirements 293

All research involving human participants that is conducted or supported by the Department of 294 Health and Human Services (HHS) is subject to the U.S. Code of Federal Regulations at 45 CFR 46, 295 including NIAID (DAIDS) supported and/or sponsored non-exempt clinical research. Therefore, 296 NIAID (DAIDS) protocol ICF(s) must be written in compliance with the 45 CFR 46.116., which 297 clearly discusses the requirement to minimize the possibility of coercion or undue influence. In 298 other words, the importance of focusing the ICF(s) on true voluntariness. The Belmont Report 299 states that “ An agreement to participate in research constitutes a valid consent only if voluntarily 300 given.” Thus, all ICFs must be free of coercion and undue influence, as defined by the report: 301 “Coercion occurs when an overt threat of harm is intentionally presented by one person to another 302 in order to obtain compliance; Undue influence, by contrast, occurs through an offer of an 303

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excessive, unwarranted, inappropriate or improper reward or other overture in order to obtain 304 compliance. Also, inducements that 305

would ordinarily be acceptable may become undue influences if the subject is especially 306 vulnerable.” Thus, all ICF(s) offered by investigators should give each participant the opportunity 307 to consider if he/she wants to participate in the study and should be a process and a form that 308 minimize the possibility of coercion or undue influence. 309

Another important aspect of this voluntariness is that the consent process should not include any 310 exculpatory language. Language used to ask the study participant to “waive or appear to waive 311 any of his or her legal rights, or release or appear to release the investigator, the sponsor, the 312 institution, or its agents from liability for negligence.” The regulations consider exculpatory 313 language to be “language that has the general effect of freeing or appearing to free an individual 314 or an entity from malpractice, negligence, blame, fault, or guilt.” (21 cfr section 50.20 and 45 cfr 315 46.116) 316

ICFs must also be in compliance with the International Conference on Harmonisation (ICH), 317 Guidance for Industry, and E6 (R2) Good Clinical Practice, section 4.8. This section entitled 318 Informed Consent of Trial Subjects, contains similar required informed consent form elements as 319 required by HHS and FDA (basic and additional elements) (E6(R2) Good Clinical Practice: 320 Integrated Addendum to ICH E6(R1) Guidance for Industry). 321

Furthermore, those protocols that are subject to FDA regulations must also adhere to 21 CFR 322 50.25 (CFR - Code of Federal Regulations Title 21). 323

Reviewing IRBs/ECs have the final authority for ensuring the adequacy of the information in the 324 IC documents. 325

4.3. Basic Elements of Informed Consent 326

45 CFR 46.116(a), 21 CFR 50.25(a), and ICH E6 (R2), section 4.8.10. In seeking informed consent, 327 information related to the eight required basic elements as per §46.116(a) and §50.25(a) must 328 be provided to each participant: 329

4.3.1. Purpose and Procedures 330

“A statement that the study involves research, an explanation of the purposes of the research and 331 the expected duration of the subject's participation, a description of the procedures to be 332 followed, and identification of any procedures which are experimental.” 333

Potential participants need to be clearly informed that the study involves research, and that study 334 participation is primarily to contribute to science rather than to receive personal medical 335 treatment. Also, participants must be informed about the study’s purpose. For instance, IC 336 documents should include information related to the primary objective(s) of the study, should 337 include “safety” even if it is a secondary objective (if applicable), and should indicate if a study 338 intervention is experimental (if applicable). 339

Additional information to be incorporated into IC documents includes but is not limited to: 340

• Reasons for a potential participant’s selection (e.g., HIV-infected, CD4 count ≥500)341

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• Available preliminary data related to the study product(s), intervention(s), strategy(ies) such 342 as previous studies, previous use/indications, etc.343

• Procedures related solely to research such as randomization, blinding, receipt of a placebo as344 well as a lay description of these procedures345

• Standard of care tests/procedures that will not be done during study participation and any346 potential consequences associated with not undergoing these tests/procedures347

• Outline of the participant’s involvement in order to comply with the protocol (e.g., number348 of clinic visits, expected length of study visit(s), medication and activity restrictions including349 participating in other studies, etc.)350

• Expected duration of the participant’s involvement, including any long-term follow-up.351

4.3.2. Risks and Discomforts 352

“A description of any reasonably foreseeable risks or discomforts to the subject.” 353

Research-related risks have been categorized as physical, psychological, social, legal, or 354 economic, occurring as a result of participation in a research study, and ranging from minimal to 355 significant. As per U.S. regulations, IC documents should describe any reasonably foreseeable 356 risks corresponding with the risks communicated in the protocol, especially risks that are more 357 likely to occur, those that are serious, and those that may carry significant risk of morbidity or 358 mortality. IC documents can include a description of the methods that will be used to mitigate 359 risks. 360

4.3.2.1. Risk information associated with the study product(s)/intervention(s)/strategy(ies) to be 361 incorporated into IC documents includes: 362

• Risk information described in the protocol, package insert (PI), Investigator’s Brochure363 (IB), and/or relevant publications, as well as risks associated with the study procedures364 (e.g., phlebotomy, pelvic exams, DEXA scans). If long-term safety studies are ongoing at365 the time the study is implemented, participants should be informed that studies that may366 identify potential risks have not yet been completed.367

o Use the DAIDS-approved core risk information lists, if available, for study368 product(s) risk information that should be included in IC documents. Risk369 information language used in the related DAIDS-approved core risk list(s) may be370 modified by the protocol team. However, all key concepts listed in the DAIDS core371 risk list(s) should remain in the informed consent form documents.372

o Consult all relevant up-to-date sources of risk information, including the most recent373 package insert (PI) for FDA approved products, Investigator’s Brochure (IB) for374 investigational products, etc. to obtain the most current information on study product375 risks, interactions, contraindications, and precautions. Address the updated376 information in the protocol as well as in the IC documents.377

o Revise risk information in the protocol and IC documents as appropriate during the378 course of the study, based on interim safety information and other relevant379

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information (e.g., results of similar studies; receipt of IND safety reports; MedWatch 380 reports MedWatch: The FDA Safety Information and Adverse Event Reporting 381 Program, etc.). 382

NOTE: Additional risks for a particular study product can be added to the IC documents, if this 383 information is described in the body of the protocol. 384

o Consider describing the probability, frequency, and severity of potential risks as385 follows:386

▪ "Common, some may be Serious" - Occurring in greater than 20% of387 participants receiving the study agent(s).388

▪ "Occasional, some may be Serious" - Occurring in 4% to 20% of participants389 receiving the study agent(s).390

▪ "Rare, and Serious" - Occurring in 3% or fewer participants and that are not391 considered reasonably foreseeable but are serious.392

▪ "Possible, some may be Serious" - Relating to IND agents for which the393 frequency of individual risks has not yet been determined.394

SEE: NCI INFORMED CONSENT TEMPLATE FOR ADULT CANCER TRIALS PAGE 33: NCI Informed 395 Consent Template for Adult Cancer Trials 396

NOTE: Descriptions of risks of individual drugs or agents not specified in the protocol (e.g., 397 drugs/agents not provided through the study) do not need to be included in consent 398 documents; however, general statements regarding common risks for relevant drug classes 399 or referral to package inserts could be included. 400

4.3.2.2. Additional risk information considerations to be addressed: 401

• Risks related to study participation (e.g., due to changes to a participant’s regular/stable402 medication regimen; developing drug resistance due to sub-optimal treatment and403 consequential limitation of future treatment options; development of vaccine-induced404 seropositive test result after receiving an experimental preventative HIV vaccine; risks405 related to randomization; risks of long-term effects). Consider including potential risks406 related to participating in more than one study (e.g., study product interactions, etc.).407

• Risks related to differences in efficacy of the study products, based on the data available408 at the study’s commencement (e.g., difference in efficacy may impact a participant’s risk409 of HIV acquisition).410

• Risks such as social impact events (e.g., inadvertent disclosure of study participation411 resulting in stigmatization or discrimination), as well as legal and economic risks (e.g.,412 unintentional disclosure of drug or alcohol use or illegal activities; loss of employment;413 procedures or treatment billed to a participant’s insurance company).414

• Risks related to the future research use of samples and associated health information415 (e.g., secondary use) as well as risks associated with general and genomic data-sharing.416 Oftentimes, such studies do not involve interaction with research participants. However,417

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there are potential risks, many of which are informational, that may increase as 418 technology evolves. These risks include but are not limited to: 419

o Inappropriate disclosure of information leading to privacy and confidentiality risks420 (e.g., unauthorized exposure of personal identifiers, breach of confidentiality, etc.)421

o Participant re-identification, including the combined use of publicly available data422 and genomic data423

o Emotional, social, or financial consequences related to privacy and confidentially424 breaches425

o Discrimination related to privacy and confidentiality breaches426

o Psychological risks such as stress, anxiety, invasion of privacy, etc.427

o Potential risks to others who are not study participants (e.g., live-attenuated428 vaccine where close proximity to a participant may present a risk to an429 immunocompromised household member).430

• Risks unknown at the study’s commencement.431

• Risks particular to vulnerable populations who may be susceptible to coercion or undue432 influence, etc.433

4.3.3. Benefits 434

“A description of any benefits to the subject or to others which may reasonably be expected from 435 the research.” 436

IC documents should describe any reasonably foreseeable, potential direct benefits related to 437 the study product(s), intervention(s), and/or strategy(ies), if any. Additionally, IC documents 438 should explain any potential ancillary benefits to the study participant (e.g., additional 439 monitoring, increased health awareness, access to early treatment for any secondary diagnosis) 440 and to society (e.g., future knowledge about the condition), if any. 441

If there is no prospect of direct benefit from study product(s)/intervention(s)/strategy(ies), such 442 as in Phase I studies, IC documents should state this information clearly. Furthermore, the 443 benefits statement in IC documents must correspond with the benefits described in the protocol, 444 must be clear and balanced, and must not be overstated. 445

NOTE: Participant compensation is not considered a “benefit”; compensation is usually provided 446 to offset the time, inconvenience, and expenses related to study participation, not as “payment” 447 for participation. 448

4.3.4. Alternative Treatment and Procedures 449

“A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be 450 advantageous to the subject.” 451

IC documents should discuss the various alternatives to participation in the study and should 452 contain sufficient information for a potential participant to make an informed decision. These 453 alternatives may include any treatment or procedures available outside of the research study 454

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under consideration, including the established standard treatment, especially if the study 455 involves the administration of investigational drugs or the use of new therapeutic procedures. 456 For example, in HIV treatment studies, antiretroviral medication(s) may be available through a 457 participant’s family doctor or clinic without the need to participate in a study. The alternatives 458 section should clearly state the possible choices, including the important potential benefits and 459 risks of these alternative(s). Alternatives to study participation can include: no treatment, 460 standard of care therapy, other experimental treatments, or some or all of the study treatment, 461 but without participating in the study. Additional information may include notifying participants: 462

• That standard treatment will be withheld as a result of study participation463

• That there are no alternative treatments464

• That one alternative is not to participate in the study (for both participants who have the465 underlying condition under study as well as normal, healthy volunteers)466

• That participation in a particular study may preclude participation in other studies now467 and/or in the future (e.g., receiving a preventative HIV vaccine may make a volunteer468 ineligible for other HIV vaccine studies)469

• That participation may make the participant ineligible for specific standard of care options470 (e.g., a particular class of antiretroviral agents)471

4.3.5. Confidentiality 472

“A statement describing the extent, if any, to which confidentiality of records identifying the 473 subject will be maintained.” 474

IC documents should identify all entities that may have access to study records, including the 475 possibility that the FDA and other regulatory entities (RE) may inspect the records for FDA-476 regulated studies. Entities may include the study sponsor such as the NIH, pharmaceutical 477 company(ies) providing study medications and/or supporting the study, the IRB/EC/RE, OHRP, 478 the network supporting the study, study staff, and study monitors and their designees. 479 Specifically, participants must be informed that “U.S., local and international regulatory 480 authorities/entities” may also review study records. Additional confidentiality issues may include 481 informing participants: 482

• If any data will be made available to others (e.g., associated health information that may be483 provided to investigators when conducting future research with leftover samples)484

• If a Certificate of Confidentiality has been obtained which protects the investigators from485 involuntary release of participant information (e.g., subpoena) (SEE: Section 4.6.1)486

• If audio or videotape recording, photographs, and/or movies will be taken as part of the487 study, the duration of time they will be kept, how confidentiality will be maintained, and488 whether they will eventually be erased or destroyed (timing dependent on the Storage and489 Retention of Clinical Research Records Policy)490

• About any steps that will be taken to maintain confidentiality and privacy (e.g., keeping paper491 study records in a secure and locked place; not using identified information in publications,492

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meetings, or stored samples; using a code to identify participants and samples; securely 493 storing the participant identification code (PID) list, maintaining it separately from the 494 research records, and limiting access to the PID list) 495

In addition, DAIDS requires clinical research sites (CRSs) to verify the ages and identities of 496 potential participants before enrollment and throughout the duration of their study 497 participation. Verification includes data sharing among DAIDS and non-DAIDS sponsored clinical 498 research sites. Data sharing procedures must be done in such a way that maintains participants’ 499 confidentiality. Participants should be informed about any data-sharing procedures pertaining 500 to co-enrollment procedures, and any related risks. 501

SEE: The Age and Identity Verification and Co-Enrollment Prevention Policy 502

4.3.6. Compensation, Treatment of injury 503

“For research involving more than minimal risk, an explanation as to whether any compensation 504 and an explanation as to whether any medical treatments are available if injury occurs and, if so, 505 what they consist of, or where further information may be obtained.” 506

OHRP recommends the use of the “healthy person” standard when determining what is 507 considered minimal risk--§46.102(i): “Minimal risk means that the probability and magnitude of 508 harm or discomfort anticipated in the research are not greater in and of themselves than those 509 ordinarily encountered in daily life or during the performance of routine physical or psychological 510 examinations or tests.” 511

IC documents must include a statement about research-related injury, even if there is no 512 mechanism for compensation. These documents should describe any compensation and medical 513 treatment available through the study and at the local level, as compensation and treatment may 514 vary depending on the protocol’s Clinical Trials Agreement (CTA), individual participant, policies 515 of the institution and/or sponsor, CRS capabilities, geographic area, and/or local IRB/EC and in-516 country requirements (e.g., laws, regulations, etc.). IC documents should also clarify for which 517 type(s) of research-related injury (e.g., physical such as liver damage, psychological such as 518 emotional distress, social such as family discrimination, financial such as lost wages, etc.) 519 participants may receive compensation. IC documents, when applicable, should include relevant 520 information about what research-related treatment is available at the site as well as any referrals 521 for care. 522

However, if the institution and/or site will not be providing compensation for research-related 523 injury, the IC document needs to specifically state this. In this instance, the ICF must also state 524 that the NIH does not have a mechanism to provide direct compensation for research related 525 injury. 526

If Clinical Trials Insurance (CTI) is an in-country requirement, the ICF must include related 527 information. CTI is a policy that may include coverage against any bodily injury or property 528 damage that a drug, device, or treatment may cause to a participant (SEE: Definition of CTI). 529 Similarly, ICH E6 (R2) section 5.8.1 requires sponsors to provide compensation for participants(s) 530 for research-related injury for studies conducted in countries where this is a requirement by 531

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regulation. Participants should be informed about the availability of CTI, and the types of “injury” 532 that is covered (e.g., physical, psychological, social, financial, etc.). (SEE: Section 5.2) 533

When applicable, a site can adopt and revise the following language for its site-specific ICF: 534

“Consistent with in-country guidelines (add as appropriate: regulations, laws, institutional 535 policies, etc.), our clinic has purchased insurance to cover your medical treatment for 536 study-related physical injuries that you are experiencing from participating in this study. 537 We can also provide compensation for (add/clarify as appropriate: type of non-physical 538 research-related injury compensation coverage provided by the site’s policy, e.g., 539 psychological such as emotional distress, social such as family discrimination, financial 540 such as lost wages, etc.)”. 541

NOTE: The regulations do not limit research-related injury to "physical injury" 542

4.3.7. Problems and Questions 543

“An explanation of whom to contact for answers to pertinent questions about the research and 544 research subjects' rights, and whom to contact in the event of a research-related injury to the 545 subject.” 546

Each IC document is expected to have at least two names with local telephone numbers for 547 contacts to answer questions in these specified areas. 548

The contact for questions related to the research needs to be someone who would be 549 knowledgeable about the research, such as the investigator or his/her designee. 550

The contact for questions related to participant’s rights should not be a member of the research 551 team because of potential conflicts of interest and because participants may be uncomfortable 552 identifying possible problems to someone who is a member of the research team. 553

The contact for questions related to the rights of participants or research-related injuries could 554 be the IRB/EC, an ombudsman, an ethics committee, or other informed administrative body. 555

Contact information should include the contact names or offices as well as their telephone 556 numbers, including any 24-hour contact information (if applicable). 557

4.3.8. Voluntary Participation Statement 558

“A statement that participation is voluntary, refusal to participate will involve no penalty or loss 559 of benefits to which the subject is otherwise entitled, and the subject may discontinue 560 participation at any time without penalty or loss of benefits to which the subject is otherwise 561 entitled.” 562

Participants must be informed that they may decline to take part in a study and/or may decide 563 to withdraw from the study at any time. In either case, the participant will not incur any penalty 564 or loss of benefits in which they are already eligible at the CRS outside the research. 565

Participants must be informed about any foreseeable issues should they decide to withdraw from 566 the study. Include any special withdrawal procedures that are recommended in order to ensure 567 the participant's safety and/or any health consequences if the participant should stop the study 568 product or study intervention early. Participants should be informed that any data that were 569

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collected about them prior to their withdrawal from the study will still be part of the study since 570 their deletion would impact the integrity of the research (for those studies subject to FDA 571 regulations). 572

4.4. Additional Elements of Informed Consent as per §46.116(b) and §50.25(b) 573

The HHS and FDA regulations identify additional elements of informed consent. It is up to each 574 reviewing IRB/EC/RE to determine whether some or all of the additional elements listed below 575 need to be included in the IC documents for a study, based on the nature of the research and the 576 local context. 577

NOTE: many of the HHS and FDA additional elements are included in ICH E6 (R2) section 4.8.10 578 and, therefore, should be included in IC documents. 579

Additionally, an IRB/EC/RE may require information to be included in IC documents beyond the 580 basic and additional elements described in §46.116 and §50.25. 581

When appropriate, provide one or more of the following additional elements and their related 582 information to each participant. 583

4.4.1. Risks to Participant/Risks to Fetus during Pregnancy 584

“A statement that the particular treatment or procedure may involve risks to the subject (or to 585 the embryo or fetus, if the subject is or may become pregnant) which are currently 586 unforeseeable.” 587

• Participants should be informed that a study product/intervention/strategy may involve risks 588 to the participant/embryo/fetus that are not known at the time at the study’s start. 589

• Participants should be informed, if applicable, if long-term bench and animal testing and any 590 related “first in human” studies have not yet been completed by the study’s start since these 591 studies may identify additional potential risks to the participant/embryo/fetus. 592

• Participants should be informed about any pregnancy, lactation, and/or reproductive-related 593 risks (e.g., birth defects; risks related to ongoing fetal or infant exposure to the study drug), 594 based on the study product(s) (including package inserts and IBs), intervention(s), and/or 595 strategy(ies). IC documents need to clearly describe any known risks as well as any risks that 596 are currently unforeseeable to the participant or to the embryo or fetus should pregnancy 597 occur. Additionally, IC documents should include methods to mitigate potential risks, which 598 may include informing: 599

o Women of childbearing potential to avoid pregnancy or nursing during or after 600 participating in a study to protect the health and safety of the mother and/or 601 embryo/fetus/infant 602

o Males to avoid impregnating a woman if there is a risk of transferring a study product 603 via semen 604

o Participants not to partake in a conception process for a specified time before, during 605 and/or after study participation 606

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o Participants about the number, type(s), and length of time contraception may be607 required (e.g., 2 forms of contraception, including one that is a barrier method, 21608 days prior to entering the study until the last study visit)609

o Participants about pregnancy testing, including the timing and frequency of these this610 testing; testing may occur before, during, and/or after the study611

o Participants about the need to monitor for pregnancy outcomes, as applicable (e.g.,612 Antiretroviral Pregnancy Registry; follow-up visits/phone calls for pregnancy outcome613 information)614

SEE: The Therapeutics Research Program Guidance for the Development of Protocol Procedures 615 to Address Reproductive Risk document for additional information (DAIDS Therapeutics Research 616 Program Guidance for the Development of Protocol Procedures to Address Reproductive Risk). 617

4.4.2. Involuntary Termination of Study Participation 618

“Anticipated circumstances under which the subject's participation may be terminated by the 619 investigator without regard to the subject's consent.” 620

Participants should be informed about any circumstances that may result in their involuntary 621 termination from study participation. If study participation is discontinued, the participant 622 should be told about the reason(s), any other available treatment or research options, and any 623 plans to follow the participant for safety reasons, if applicable. Describe any anticipated 624 conditions which can lead to involuntary termination, including but not limited to: 625

• The participant is unable to follow the study’s requirements (e.g., repeatedly misses study626 visits)627

• The participant no longer meets the study’s eligibility criteria (e.g., subsequently becomes628 HIV-infected in a preventative vaccine study; needs a medication that is prohibited while on629 study)630

• The CRS withdraws from the study and there is no CRS in the vicinity to accept the participant631 as a transfer632

• The investigator believes it is in the participant’s best interest not to continue study633 participation (e.g., the participant is having severe side effects from the study product)634

• The study is stopped or canceled by the study sponsor (e.g., U.S NIAID, U.S. FDA, U.S. OHRP,635 EMA, the reviewing IRB/EC/RE)636

• The participant’s parent/legal guardian withdraws his/her permission for the child’s study637 participation638

4.4.3. Additional Costs 639

“Any additional costs to the subject that may result from participation in the research.” 640

IC documents need to describe any study-related costs, which may include: 641

• Costs such as loss of income related to time off from work needed to participate in the study,642 transportation costs, childcare costs, etc.643

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• Costs of study lab tests, procedures, exams, and/or products that may be charged to the 644 participant, the participant’s insurance, or any other reimbursement mechanism 645

• If applicable at the local level, costs to participants related to insurance or other forms of 646 reimbursement not paying for their medical care due to their study participation, even if this 647 care is the standard of care they would have received outside of the study 648

• If applicable at the local level, costs to participants related to insurance or other forms of 649 reimbursement not paying for any care due to research-related complications or injuries 650

• If applicable at the local level, costs to participants related to any deductibles or co-payments 651 in the event their insurance is charged 652

4.4.4. Early Withdrawal from Study/ Orderly Termination 653

“The consequences of a subject's decision to withdraw from the research and procedures for 654 orderly termination of participation by the subject.” 655

Inform participants about the following issues, including but not limited to: 656

• Any potential anticipable/known adverse effects of stopping the study product(s) and/study 657 intervention(s) early 658

• Any special withdrawal procedures that are recommended to ensure the participant's safety 659 and why these procedures are important (e.g., gradual withdrawal of the study product; 660 follow-up safety visits even though the participant has stopped receiving study product) 661

• If applicable at the local level, any impact of premature discontinuation on study 662 compensation/reimbursement 663

4.4.5. New Findings 664

“A statement that significant new findings developed during the course of the research which may 665 relate to the subject's willingness to continue participation will be provided to the subject.” 666

Participants should be informed, in a timely manner, about any significant new findings during 667 the course of an ongoing study that may impact a participant’s willingness to continue study 668 participation. Related issues that should be considered include but are not limited to: 669

• Any unexpected adverse events or risks and/or adverse events that are occurring at a greater 670 frequency or severity than what was previously stated in the IC document(s) resulting in a 671 change to the risk/benefit profile of the study (e.g. an increase in the magnitude of known 672 suspected risks, a decrease in the expected benefit) 673

• Any interim findings from the ongoing study or external studies that show statistically 674 significant survival/efficacy/improvements from a particular study 675 product/intervention/strategy 676

• Any changes in the level of discomfort or other inconvenience 677

• Any new regulatory approval (e.g., FDA, MCC/SAHPRA, EMA) of study products/intervention 678 used in the study 679

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• Any new alternative treatment options that become available 680

• Any major changes to the study based on these new findings such as revised/additional study 681 procedures, changes in the dose or frequency of the study product, modifications to the study 682 design including extended follow-up and/or additional study visits, changes to 683 compensation/reimbursement or costs related to study participation, etc. 684

• Methods of communicating new findings to participants include but are not limited to: in 685 person, documented phone contact, re-consent with a revised informed consent document, 686 consent addendum, and “Dear Participant” letters (SEE section 6.6.3). 687

4.4.6. Number of Participants 688

“The approximate number of subjects involved in the study.” 689

Participants should be informed about the approximate number of participants involved in the 690 specific research study, including why this number is important especially if this information may 691 impact his/her decision to participate (e.g., the study is a first in human study or a Phase 1 study; 692 a small number of participants may jeopardize confidentiality). 693

Participants could be informed about the countries, the number of sites, and the approximate 694 number of participants at each site in multi-site, multi-national studies. Potential participants 695 may want to know this information prior to deciding to join the study (e.g., to allay any potential 696 concerns about exploitation if a riskier study is only being conducted in resource-limited settings) 697

SEE: Section 8.0 for information related to the new Informed Consent elements required by the 698 Revised Common Rule (To be implemented January 2019). 699

4.5. Additional Pregnancy-Related Informed Consent Form Requirements and Considerations 700

4.5.1. Pregnancy Prevention Considerations 701

If applicable, advise participants of any pregnancy-prevention measures (e.g., use of 702 contraception, avoidance of conception) to be taken while on the study. ICF(s) should include 703 contraception and conception information based on the available reproduction toxicity data of 704 the study intervention(s)/agent(s), the FDA-Use-in-Pregnancy drug categories (if applicable), 705 and/or the revised FDA pregnancy, lactation, and reproductive potential labelling requirements 706 (e.g., the number and type of required contraceptive methods and the length of time of their 707 required use). 708

4.5.2. Subsequent Pregnancy Considerations 709

Despite instructions to avoid pregnancy for a time before, during or following study participation 710 and the use of pregnancy prevention measures, pregnancy may occur. The protocol and ICF(s) 711 need to describe any procedures to be followed in the event that a female participant 712 subsequently suspects or becomes pregnant while on study. Considerations include: 713

• Premature study discontinuation procedures for participants who become pregnant after 714 study enrollment (e.g., off study product(s), intervention(s), and/or strategy(ies) and off study 715 participation) 716

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• “Pregnancy visit” procedures, outlining appropriate modifications to study procedures and 717 any additional safeguard procedures (e.g., discontinuation of study 718 product(s)/intervention(s), conditions under which continuation of the intervention may 719 occur, alterations in study evaluations such as limiting radiation exposure or blood volumes, 720 ultrasounds and other procedures to monitor fetal growth). ICF(s) should indicate whether 721 the participant will be allowed to continue to receive the study product(s)/intervention(s) 722 and/or strategy(ies). Additionally, ICF(s) should provide any other guidance relevant to the 723 study product/intervention and pregnancy and/or breastfeeding. (e.g., the participant may 724 be allowed to continue to receive study product during pregnancy but will not be allowed to 725 breastfeed) 726

• Study-specific pregnancy consent form and informed consent process that reflects any 727 additional risk/benefit considerations, if applicable 728

SEE: FDA Draft Guidance 4/2018: 729

• Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials 730 Guidance for Industry; 731

• Pregnancy and Lactation Labeling (Drugs) Final Rule; 732

• FDA Draft Guidance 12/2014: 733

• Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug 734 and Biological Products —Content and Format Guidance for Industry 735

4.5.3. Pregnancy Outcome Monitoring Considerations 736

The IC documents need to include information regarding how pregnancy outcomes may be 737 monitored, including: 738

• Phone and/or in person study clinic visit follow-up to ascertain the pregnancy outcome 739

• Rollover study or pregnancy registry/follow-up study (e.g., MTN 016) for the female and/or 740 the infant/child 741

• Voluntary or required pregnancy registries for participant’s receiving antiretrovirals or other 742 products for which such registries exist (e.g., pregnancy exposure registries such as the 743 Antiretroviral Pregnancy Registry, The Antiretroviral Pregnancy Registry ) 744

SEE: DAIDS Clinical Trial Protocol Documents Manual section 14.3 745

4.5.4. Replacement Feeding/Breastfeeding ICF Considerations 746

As determined by the study product(s), intervention(s), and/or strategy(ies), participants able to 747 become pregnant are sometimes instructed to avoid breastfeeding during or after participating 748 in a study to protect the health and safety of the infant. Permitting breastfeeding may be based 749 on current WHO or applicable in-country infant feeding guidelines. If relevant, ICF(s) need to 750 address breastfeeding/replacement feeding issues as well as any related risks and/or benefits, 751 based on the information included in the protocol. Some considerations include: 752

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• If breastfeeding is permitted during study participation, the ICF(s) need to include relevant 753 information for participants who plan to breastfeed their infants while on study 754

• When replacement feeding is acceptable, feasible, affordable, sustainable, and safe, 755 avoidance of all breastfeeding by HIV-infected mothers is currently recommended; however, 756 if formula feeding is permissible, include pertinent information in the ICF(s) (e.g., whether 757 safe water to reconstitute formula needs to be readily available) 758

• If a participant subsequently becomes pregnant while on study and continued study 759 participation is permitted, the ICF(s) should include information indicating if breastfeeding is 760 permissible or if replacement feeding (e.g., formula-feeding) is required 761

4.6. Additional Regulatory, Policy, and Miscellaneous IC document Requirements and Considerations 762

All informed consent documents must meet U.S. regulatory informed consent requirements, ICH 763 E6 (R2), relevant NIH and DAIDS policies and guidance, as well as any local, state, and/or national 764 regulations, guidance, and institutional policies. The more stringent law, regulation, guidance, 765 and/or policy(ies) applies. Additional regulatory, policy, and miscellaneous considerations 766 include: 767

4.6.1. U.S. Certificates of Confidentiality 768

Certificates of Confidentiality (CoC) are used to protect the privacy of research participants by 769 protecting investigators and institutions from being compelled to disclose identifying information 770 that could have adverse consequences for participants. Certificates of Confidentiality can be 771 used for biomedical, behavioral, clinical, or other types of research that are considered to be 772 collecting or using identifiable sensitive information, e.g., research activities that include 773 collecting genetic information, information on the psychological well-being of participants, data 774 on substance abuse or other illegal high-risk behaviors. Note: all NIAID (DAIDS) supported 775 research involving human participants or using individually identifiable biospecimens are subject 776 to the NIH Policy for Issuing Certificates of Confidentiality and are automatically issued a CoC 777 through a term and condition of award. 778

If the research is covered under a Certificate of Confidentiality, participants should be informed 779 in the IC form of the use and limits of the certificate. 780

NOTE: Certificates of Confidentiality are issued for applicable research regardless of the country 781 where the investigator or the protected information resides but they may not be effective for 782 data held in foreign countries. If data from the research are collected in a country outside of the 783 U.S. but these data are sent and maintained in the U.S., the certificate would be in effect (these 784 data would be protected by the CoC from legal demand by the U.S legal system). In this instance, 785 CoC-related language should be included in IC documents. 786

SEE: 787

• Certificates of Confidentiality (CoC); General Information on Certificates; 788

• Notice of Changes to NIH Policy for Issuing Certificates of Confidentiality; 789

• Suggested Consent Language Describing the CoC Protections 790

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4.6.2. U.S. ClinicalTrials.gov Considerations 791

ClinicalTrials.gov is the trial registry databank maintained by the NIH National Library of Medicine 792 (NLM). This databank was created to meet section 801 of the 2007 U.S. Food and Drug 793 Administration (FDA) Amendments Act, known as FDAAA 801, that requires clinical trial 794 registration and results submission for applicable clinical trials under this statute. Through 795 FDAAA, the FDA modified the informed consent regulations at 21 CFR 50.25 to require that all IC 796 documents for applicable drug and device clinical trials include a specific statement about trial 797 registration into ClinicalTrials.gov. The Final Rule for Clinical Trials Registration and Results 798 Information Submission (42 CFR Part 11), which was released in September 2016, clarified and 799 expanded the FDAAA 801 requirements. 800

SEE: 801

• FDAAA 801 and the Final Rule; Which Trials Must Be Registered on ClinicalTrials.gov?;802

• See also section 4.6.9 for the related NIH policy - NIH Policy on Dissemination of NIH-Funded803 Clinical Trial Information (2017)804

For applicable clinical trials, the following language MUST be included verbatim in informed 805 consent forms: 806

“A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by U.S. 807 law. This Website will not include information that can identify you. At most, the Website will 808 include a summary of the results. You can search this Website at any time.” 809

If the inclusion of the ClinicalTrials.gov-related language is mandated to be included in IC forms 810 by the reviewing IRB/EC/RE for non-applicable trials, the FDA-required language may be modified 811 as necessary. 812

SEE: 813

• The Protocol Registration Manual for detailed instructions;814

• 21 CFR 50.25(c); FDA Guidance 2/2012: Guidance for Sponsors, Investigators, and815 Institutional Review Boards, Questions and Answers on Informed Consent Elements, 21 CFR816 § 50.25(c)817

4.6.3. European General Data Protection Regulation (GDPR) 818

The European General Data Protection Regulation (GDPR) EU) 2016/679) went into effect on 819 May 25, 2018. This regulation was enacted to protect the personal data of European Union (EU) 820 citizens and includes anyone who can be identified directly or indirectly in a file or database (e.g., 821 databases that contain a person’s name or an ID). U.S. federally funded human subjects research 822 conducted in the EU, or is otherwise subject to EU regulations, is affected. IC documents, 823 especially those used for obtaining consent for the use of participant data, need to address the 824 requirements contained in the GDPR. To briefly summarize: 825

• Participants ages 16 and older, must be consented for the use (processing) of their personal826 data. Parental or guardian consent is required for those participants under age 16.827

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• Consent must be “presented in a manner which is clearly distinguishable from the other 828 matters, in an intelligible and easily accessible form, using clear and plain language”. 829

• Participant have the right to withdraw consent at any time and must be informed of this right 830 prior to giving consent. 831

SEE: OHRP’s Guidance 7/2018: Compilation of Guidances on the EU General Data Protection 832 Directive 833

4.6.4. U.S. Genetic Information Nondiscrimination Act (GINA) 834

GINA is a U.S. Federal law that prohibits discrimination in health coverage and employment based 835 on genetic information. Consider the protections provided by GINA when developing informed 836 consent processes and IC forms for genetic research, especially the impact of GINA on the risks 837 and confidentiality protections for such research. 838

When applicable, ensure that GINA-related informed consent language accurately describes 839 these protections. 840

NOTE: GINA protections are only effective in the U.S. 841

SEE: Genetic Information Nondiscrimination Act Guidance (2009) for guidance and sample 842 informed consent language. 843

4.6.5. U.S. Health Insurance Portability and Accountability Act of 1996 (HIPAA Privacy Rule) 844

The 1996 U.S. Privacy Rule provides regulations pertaining to individually identifiable health and 845 research information, otherwise referred to as “protected health information” or PHI. The Privacy 846 Rule applies to certain U.S. health care providers and institutions that meet the requirements of 847 a “covered entity”. A Privacy Board oversees the covered entities’ use and disclosure of PHI. 848 Often, the IRB/EC serves as the Privacy Board and includes HIPAA-related language in the IC form. 849 HIPAA-related language can be combined with, or is in addition to, the basic and additional 850 elements of informed consent, as found in the HHS regulation at 45 CFR 46.116(a) and (b). 851

NOTE: The HIPAA Privacy Rule is only effective in the U.S. It is up to the CRS to determine if this 852 rule is applicable at their site, and up to the Privacy Board for a covered entity to determine when 853 obtaining HIPAA authorization is necessary. 854

SEE: 45 CFR Parts 160, 162, and 164 855

4.6.6. International Committee of Medical Journal Editors (ICMJE) Requirements 856

Effective July 1, 2018, reports from clinical trials submitted to ICMJE member journals must 857 contain “a data-sharing statement”. Trials that begin enrolling participants on or after January 1, 858 2019, must include a data-sharing plan at the time of trial registration on ClinicalTrials.gov or the 859 WHO International Clinical Trials Registry Platform. 860

SEE: The ICMJE’s clinical trial registration policy 861

Informed consent considerations may include (if applicable): 862

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• Informing participants that their de-identified data may be shared with future investigators, 863 as well as the conditions under which their data may be shared (e.g., who may have access 864 to their data and how, where their data may be stored) 865

• Informing participants about any data-sharing related risks such as risks to their privacy and 866 confidentiality, and how these risks may be mitigated. 867

4.6.7. U.S. NIH Data-Sharing Policy 868

The 2003 NIH data sharing policy applies to those applicants seeking NIH funding of $500,000 or 869 more in direct costs in any one year. This policy was established to ensure that data from NIH-870 funded research are shared as widely and freely as possible so that future research can build on 871 previous efforts and discoveries, while safeguarding the privacy of participants and protecting 872 confidential and proprietary data. The policy expects final research data, especially unique data, 873 be made available to other investigators. Information should be included in the IC form about 874 any steps that will be taken to minimize the risk of unauthorized disclosure of personal identifiers 875 and participant re-identification, e.g., removing identifiers, withholding part of the data, and 876 entering into data-sharing agreements. 877

SEE NIH Data Sharing Policy and Implementation Guidance (Updated: March 5, 2003) 878

4.6.8. U.S. NIH Genomic Data-Sharing (GDS) Policy 879

The 2014 GDS policy applies to the all NIH-funded research generating large-scale human or non-880 human genomic data and the use of these data for subsequent research. According to this policy, 881 investigators who plan to use research or clinical samples or cell lines to generate genomic data 882 may only do so if the participant has provided consent, even if these data are generated from 883 samples that are de-identified. For research that meets the GDS policy (research that plans for 884 “more complete” genetic testing, e.g., GWAS, rather than “limited” genetic testing such as HLA 885 testing, etc.), IC documents should be reviewed to determine if it is appropriate for these data to 886 be shared for secondary research use. NIH strongly encourages investigators to obtain consent 887 that meets the GDS policy informed consent requirements as described below. 888

Convey the following information in language understandable to participants: 889

• Broad sharing: Participant’s genomic and phenotypic data and any other relevant data (e.g., 890 disease status) may be used for future research purposes on any topic and shared broadly. If 891 a participant does not consent to broad sharing of data, he or she may still be enrolled in the 892 initial study, but the data may not be shared for future research. 893

• Databases: Data will be submitted to an NIH-designated data repository (e.g., dbGaP) after 894 personal identifiers such as name, address, account and other identification numbers have 895 been removed. 896

• Access: De-identified participant-level data may only be accessed in a controlled 897 environment, unless participants explicitly consent to allow unrestricted access to and use of 898 their data for any purpose. 899

• Re-identification: It may be possible to re-identify de-identified genomic data, even if access 900 to data is controlled and data security standards are met, so confidentiality cannot be 901

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guaranteed. Risks may include potential discrimination or stigmatization against participants, 902 their families, or groups. There may also be unknown risks. 903

• Early Study Discontinuation: Participants may withdraw consent for research use of their 904 genomic or phenotypic data at any time. However, data already distributed for research use 905 will not be able to be retrieved. 906

• Secondary Research: Participants should be informed that no direct benefits should be 907 expected from any secondary research use. 908

• Study Information: Participants should be provided with the name and contact information 909 of an individual who is familiar with the research, will be available to address participant 910 questions, and who is affiliated with the institution. 911

SEE: NIH Guidance on Consent for Future Research Use and Broad Sharing of Human Genomic 912 and Phenotypic Data Subject to the NIH Genomic Data Sharing Policy 913

4.6.9. U.S. NIH Policy on Dissemination of NIH-Funded Clinical Trial Information 914

The 2017 NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information requires 915 registration and submission of results information in ClinicalTrials.gov, like that required by 916 FDAAA (e.g., summary results, including adverse event information), for every NIH-funded clinical 917 trial, including NIH-funded Phase 1 trials, trials of behavioral interventions and other non-FDA 918 regulated products, regardless of whether they are subject to the FDAAA 801. This Policy is 919 complementary to the statutory mandate under FDAAA (SEE: Section 4.5.2). IC documents for 920 clinical trials subject to this NIH policy need to include a specific statement relating to posting of 921 clinical trial information at ClinicalTrials.gov. (SEE: Section 4.6.2). 922

• If the clinical trial is only subject to this NIH policy, the FDAAA informed consent language 923 may be used. However, the phrase “as required by U.S. law” should be omitted. 924

• If the clinical trial is also subject to FDAAA 801 or the Final Rule for Clinical Trials Registration 925 and Results Information Submission (42 CFR Part 11), then the FDAAA-required informed 926 consent language must be included verbatim in the IC documents (SEE section 4.6.2). 927

SEE: NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information 928

4.6.10. Post-Trial Access Considerations 929

Many Division of AIDS (DAIDS)-sponsored studies provide antiretrovirals and other study 930 product(s)/intervention(s), both investigational and FDA-approved, to study participants during 931 the conduct of the study. The Declaration of Helsinki and the Council for International 932 Organizations of Medical Sciences (CIOMS) guidelines emphasize the importance of post-trial 933 access. DAIDS recognizes the importance of study participants having access to beneficial 934 interventions in relevant circumstances at the conclusion of a study. This post-trial access is 935 especially relevant after efficacy trials when one or more products are proven effective. 936 However, NIH’s Congressional mandate to “encourage and support research” (42 USC 937 284(b)(1)(A)) does not allow DAIDS to directly fund post-trial access to effective interventions, or 938 any treatment. 939

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Predicting and managing study product(s)/intervention(s) availability depends on multiple 940 factors. During study planning, it is appropriate for investigators to discuss post-trial access by 941 engaging with host countries’ authorities, pharmaceutical partners and other relevant 942 stakeholders with the aim of facilitating post-trial access where appropriate. 943

When relevant, language related to post-trial access, including any referral to standard care, 944 should be included in the ICF(s). This language may also include informing participants that the 945 study can no longer provide the study product(s)/intervention(s) after participants complete 946 their participation in a DAIDS-sponsored trial. 947

The current DAIDS General Use SIC Instructions and Template provides sample language for the 948 ICF(s), addressing post-trial access (Protocol Templates: Informed Consent Documents). 949

“What happens at the end of this study?” section of the ICF template: 950

• Add information on the study product/intervention/interaction availability when the study is 951 completed. If applicable, explain any plans for long-term followup, (e.g., tests, procedures, 952 exams, etc.). 953

• Add the following for studies providing a drug, agent or device, and edit the language as 954 appropriate. Include specific information related to any post-trial access programs or 955 research studies providing drugs that may not be available locally: 956

“Once you finish this study, researchers cannot give you ___ (insert drugs/agents, etc.). If ____ 957 (insert drugs/agents, etc.) is helping you, the study staff may be able to tell you how to get it. But, 958 it could be that you can only get something similar”. 959

4.6.11. Stored Samples and Associated Data Considerations 960

Human samples and associated data are an invaluable resource for current and future research 961 on human health and disease. Protocol teams need to consider the technical aspects as well as 962 the ethical, social, and regulatory issues surrounding the collection, storage, and use of samples 963 and associated data. 964

Consider the following for inclusion in ICF documents, as applicable: 965

• Type of sample(s) to be used/collected/stored (e.g., vaginal secretions, blood, etc.) 966

• Collection of additional samples, if any, to be stored for future use 967

• How samples and/or associated data will be used in the current and/or future study(ies) 968

• Disposition of samples at the study’s completion (destroyed versus stored for future use) 969

• Length of time of storage (i.e., indefinite versus a finite specified length of time) 970

• Description of any planned genetic testing in the current and/or future research (i.e., limited 971 versus broad genetic testing), development of cell lines, future research on HIV and related 972 diseases, etc., and any associated risks 973

• Mandatory versus voluntary storage of leftover samples after the study’s completion 974

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• Location of where samples may be stored, or whether samples will be shipped and/or stored 975 outside of the country where they were collected 976

• Possibility of being re-contacted for the use of samples for future research not described in 977 the IC form 978

• Discussion of GWAS, more complete genomic testing, NIH-designated genomic repositories 979 (e.g., dbGaP), and other related issues for those studies that meet the NIH Genomic Data 980 Sharing Policy (SEE section 4.6.8). 981

NOTE: Some ICF considerations are based on whether stored samples will only be used for 982 the current study and/or for future research. 983

• Protocol batched testing: For protocols that will only store biological samples for batched 984 testing for the current study and/or will not store samples for future research, the ICF(s) 985 should address the issue of samples disposition at the study’s conclusion (e.g., all samples will 986 be destroyed). 987

• Future research: For protocols that plan to use/store/collect biological samples (including 988 leftover samples) and/or participant’s associated health data for future research, DAIDS 989 strongly recommends the development of a separate ICF. 990

SEE: 991

• OHRP Guidance: Issues to Consider in the Research Use of Stored Data or Tissues; 992

• OHRP Guidance: Coded Private Information or Biological Specimens Use in Research; 993

• NIH Genomic Data Sharing Policy; 994

• NIH Website for the database of Genotypes and Phenotypes (dbGaP); 995

• DAIDS Sample Informed Consent Template for Stored Samples for Future Use 996

4.6.12. Incidental Findings (IFs) Considerations 997

An incidental finding (IF) is a finding concerning an individual research participant that has 998 potential health or reproductive importance and is discovered in the course of conducting 999 research but is beyond the aims of the study. Protocols and ICF(s) should include any relevant 1000 information related to incidental findings, if applicable, including: 1001

• The information to be offered back to participants 1002

• The description of the approach to be used regarding the return of IFs to participants 1003

• The type of IFs to be shared with participants: 1004

o All incidental findings, regardless of their importance, or 1005

o Only IFs that are important and actionable (at the site/CRS level), or 1006

o None 1007

• If and how participants are to be re-contacted 1008

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SEE: Section 8.2.4 Broad Consent and Secondary Research and section 8.2.5 Incidental Findings 1009 and Individual Research Results Disclosure from Secondary Research with Stored Biospecimens 1010 for informed consent considerations under the revised common rule (section 8.0). 1011

4.6.13. Individual Research Results (IRRs) Considerations 1012

In contrast to an IF, an individual research result (IRR) is a finding about a participant discovered 1013 during research on the focal variables under study in meeting the study’s aims. (Return of 1014 Individual Research Results & Incidental Findings: Facing the Challenges of Translational Science). 1015

However, for practical purposes of research implementation, IFs and IRRs may be 1016 indistinguishable from each other. For example, in a research study to determine some genetic 1017 predispositions, some other associated predispositions may also be listed in the laboratory 1018 report, which are part of the study objectives. Thus, the genetic predispositions with clinical 1019 significance that are part of the research question would be IRRs, and the other associated 1020 predispositions that may also have clinical significance would be IFs. However, from the point of 1021 view of what to do with the information, the study team and the CRSs may decide to implement 1022 an approach to address both IRRs and IFs together without differentiating their separate origins. 1023 As such, protocols and ICF(s) should include relevant information on IRRs, similar to the IFs 1024 considerations described above. 1025

NOTE: Both DAIDS IC templates (Protocol Specific IC form, and the Future Research Use of Stored 1026 Samples and Associated Health Information IC form) ask HIV research participants for their 1027 permission to be re-contacted for IFs that are both important for their health and actionable at 1028 the participant’s level, a variation of the approach above. 1029

SEE: 1030

• NIH Frequently Asked Question from Applicants-- Incidental Findings; 1031

• NIH Genomic Data Sharing (GDS) Policy; 1032

• DAIDS Sample Informed Consent Template for Stored Samples for Future Use and 1033 Instructions; DAIDS Protocol Specific Informed Consent Template — General Use and 1034 Instructions 1035

5. GUIDANCE FOR SITE-SPECIFIC INFORMED CONSENT DOCUMENTS 1036

Include in the site-specific ICF(s) essential information necessary for a potential participant to make an 1037 informed decision about study participation. Use culturally appropriate local “lay language”, and a 1038 language level and language understandable to the participant being consented. Information in site-1039 specific ICF(s) need to be from the local perspective. 1040

5.1. Site-specific ICF(s) 1041

SSICFs must reflect awareness of and compliance with the following: 1042

• U.S. regulatory informed consent element requirements, including compliance with 45 CFR 1043 46.116 and 21 CFR 50.25 for research conducted under an IND and/or IDE (i.e., incorporating 1044 all the basic and additional elements of informed consent as appropriate) 1045

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• ICH E6 (R2) Informed Consent requirements, section 4.8, “Informed Consent of Trial Subjects” 1046

• Relevant DAIDS policies and guidance directing aspects of ICF development and 1047 implementation (e.g., Enrolling Children (including Adolescents) in Clinical Research: Clinical 1048 Research Site Requirements, Protocol Registration) Division of AIDS Clinical Research Policies 1049 and Standard Procedures Documents). 1050

• All applicable laws, regulations, guidance, and institutional policies at each clinical research 1051 site as well as any applicable NIH, NIAID, and DAIDS policies. 1052

5.2. Additional Regulations and NIH Policies 1053

There are additional regulations and NIH polices related to informed consent form development 1054 considerations include: 1055

• Site-specific ICF(s) must include verbatim the FDA-mandated ClinicalTrials.gov language for 1056 applicable clinical trials (21 CFR 50.25(c)). If the reviewing IRB/EC/RE requires 1057 ClinicalTrials.gov-related language to be included in the site’s ICF(s) for non-applicable trials, 1058 the FDA-required language may be modified as necessary. 1059

SEE: section 4.6.2 and the Protocol Registration Manual (PROTOCOL REGISTRATION 1060 MANUAL: Office for Policy in Clinical Research Operations Division of AIDS). 1061

• Site-specific ICF(s) must include language pertaining to Certificates of Confidentiality for 1062 applicable research conducted at U.S sites (research protocols that will be collecting 1063 personally identifiable, sensitive information). Additionally, if data from the research are 1064 collected outside of the U.S. but these data are sent and maintained in the U.S., the site-1065 specific should include related language. 1066

SEE: section 4.6.1 and Certificates of Confidentiality (CoC) 1067

• Site-specific ICF(s) at U.S clinical research sites need to describe Genetic Information 1068 Nondiscrimination Act (GINA)-related protections, if applicable. 1069

SEE: section 4.6.4 and the Genetic Information Nondiscrimination Act Guidance (2009) 1070

• Site-specific ICF(s) should include relevant local level information pertaining to the NIH 1071 Genomic Data Sharing (GDS), for studies meeting the GDS policy requirements 1072

SEE: section 4.6.8 and the NIH Genomic Data Sharing Policy. 1073

• Site-specific ICF(s) need to include relevant information about Clinical Trials Insurance, if 1074 applicable (SEE: Section 4.3.6). A site can adopt/revise the following language, as 1075 appropriate, for their site-specific ICF(s): 1076

“Consistent with in-country guidelines (add as appropriate: regulations, laws, institutional 1077 policies, etc.), our clinic has purchased insurance to cover your medical treatment for 1078 study-related physical injuries that you are experiencing from participating in this study. 1079 We can also provide compensation for (add/clarify as appropriate: type of non-physical 1080 research-related injury compensation coverage provided by the site’s policy, e.g., 1081

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psychological such as emotional distress, social such as family discrimination, financial 1082 such as lost wages, etc.)”. 1083

5.3. IRB/EC/RE Considerations 1084

• Site-specific ICF(s) must accurately reflect the information content of the protocol document, 1085 protocol ICF(s), and applicable protocol appendices, e.g., Schedule of Procedures. 1086

NOTE: If the IRB/EC/RE requires any substantive changes or deletions of the informational 1087 contents of the protocol-specific ICF(s), the CRS may need to provide written documentation 1088 at the time of protocol registration, if applicable 1089

SEE: The Protocol Registration Manual and Protocol Registration Policy 1090

• Site-specific ICF(s), including English and/or local language versions (as applicable) as well as 1091 the protocol ICF(s) must be submitted for review and approval by the reviewing IRB/EC/RE 1092 and the DAIDS Protocol Registration Office (PRO), if applicable, prior to implementation at 1093 the clinical research site. 1094

• English and local language versions of the same site-specific ICF(s) (e.g., enrollment ICF) must 1095 include the same information content. 1096

• Language/wording used in site-specific ICF(s) does not need to match verbatim to the 1097 language used in the protocol-specific sample ICF(s) as long as the information content is the 1098 same; the focus is on mandated concepts rather than on mandated language. 1099

NOTE: Information content from the protocol sample ICF(s) is not required to be in a specific 1100 section of the site-specific ICF(s) as long as this content is contained somewhere in the site-1101 specific ICF(s). 1102

• Reviewing IRBs/ECs/REs may determine that additional ICF(s) for a particular study are 1103 needed at the clinical research site as well as generic screening protocols/ICFs (e.g., 1104 screening, study participation, future use of samples and associated health information, 1105 written assent, etc.). 1106

• Developing a separate site-specific ICF is strongly recommended if biological samples 1107 (including leftover samples) and/or participant's associated health information will be 1108 collected and stored for future research. 1109

SEE: Stored Samples and Associated Data Considerations, section 4.6.11 1110

5.4. Key Concepts/Issues 1111

There are some key concepts/issues that should be addressed at the local/site level, if applicable: 1112

• Reasonably foreseeable risks, including those risks associated with the study 1113 intervention(s)/product(s)/strategy(ies), study procedures, social impact events, study 1114 participation, and any risks to a developing fetus (reproductive risks) and/or breastfeeding 1115 infant. The risk information in the site-specific ICF(s) should reflect the risk information 1116 included in the protocol and protocol-specific sample ICF(s). 1117

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NOTE: Reviewing IRBs/ECs/REs can require that site-specific ICF(s) include additional risk 1118 information than what is included in the protocol sample informed consent. Also, risk 1119 information in the protocol sample ICF(s) does not need to be included verbatim in the site-1120 specific ICF(s) as long as the content is the same. 1121

• Reasonably foreseeable direct and ancillary benefits at the site level, if any. 1122

• Breastfeeding/replacement feeding requirements and related issues at the site level (e.g., 1123 availability of clean water). 1124

• Disposition of biological samples at the study’s completion at the local level (e.g., destroyed 1125 versus stored locally or shipped outside of the country). 1126

• Information related to incidental findings (IFs), if applicable. The following issues should be 1127 addressed if IFs will be disclosed to participants: (1) the possibility of discovering IFs; (2) 1128 participant’s choice to receive IFs; (3) participant’s permission to be re-contacted regarding 1129 IFs; and (4) if there is actionability at the site level for those IFs deemed to be clinically 1130 relevant and important. (SEE: Section 4.6.12). 1131

• Individual Research Results (IRRs) considerations. (SEE: Section 4.6.13) 1132

• Research-related injury issues at the local level, including the availability of treatment and 1133 compensation for injury. 1134

• Information related to any referral to care and/or provision of care at the site level (e.g., 1135 treatment of STIs and provision of contraception/condoms). 1136

• Post-trial availability of a study product/intervention at the site level 1137

• Reimbursement for study participation at the local level as determined by the reviewing 1138 IRB/EC (e.g., time, effort, transportation). 1139

NOTE: Reimbursement is not the same as compensation for research-related injury. 1140

• Social impact events (e.g., inadvertent disclosure of study participation resulting in 1141 stigmatization or discrimination) that may be affected by local issues (e.g., anti-gay laws) 1142 should be described in the site-specific ICF(s), as applicable. 1143

6. THE INFORMED CONSENT PROCESS 1144

The informed consent process is a process by which a participant voluntarily confirms his or her 1145 willingness to participate in a particular study after having been informed of all aspects of the trial that 1146 are relevant to the participant’s decision to participate. (ICH E6 (R2)) 1147

6.1. Recruitment 1148

The consent process starts with the participant recruitment. Any study specific materials used 1149 for recruitment, such as posters or brochures or flyers, presenting the research study to the 1150 prospective participant must reviewed and approved by the appropriate IRB/EC/Regulatory 1151 Entity approval(s) prior to use. 1152

6.2. Eligibility 1153

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Each study’s protocol has inclusion/exclusion criteria to determine who can or cannot participate 1154 in the study. These criteria describe characteristics that must be shared by all participants, e.g., 1155 age, gender, medical history, and current health status. 1156

Enrolling participants with similar characteristics guarantees that the data from the study be 1157 related to the scientific question and not due to random factors. These criteria also make certain 1158 that people who could be made worse by participating in the study are not exposed to the risk. 1159

Eligibility can be established by stand-alone screening consent process versus full study ICF 1160 process: 1161

• In the stand-alone screening approach, potential participants are asked to provide private 1162 identifiable information and/or to submit themselves to various tests, for example laboratory 1163 tests, biopsies, etc. that would determine if they meet study specific inclusion/exclusion 1164 criteria and thus be eligible to enroll in the study. If they are found to be eligible for the study, 1165 candidates would then be offered a separate study specific ICF to be enrolled in the study. 1166

• In the full study ICF process, potential participants give their consent to enroll in the study 1167 prior to being asked any specific inclusion/exclusion information or tests that are used to 1168 determine specific study eligibility, and thus remain or discontinue study participation. 1169

6.3. Ongoing Consent Process 1170

Obtaining a signature on an ICF does not complete the consent process. Maintaining informed 1171 consent requires that participants be provided with any new information and/or substantive 1172 change in the conditions or study procedures that arises during the course of the study (such as 1173 changes in risk, benefit, etc.) that may affect the participant’s decision to continue participation 1174 in the study. Participants should be provided with this information in a timely manner. As such, 1175 the informed consent process is ongoing throughout the entire research study until the 1176 participant decides to end his/her participation or until the study closes. 1177

6.4. Study Closure 1178

Once the study has concluded, as part of the ongoing consent process, participants should be 1179 notified of aggregated findings that may or may not impact each individual participant. 1180 Furthermore, if these findings result in changes to standard of care for the condition under study, 1181 alternative treatments and/or post-trial access information should be provided to all 1182 participants. 1183

NOTES: 1184

• Once a participant is enrolled in the study, the informed consent process continues with the research 1185 staff providing information regarding the study. The informed consent form is then presented and 1186 used as a guide for the verbal explanation of the study. The informed consent form must not serve 1187 as a substitute for discussion. 1188

• It is important to the informed consent process that the research staff not only answer questions but 1189 also ask questions. Asking questions can further the discussion, initiate any questions from the 1190 potential participant, and help the research staff decide whether the person is truly understanding 1191 the study. However, research staff must be careful not to ask “trick” questions to test a participant’s 1192

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understanding, but rather ask direct questions with unique answers that can be easily recalled by the 1193 participant. 1194

• In addition, it is important that the participant be given enough time and opportunity to review all 1195 possible options before signing the informed consent. The participant’s/LAR’s/parent(s)’s signature 1196 or mark provides documentation of agreement to participate in a study. Study-specific procedures 1197 cannot be conducted prior to obtaining research consent through an ICF(s) e.g., procedures done to 1198 verified study eligibility, directions to stop standard of care prior to study enrollment. 1199

6.5. DAIDS Informed Consent Process Requirements 1200

DAIDS permits the delegation of the task/responsibility of conducting the informed consent 1201 process discussion and obtaining informed consent, if this practice is permissible as per 1202 applicable local laws, regulations, guidance, and institutional policies, since the delegation of this 1203 task/responsibility is allowable as per HHS and FDA regulations. However, as is the case with any 1204 delegation of duties, staff conducting informed consent processes need to be “qualified” by 1205 education, experience, training, as well as knowledge of the study. Furthermore, when this 1206 task/responsibility is delegated, the investigator still retains the overall responsibility for the 1207 conduct of the study at the site, including this and any other delegated tasks/responsibilities 1208

SEE: DAIDS Delegation of Duties (Delegation of Responsibilities/Authorities) Log-Policy (in draft). 1209

NOTE: Consult your local, state, and/or national regulations, guidance, and institutional policies 1210 regarding the delegation of obtaining informed consent. Follow the strictest of these regulations, 1211 as applicable. 1212

To ensure that DAIDS supported and/or sponsored clinical research complies with HHS, FDA 1213 regulations as well as ICH E6 (R2) process standards, DAIDS requires all CRSs to have the following 1214 in place: 1215

6.5.1. Informed Consent Process SOP and Documentation 1216

All active sites conducting DAIDS sponsored and/or supported research must develop and 1217 implement an Informed Consent Process SOP. This SOP must include the following: 1218

• Information about applicable local laws, regulations, guidance, and institutional policies 1219 pertaining to the informed consent process, including information related to delegating the 1220 task/responsibility of obtaining and documenting informed consent. The most stringent 1221 approach applies at the site level. 1222

NOTE: A weblink, appendix, reference, and/or description in the SOP is acceptable. 1223

• Information related to obtaining and documenting informed consent when vulnerable (e.g., 1224 children, prisoners, pregnant women, fetuses, neonates, decisionally impaired persons, etc.) 1225 and illiterate populations are participants (SEE: section 6.6). 1226

• Information about who can serve as an impartial witness, when appropriate, based on local 1227 laws, regulations, guidance, and institutional policies 1228

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• Relevant information about the investigator’s availability/involvement in the informed 1229 consent process, and how the investigator will supervise staff to whom trial-related duties 1230 such as obtaining informed consent (ICH E6 R2 section 4.2.5). 1231

Clearly document the IC process in the participant’s research record. Documentation includes 1232 but is not limited to: 1233

• Indicating the investigator's availability/involvement during the IC process (e.g., investigator 1234 was available to answer participant questions) 1235

• Specifying the staff involved during the informed consent discussion (e.g., impartial witness, 1236 interpreter, study coordinator, etc.) 1237

• Signifying that this IC process preceded study procedures, participant's questions were 1238 answered, etc. 1239

6.5.2. FDA Form 1572/DAIDS IoR Form – Delegation of Duties Including Informed Consent 1240

In accordance with the DAIDS Protocol Registration Manual and Policy, site personnel who are 1241 responsible for making a “direct and significant contribution to the data” need to be listed on the 1242 FDA Form 1572/DAIDS IoR Form. Sites should include listing staff on these forms who have a 1243 significant role in conducting the informed consent discussion and obtaining informed consent. 1244

The investigator ultimately makes the decision of who to list on the FDA Form 1572/DAIDS IoR 1245 Form, taking into account staff who routinely perform significant part(s) of the informed consent 1246 process. For example, the person providing the ICF document but who is not part of the 1247 discussion would be considered as having an insignificant role in the process. However, the 1248 person who performs the bulk of the informed consent discussion and/or any assessment of 1249 understanding of the discussion, and the person signing the ICF form would be considered as 1250 having a significant level of responsibility in the informed consent process and should be listed 1251 on the 1572 and IoR forms. 1252

SEE: The Protocol Registration Manual for additional information on completing the FDA Form 1253 1572/DAIDS IoR Form at: DAIDS Protocol Registration Manual 1254

6.5.3. Document Maintenance 1255

• Maintain the IC process SOP and study-specific DoD Logs as well as any relevant 1256 documentation, such as applicable local laws and guidance references and training 1257 documentation, in the site’s essential documents/regulatory binder/files. Please note that 1258 DAIDS does not require the IC process SOP or DoD Logs to be submitted to OCSO or to the 1259 Protocol Registration Office. 1260

• Keep relevant correspondence (e.g., from the IRB/EC/RE, DAIDS, etc.) in the site’s essential 1261 documents/regulatory binder/files. 1262

• Retain previous versions of all Informed Consent Process SOPs and DoD Logs in the site’s 1263 essential documents/regulatory binder/files. 1264

SEE: 1265

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• Delegation of Duties Log Policy; Delegation of Duties Log Instructions; Delegation of Duties 1266 Log Template (in draft) 1267

• Requirements for Essential Documents at Clinical Research Sites Conducting DAIDS Funded 1268 and/or Sponsored Clinical Trial; Appendix 1. Essential Documents Recordkeeping 1269 Requirements (new version pending) 1270

6.5.4. Clinical Quality Management Plans and the Informed Consent Process (CQMP) 1271

CTU PIs/CRS Leaders/ Principal Investigators are responsible for verifying that informed consent 1272 Quality Assurance (QA)/Quality Control (QC) checks are part of the site’s overall Clinical Quality 1273 Management Plan, as currently required by the DAIDS Requirements for Clinical Quality 1274 Management Plans policy. As a best practice, site staff delegated to conduct and oversee the 1275 consent process should always review and re-review IC documents to ensure that all required 1276 dates, entries and signatures are recorded prior to participant departure from the clinic. 1277

SEE: Policy: Requirements for Clinical Quality Management Plans 1278

6.6. Notifying Participants of New Findings or Changes to the Study 1279

Circumstances may arise when it is necessary to revise ICF(s) to include important new 1280 information and/or changes to the study that are relevant for potential participants, as well as 1281 for those who are already-enrolled. These circumstances can include: 1282

• New findings that change the risk/benefit profile (e.g., an unexpected adverse event or an 1283 adverse event occurring at greater frequency or severity than previously stated during the 1284 consent process); 1285

• Procedures have been added, modified, or removed; 1286

• New alternative treatments become available; and/or 1287

• General study amendments. 1288

Site-initiated revisions can also be made to site-specific ICF(s) due to: IRB/EC/RE stipulations; 1289 administrative changes (i.e., contact information), changes made to clarify ICF content, etc. The 1290 revised IRB/EC/RE-approved ICF(s) is/are then used to obtain participants consent to join or 1291 continue in the study. 1292

These significant new findings and/or study changes may impact a participant’s willingness to 1293 join the study or to continue study participation. How participants are notified of these new 1294 findings or changes to the study may depend on the impact on study risk to participants and the 1295 immediacy needed to communicate the information. 1296

While the study sponsor, protocol teams, and /or Investigators may suggest methods for 1297 disclosing information to participants, it is up to the IRB/EC/RE to ultimately determine the 1298 appropriate method for informing participants of any important new information and/or changes 1299 to the study. 1300

NOTE: For already-enrolled participants, sponsors and IRBs/ECs/REs will determine if it is 1301 necessary to obtain the participant’s consent (i.e., re-consent) to the changes or new information 1302

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based upon the nature of the change in the research study and the new information that 1303 warranted the change. 1304

6.6.1. New Findings 1305

The HHS regulations at 45 CFR 46.116(b)(5) and the FDA regulations at 21 CFR 50.25(b)(5) state: 1306

“A statement that significant new findings developed during the course of the research 1307 which may relate to the subject’s willingness to continue participation will be provided to 1308 the subject.” 1309

ICH E6 (R2), section 4.8.10(p) states: 1310

“… that the subject or the subject’s legally acceptable representative will be informed in a 1311 timely manner if information becomes available that may be relevant to the subject’s 1312 willingness to continue participation in the trial.” 1313

However, the U.S. regulations and applicable guidance do not mandate a timeframe within which 1314 the new information will be provided to a participant. ICH E6 (R2) uses the phrase “timely 1315 manner” but does not quantify this term. 1316

It is DAIDS expectation that when there are any changes made to ICF(s), these updated ICF(s) 1317 must be reviewed and approved by the IRB/EC/RE, as appropriate, and be implemented 1318 “immediately”, upon receipt of the IRB/EC/RE-approved ICF(s). This requirement applies to 1319 consenting new study participants as well as to re-consenting already-enrolled participants 1320 (when re-consent is mandated by the sponsor and/or IRBs/ECs/REs). In this context, 1321 “immediately” and “timely manner” is interpreted as “without delay”, usually by or at the 1322 participant’s next study visit. 1323

NOTES: 1324

• When appropriate, consent documents should include a statement that significant new 1325 findings will be provided to the participant. The U.S. regulations and guidance and ICH E6 1326 (R2) (section 4.8.2) require that ICF(s) be revised whenever important new information 1327 becomes available that may be relevant to the participant’s consent. 1328

• For already-enrolled participants, sponsors and IRBs/ECs/REs will determine if it is necessary 1329 to obtain the participant’s consent to the changes or new information based upon the nature 1330 of the change in the research study and the new information that warranted the change. This 1331 is process is referred to as “re-consenting” the participant. When participants are re-1332 consented, they need to be provided a signed and dated copy of the ICF (ICH E6 R2 4.8.11, 1333 and DAIDS Guidance on Reconsenting). 1334

6.6.2. Study Amendments Full Version Protocol Amendment or Letters of Amendment (LoA) 1335

Changes to the study are made through amendments that are submitted to and reviewed and 1336 approved by the IRB/EC/RE as applicable. 1337

When required by the sponsor and/or IRB/EC/RE, communicate change(s) in study related 1338 information that may influence a participant’s decision to participate or continue his/her 1339

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participation in a study through the revised consent document. Any associated study changes 1340 are not to be implemented until after written re-consent is obtained from the participant. 1341

Similar to obtaining initial informed consent, each participant is given sufficient time to read the 1342 new information and revised consent documents, and ask questions, before being asked to sign 1343 the revised IC. The participant’s signature is affirmation of his/her willingness to continue study 1344 participation. 1345

6.6.3. DAIDS Dear Participant Letters or Participant Notifications 1346

A DAIDS Dear Participant Letter is a letter, text, or other means of quickly disseminating written 1347 information which may be used to notify participants of planned actions or other new 1348 information. Depending on the nature of new information, this communication can be either 1349 “urgent” or “non-urgent”. 1350

• Expedited Safety Notification or “Urgent” Dear Participant Letters 1351

This type of notification is used when there are significant and immediate participant 1352 safety concerns related to a study product/intervention/strategy; and sites, participants, 1353 investigators, and IRBs/ECs/REs must be notified in an expedited manner to ameliorate 1354 real and apparent immediate study-related harm. Plans to ameliorate the immediate 1355 potential for harm, including planned participant communication must be promptly sent 1356 to the IRB/EC/RE. Once the IRB/EC/RE notification is made, an amendment to the 1357 protocol and IC documents is submitted for IRB/EC/RE review and approval. 1358

While this mechanism does not require IRB/EC/RE approval prior to distribution, 1359 IRBs/ECs/REs must be promptly notified of any event that increases immediate risk of 1360 harm to participants. This initial notification to participants may be done verbally and 1361 may occur before an official and complete Dear Participant Letter is finalized. This verbal 1362 notification must be document in the participant’s study records. 1363

NOTE: When the sponsor and/or IRB/EC/RE requires re-consent, Dear Participant Letters 1364 CANNOT be used in lieu of a complete informed consent form and process to document 1365 a participant’s agreement to continue study participation. If participants are asked to sign 1366 these letters to document receipt, their signatures DO NOT constitute any type of 1367 consent. Document in each participant’s research record that the participant was sent 1368 the Dear Participant Letter, and if applicable, that it was received. 1369

• “Non-Urgent” Dear Participant Letters 1370

This type of notification can be used to convey non-urgent new information and/or 1371 changes to current or past study participants, such as aggregate study findings, study 1372 completion, etc. Since the intent of such letters is not to communicate information to 1373 eliminate apparent immediate harm, this type of Dear Participant letter requires 1374 IRB/EC/RE review and approval, as applicable, prior to distribution. 1375

6.6.4. Addenda 1376

Another means of conveying new information is the use of an addendum to the IC document. 1377 This method can be used to convey information that does not change the risk of harm to 1378

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participants but informs them of a change, e.g., the closure of a study arm, a change in visit 1379 schedule, etc. Each addendum must be approved by the IRB/EC/RE before it is provided to 1380 participants. 1381

6.6.5. Scripts 1382

Scripts are the written dialogs that are used to convey study specific information to participants. 1383 By reciting the same information, message consistency is maintained. This information must be 1384 IRB/EC/RE approved except when used to eliminate apparent immediate harm to study 1385 participants. Scripts may also be used, for example, when conducting study visits and to 1386 communicate visit reminders or adherence measures and HIV counseling. 1387

Some important tips to remember when writing this type of script are: 1388

• Create scripts that are engaging and motivate a conversation rather than being instructive 1389 in nature 1390

• Refer to yourself as “I” and to the participant as “you” 1391

• Write the script as if you were speaking 1392

• Rehearse the script by yourself, or talking to a friend, the oral script presentation prior 1393 doing with real participants 1394

NOTE: the use of Scripts for consenting potential participants who cannot read or write in any 1395 language, or who have only basic levels of education, may be a beneficial tool. 1396

6.7. Vulnerable Populations 1397

Vulnerable populations may be considered as potential research participants if adequate 1398 provisions are established. When some or all of the research participants are likely to be 1399 vulnerable to coercion or undue influence, additional specific safeguards to protect the rights and 1400 welfare of these participants must be included in the study and informed consent process as per 1401 HHS and FDA regulations and ICH E6 (R2). Vulnerable participants may include children, 1402 prisoners, fetuses, neonates, decisionally impaired persons, ethnic minority groups, members of 1403 a group with a hierarchical structure, persons with incurable diseases, persons in nursing homes, 1404 refugees, persons in emergency situations, and the economically or educationally disadvantaged. 1405

The Council for International Organizations of Medical Sciences (CIOMS) Guidance addresses the 1406 vulnerable populations issue from a more general perspective. CIOMS states: “Sponsors, 1407 researchers, governmental authorities, research ethics committees and other stakeholders must 1408 ensure that the benefits and burdens of research are equitably distributed. Groups, communities 1409 and individuals invited to participate in research must be selected for scientific reasons and not 1410 because they are easy to recruit because of their compromised social or economic position or 1411 their ease of manipulation”. In addition, “… The equitable distribution of benefits and burdens in 1412 the selection of study populations requires that the benefits of research be distributed fairly and 1413 that no group or class of persons bears more than its fair share of the risks or burdens from 1414 research participation”. 1415

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CIOMS guidelines call for investigators and sponsors to respect the autonomy of all research 1416 participants and to implement research that follows the principal of “Justice”. In this respect 1417 CIOMS states: “Justice requires also that the research be responsive to the health conditions or 1418 needs of vulnerable subjects. The subjects selected should be the least vulnerable necessary to 1419 accomplish the purposes of the research. Risk to vulnerable subjects is most easily justified when 1420 it arises from interventions or procedures that hold out for them the prospect of direct health-1421 related benefit. Risk that does not hold out such prospect must be justified by the anticipated 1422 benefit to the population of which the individual research subject is representative”. 1423

SEE: 1424

• The Council for International Organizations of Medical Sciences (CIOMS) International ethical 1425 guidelines for health-related research involving humans sections (3): Equitable distribution of 1426 benefits and burdens in the selection of individuals and groups of participants in research; 1427 (4): Individual informed consent; (13): Research involving vulnerable persons; (14): Research 1428 involving children; and (15): Research involving individuals who by reason of mental or 1429 behavioural disorders are not capable of giving adequately informed consent; 1430

• DAIDS: Clinical Trial Protocol Documents Manual ,section 18.2; 1431

• ICH E6 R2, sections 1.6.1 and 3.1.1 1432

6.7.1. Children in Research 1433

Children and adolescents can participate in research, unless there is a sound scientific 1434 justification for their exclusion. Due to their changing physical and emotional development, 1435 children may be at increased risk of harm when participating in research. In addition, their 1436 evolving capacity to consent may limit their ability to make fully informed decisions regarding 1437 participation. Thus, the HHS regulations at 45 CFR part 46 Subpart D and when applicable, 21 1438 CFR 50 Subpart D, require additional safeguards and protections for children involved in research. 1439

A child is a person who has not attained the legal age for consent to treatments or procedures 1440 involved in the research, under the applicable law of the jurisdiction in which the research will 1441

be conducted 45 CFR part 46.402(a) and 21 CFR part 50.3(o). Who is legally considered a child 1442 may vary from location to location. In addition, there may be some circumstances under which 1443 a minor would not meet the definition of a child and can therefore consent for themselves for 1444 clinical care and/or research, depending on the locale. 1445

Children may participate in research if all of the applicable requirements at 45 CFR part 46 1446 Subpart A and D (and 21 CFR 50 Subpart D for FDA-regulated research) are satisfied. Proposed 1447 research with children is permissible with IRB/EC approval under §46.404, 405 or 406 and §50.51, 1448 52, and 53, when applicable. Research not otherwise approvable by the IRB/EC (§46.407 and 1449 §50.54), may be permissible after HHS-level review. 1450

For all permissible categories of research with children, the IRB/EC is responsible for determining 1451 that adequate provisions are made for soliciting the assent of the children, soliciting the 1452 permission of each child's parents or guardian-or one parent or guardian, as appropriate as per 1453 §46.408 and §50.55, when applicable (SEE: sections 6.3.1.1 and 6.3.1.2). 1454

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SEE: 1455

• OHRP Research with Children FAQs; 1456

• DAIDS Policy: Enrolling Children (including Adolescents) in Clinical Research: Protocol 1457 Document Requirements; Appendix 1-Risk/Benefit Categories; Appendix 2-Examples of 1458 Template Language; Appendix 3 Wards; and Appendix 4- Waivers of Parental/Guardian 1459 Permission or Child Assent 1460

• DAIDS Policy: Enrolling Children (including Adolescents) in Clinical Research: Clinical Research 1461 Site Requirements; requires the clinical research site to submit the IRB’s/EC’s designation of 1462 a risk/benefit category and subsequent IRB/EC approval to DAIDS; 1463

• DAIDS Clinical Trial Protocol Documents Manual, section 18.3.2; 1464

• 45 CFR 46.408 - Requirements for permission by parents or guardians and for assent by 1465 children.; 1466

6.7.1.1. Assent of a Minor 1467

The IRB/EC may determine that children are capable of giving assent when children and 1468 adolescents are participating in the research. As per 45 CFR 46.402(b), “‘Assent’ means a child’s 1469 affirmative agreement to participate in research. Mere failure to object should not, absent 1470 affirmative agreement, be construed as assent”. As such, the child should be engaged in the 1471 research discussion, using age-appropriate information. The IRB/EC is responsible for 1472 determining if there are adequate provisions for obtaining child assent and parent/guardian 1473 permission. 1474

IRBs/ECs should consider age, individual circumstances, life experiences, physical and emotional 1475 development, and the proposed research when deciding the need for assent. If an IRB/EC 1476 determines that assent is required, it also determines how assent must be documented. 1477 However, if the IRB/EC determines that the capability of some or all of the children is so limited 1478 that they cannot reasonably be consulted or that the research holds out a prospect of direct 1479 benefit that is important to the health or well-being of the children and is available only in the 1480 context of the research, the assent of the children is not a necessary condition for proceeding 1481 with the research. Even where the IRB/EC determines that the participants are capable of 1482 assenting, the IRB/EC may still waive the assent requirement under circumstances in which 1483 consent may be waived in accord with 45 CFR part 46.116 of Subpart A, and 21 CFR 50.55 for 1484 FDA-regulated research. 1485

Even though the HHS regulations do not require documentation of assent, the IRB/EC may 1486 determine an appropriate method for documenting child assent. Based on all the considerations 1487 discussed above, adolescents research participants could also give consent using the adult form 1488 of the informed consent form, but parental permission would still be required. When the IRB/EC 1489 determines that written assent is not required, documentation of child’s verbal assent must be 1490 documented in the participant’s research record. The IRB/EC may also decide that the assent is 1491 not needed. 1492

SEE: 1493

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• OHRP’s Research with Children FAQs; 1494

• DAIDS Policy: Enrolling Children (including Adolescents) in Clinical Research: Protocol 1495 Document Requirements; Appendix 1-Risk/Benefit Categories; Appendix 2-Examples of 1496 Template Language; Appendix 3 Wards; and Appendix 4- Waivers of Parental/Guardian 1497 Permission or Child Assent 1498

• DAIDS Policy: Enrolling Children (including Adolescents) in Clinical Research: Clinical Research 1499 Site Requirements; 1500

• DAIDS Clinical Trial Protocol Documents Manual, section 18.3.2; 1501

• 45 CFR 46.408 - Requirements for permission by parents or guardians and for assent by 1502 children.; 1503

• ICH E6 R2 section 4.8.12; 1504

6.7.1.2. Parental/Guardian Permission 1505

In accordance with 45 CFR part 46.408 and 21 CFR 50.55 for FDA-regulated research, the IRB/EC 1506 determines that adequate provisions are made for soliciting the permission of each child's 1507 parents or guardian. Where parental permission is to be obtained, the IRB/EC may find that the 1508 permission of one parent is sufficient for research to be conducted under §46.404 or §46.405 (or 1509 §50.51 or §50.52 for FDA-regulated research). Where research is approved under §46.406 and 1510 §46.407 (or §50.53 or §50.54 for FDA-regulated research) and permission is to be obtained from 1511 parents, both parents must give their permission unless one parent is deceased, unknown, 1512 incompetent, or not reasonably available, or when only one parent has legal responsibility for 1513 the care and custody of the child. Permission by parents or guardians must be documented in 1514 accordance to the extent required by §46.117 (and §50.27 for FDA-regulated research). 1515

In general, there are three categories of research with children that can be approved by IRBs/ECs, 1516 when: 1517

• The risks of the research are no more than minimal. 1518

• More than minimal risk to children is presented by an intervention or procedure that holds 1519 out the prospect of direct benefit for the individual participant or by a monitoring procedure 1520 that is likely to contribute to the participant’s well-being; the risk is justified by the anticipated 1521 benefit to the participants; and, the relation of the anticipated benefit to the risk is at least 1522 as favorable to the participants as that presented by available alternative approaches. 1523

• More than minimal risk to children is presented by an intervention or procedure that does 1524 not hold out the prospect of direct benefit for the individual participant, or by a monitoring 1525 procedure that is not likely to contribute to the wellbeing of the child; the risk represents a 1526 minor increase over minimal risk; the intervention or procedure presents experiences to 1527 participants that are reasonably commensurate with those inherent in their actual or 1528 expected medical, dental, psychological, social or educational situations; and, the 1529 intervention or procedure is likely to yield generalizable knowledge about the participants’ 1530 disorder or condition which is of vital importance for the understanding or amelioration of 1531 the participants’ disorder or condition. 1532

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For non-FDA regulated research, if the IRB/EC determines that parental or guardian permission 1533 is not a reasonable requirement to protect the child participant (e.g., neglected or abused 1534 children), it may waive the permission requirements and substitute an appropriate mechanism 1535 for protecting these participants, if the waiver is not inconsistent with federal, state, or local law. 1536 The choice of an appropriate mechanism depends upon the nature and purpose of the 1537 procedures described in the protocol, the risk and anticipated benefit to the participant and 1538 his/her age, maturity, status, and condition. 1539

Note: children that reach the legal age of consent during their study participation need to be 1540 asked to consent to their continued participation through a written informed consent form, 1541 unless the IRB/EC determines that the requirements for obtaining informed consent can be 1542 waived. Parental permission is no longer required for the now-adult participant. 1543

SEE: 1544

• 45 CFR 46, Subpart D; 21 CFR 50, Subpart D; 1545

• ICH E6 R2 Section 4.8.12; 1546

• DAIDS Policy: Enrolling Children (including Adolescents) in Clinical Research: Protocol 1547 Document Requirements; Appendix 1-Risk/Benefit Categories; Appendix 2-Examples of 1548 Template Language; Appendix 3 Wards; and Appendix 4- Waivers of Parental/Guardian 1549 Permission or Child Assent 1550

• DAIDS Clinical Trial Protocol Documents Manual, section 18.3.2; 1551

• OHRP Research with Children FAQs: Research Involving Children NIH Policy Requirements for 1552 the Inclusion of Children in Research CIOMS Guideline 17 1553

6.7.1.3. Wards 1554

The HHS regulations at 45 CFR part 46, subpart D and 21 CFR 50, subpart D for FDA-regulated 1555 research, provide additional protections for children who are also wards of the State or any other 1556 or entity. If the research is approved under §46.406 or §46.407 (or §50.53 or §50.54), the 1557 regulations require that the IRB/EC appoint an advocate for each child who is a ward, in addition 1558 to any other individual acting on behalf of the child as guardian or in loco parentis. The advocate 1559 agrees to act in the best interests of the child throughout the duration of the child’s participation 1560 in the research. In this instance, the advocate will observe or participate in the informed consent 1561 process and to the extent possible, ensure that the child understands what will be required of 1562 him or her during the research, and that if capable, the child provides his or her assent to 1563 participate. 1564

SEE: 45 CFR 46.409 Wards; 21 CFR 50.56; 1565

OHRP Research with Children FAQs 1566

6.7.2. Pregnant Women, Fetuses, and Neonates in Research 1567

Women of child-bearing potential can participate in research, unless there is a sound scientific 1568 justification for their exclusion. However, these women need to be informed about any 1569

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additional risks to themselves and/or their developing fetus. Furthermore, women should be 1570 informed about any other related risks, including any psychological, social, physical, or legal risks 1571 if they should decide to participate in the research (e.g., risk of physical harm if their significant 1572 other finds out about their research participation, etc.). 1573

SEE: The “Additional Pregnancy-Related IC form Requirements and Other Considerations”, section 1574 4.5 1575

6.7.2.1. Pregnant Women and Fetuses 1576

When the research holds out the prospect of direct benefit to the pregnant woman or to both 1577 the pregnant woman and the fetus, or there is no prospect of benefit for the woman or the fetus 1578 but the risk to the fetus is not greater than minimal risk and the purpose of the research is the 1579 development of important biomedical knowledge that cannot be obtained by any other means, 1580 only the pregnant woman’s consent needs to be obtained in accordance with the informed 1581 consent provisions of 45 CFR 46 Subpart A and §46.204 (d). 1582

When the research holds out the prospect of direct benefit solely to the fetus, then the consent 1583 of the pregnant woman and the father are obtained in accordance with the informed consent 1584 provisions of 45 CFR part 46 Subpart A and §46.204 (e). However, the father's consent is not 1585 required if he is unable to consent because of unavailability, incompetence, or temporary 1586 incapacity or the pregnancy resulted from rape or incest. 45 CFR 46.204(e). 1587

As per §46.204(f), persons providing consent under §46.204 (d) or (e) must be fully informed of 1588 any reasonably foreseeable impact of the research on the fetus or neonate. 1589

For children, as defined at §46.402(a) (and §50.3(o)), who are pregnant and are participating in 1590 research but cannot provide consent, assent and permission are obtained in accordance with 45 1591 CFR part 46 Subpart D (and 21 CFR 50 Subpart D, if applicable). However, if the research only 1592 involves treatments or procedures for which minors can give consent outside the research 1593 context (under applicable local/in-country laws, regulations, and guidance), such participants 1594 would not meet the regulatory definition of “children”. Under these circumstances, minors may 1595 be able to consent on their own behalf. 1596

SEE: 1597

• 45 CFR part 46 Subpart B. Additional Protections for Pregnant Women, Human Fetuses and 1598 Neonates Involved in Research; 1599

• OHRP Research with Children FAQs; 1600

• FDA Draft Guidance 4/2018: Pregnant Women: Scientific and Ethical Considerations for 1601 Inclusion in Clinical Trials Guidance for Industry 1602

NOTE: FDA regulations (21 CFR 50) do not include an equivalent section to 45 CFR 46 Subpart B. 1603

6.7.2.2. Neonates 1604

As per 45 CFR 46.205 viable neonates, neonates of uncertain viability, and nonviable neonates 1605 may be involved in research if certain conditions are met. §46.202(d) defines a “neonate” as a 1606 newborn infant. The World Health Organization qualifies this definition as “a child under 28 days 1607

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of age”. In addition, a “viable neonate” is a newborn that is, after delivery, able to survive (given 1608 the benefit of available medical therapy) to the point of independently maintaining heartbeat 1609 and respiration (§46.202(h)). 1610

For neonates of uncertain viability and nonviable neonates involved in research, each individual 1611 providing consent under §46.205 (b)(2) or (c)(5) must be fully informed regarding the reasonably 1612 foreseeable impact of the research on the neonate as per §46.205 (a)(2). 1613

For neonates of uncertain viability, until it has been ascertained whether or not the neonate is 1614 viable, the neonate may not be involved in research covered by 45 CFR part 46 Subpart B unless 1615 the additional conditions at §46.205 (b) have been met. In this instance, it is necessary to obtain 1616 the legally effective informed consent of either parent of the neonate or, if neither parent is able 1617 to consent because of unavailability, incompetence, or temporary incapacity, the legally effective 1618 informed consent of either parent's legally authorized representative (LAR) in accordance with 1619 45 CFR part 46 Subpart A. If the pregnancy resulted from rape or incest, the consent of the father 1620 or his LAR is not necessary. 1621

SEE: 45 CFR part 46.205(b)(2) 1622

For neonates determined to be viable after delivery, they may be involved in research only to the 1623 extent permitted by and in accordance with the requirements of 45 CFR part 46 Subparts A and 1624 D (e.g., parental permission obtained). As per §46.202(b), “‘delivery’ means complete separation 1625 of the fetus from the woman by expulsion or extraction or any other means” (§46.202(b)). 1626

SEE: 45 CFR part 46 Subpart B. Additional Protections for Pregnant Women, Human Fetuses and 1627 Neonates Involved in Research; CIOMS Guideline 18 and 19 1628

NOTE: FDA regulations (21 CFR 50) do not include an equivalent section to 45 CFR 46 Subpart B. 1629

6.7.3. Prisoners in Research 1630

As per §46.03 (c), a “prisoner” is “any individual involuntarily confined or detained in a penal 1631 institution”. This includes “individuals sentenced to such an institution under a criminal or civil 1632 statute, individuals detained in other facilities by virtue of statutes or commitment procedures 1633 which provide alternatives to criminal prosecution or incarceration in a penal institution, and 1634 individuals detained pending arraignment, trial, or sentencing” (§46.303(c)). 1635

Prisoners may be under constraints because of their incarceration which could affect their ability 1636 to make a truly voluntary or un-coerced decision about research participation (impact on their 1637 ability to provide informed consent). The HHS regulations at 45 CFR part 46, Subpart C require 1638 additional protections for prisoners who are involved as participants in research. IRBs/ECs 1639 reviewing research involving prisoners must comply with additional composition requirements 1640 and duties of the HHS regulations at 45 CFR part §46.304 & §46.305. 1641

The risk of the participating in the research must be commensurate with risks that would be 1642 accepted by non-prisoner volunteers. (§46.305(3)). 1643

OHRP details a set of procedures about what to do if a research participant becomes a prisoner 1644 during the study, even when this circumstance is not covered by the signed IC form: 1645

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• The PI should notify the IRB/EC immediately, and the prisoner should be temporarily 1646 withdrawn from the study until all of the requirements of 45 CFR 46 Subpart C have been 1647 met. 1648

• In special circumstances in which the PI asserts that it is in the best interest of the now 1649 prisoner participant to remain in the study while incarcerated, the participant may continue 1650 to participate in the research until the requirements of 45 CFR 46 Subpart C are satisfied. 1651 However, the PI must promptly notify the IRB/EC of this occurrence, so the IRB/EC can re-1652 review the study. 1653

SEE: 1654

• 45 CFR 46 Subpart C. Additional Protections Pertaining to Biomedical and Behavioral Research 1655 Involving Prisoners as Subjects; 1656

• DAIDS Clinical Trial Protocol Documents Manual section 18.2.2; 1657

• OHRP’s Guidance - Prisoner Involvement in Research (2003); 1658

• OHRP’s Prisoner FAQs 1659

NOTE: FDA regulations (21 CFR 50) do not include an equivalent section to 45 CFR 46 Subpart C. 1660

6.7.4. Diminished capacity/Impaired Consent Capacity/Decisionally Impaired Persons in Research 1661

A wide variety of diseases, conditions, and injuries can affect an individual’s ability to weigh the 1662 advantages and disadvantages of participating in research, and to provide informed consent. 1663

An IRB/EC/RE that reviews research involving individuals with diminished capacity/impaired 1664 consent capacity/decisionally impairment must include members who are knowledgeable about 1665 or experienced in working with such participants. Investigators may want to consider developing 1666 supplemental study specific informed consent materials, which should always be reviewed and 1667 approved by the appropriate IRB/EC. Furthermore, investigators should consider: assessing the 1668 consent capacity of potential participants using standardized testing aids; determining whether 1669 the IRB/EC or a third party should observe the consent process; considering additional 1670 monitoring; extending time periods for decision making; and/or re-assessing the participant’s 1671 decision-making capacity throughout the course of the research. Informed consent may be 1672 sought from a participant’s LAR as described throughout 45 CFR part 46. 1673

Impaired consent capacity may involve partial impairment, impairment that changes over time, 1674 or complete impairment. If a participant’s consent capacity is sufficiently impaired that the 1675 participant is unable to provide legally effective informed consent, IRBs/ECs and investigators 1676 must consider whether or not a LAR can give consent/continued consent on behalf of the adult 1677 participant, if permitted by the laws of the jurisdiction in which the research is conducted. 1678

SEE: 1679

• NIH Research Involving Individuals with Questionable Capacity to Consent: Points to 1680 Consider; OHRP IC FAQ What should be considered in seeking informed consent from 1681 individuals with diminished decision-making capacity? 1682

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• ICH E6 R2, Section 4.8.12; 1683

• FDA Draft Guidance 7/2014: Informed Consent Information Sheet Guidance for IRBs, Clinical 1684 Investigators, and Sponsors; 1685

• OHRP Informed Consent FAQs. 1686

6.7.5. Local Language Speakers 1687

The HHS and FDA regulations as well as ICH E6 (R2) (section 4.8.6) require that informed consent 1688 information be presented in a language understandable to the participant. Potential participants 1689 and, when applicable, their LAR, who do not speak/understand the most commonly used local 1690 language should be presented with a consent document written in a language understandable to 1691 them, i.e., in a language and at a level they can understand, using lay terms to describe scientific 1692 and medical terms. Potential participants should not be routinely excluded from participating 1693 due to language issues and barriers. 1694

Alternatively, a presentation of the informed consent information in conjunction with a short 1695 form written consent document (stating that the HHS and FDA regulatory elements of consent 1696 have been presented orally) and an IRB/EC-approved written summary of what is presented 1697 orally may be used in lieu of a long form consent. An impartial witness to the entire oral 1698 presentation is required, and the participant is given a copy of the short form document and the 1699 summary. The oral presentation and the short form written document must be in a language 1700 understandable to the participant. The IRB/EC-approved long form IC document may serve as 1701 the summary. The witness must be fluent in both the language used in the long form consent as 1702 well as the short form consent (the language understood by the participant). When the person 1703 obtaining consent is assisted by an interpreter, the interpreter may serve as the witness; 1704 however, an interpreter who is also a witness must be not affiliated with the study. Additionally, 1705 participants must receive a copy of the long IC or the summary written in the most commonly 1706 used language at the site and a copy of the short form in the language understood by the 1707 participant (SEE: Sections 7.3 and 7.4). 1708

When investigators can reasonably anticipate potential participants that may not 1709 speak/understand the most commonly used local language but can speak/understand less 1710 common local languages, they should submit to the IRB/EC appropriately translated consent 1711 documents in these anticipated languages (i.e., either a long form or a short form with written 1712 summary). IRBs/ECs should also be provided with a description of how interpreters will be made 1713 available during the informed consent process. 1714

There may be occasions when investigators have not anticipated a potential participant who 1715 speaks/understands a less commonly used local language and, therefore, do not have an 1716 appropriate IRB/EC-approved written translation of the IC documents and summary. Some 1717 circumstances may allow sufficient time to prepare translated IC documents and receive IRB/EC 1718 approval prior to enrolling the participant. Other circumstances may not allow sufficient time. 1719 As per FDA guidance, a contingency for this situation could include translating a generic short 1720 form in multiple languages that satisfies the requirements of 21 CFR 50.27(b)(2), and obtain 1721 IRB/EC approval for using these generic short forms to enroll such participants. 1722

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SEE: 1723

• OHRP Informed Consent of Subjects Who Do Not Speak English;1724

• FDA Guidance A Guide to Informed Consent - Information Sheet Non-English Speaking1725 Subjects; 1726

• FDA Draft Guidance 7/2014 Informed Consent Information Sheet Guidance for IRBs, Clinical1727 Investigators, and Sponsors 1728

6.7.6. Illiterate persons 1729

A person who speaks and understands the language used for both the consent forms and during 1730 the consenting process, but does not read and write this language, can enroll in a study and 1731 consent to study participation. A modified informed consent process should be considered by 1732 the IRB/EC, including the use of a short form ICF, oral presentation of the information contained 1733 in the long form ICF, and a written summary. 1734

Sites need to record in the research record the method used for communication with the 1735 prospective participant and the specific means by which the prospective participant 1736 communicated agreement to participate in the study. A third party must witness the entire 1737 consent process and sign the consent document. Although an impartial witness is not required 1738 by HHS regulations, an impartial witness is required by ICH E6 (R2) and DAIDS policy (SEE: section 1739 7.3). As per ICH E6 (R2) section 4.8.9, “the witness attests that the information in the consent 1740 form and any other written information was accurately explained to, and apparently understood 1741 by, the subject or the subject’s legally acceptable representative, and that informed consent was 1742 freely given by the subject or the subject’s legally acceptable representative”. In addition, a video 1743 tape recording of the consent interview is recommended when consenting non-speakers and 1744 illiterate populations. 1745

SEE: 1746

• FDA A Guide to Informed Consent - Information Sheet Illiterate English-Speaking Subjects;1747

• FDA Draft Guidance 7/2014 Informed Consent Information Sheet Guidance for IRBs, Clinical1748 Investigators, and Sponsors 1749

• Clinical Trial Protocol Documents Manual section 18.2.4;1750

• ICH E6 R2 section 4.8.9.1751

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7. DOCUMENTATION OF INFORMED CONSENT 1752 7.1. Legal signature/thumbprint/mark/electronic signature 1753

The participant’s/LAR’s signature on the ICF documents signifies the participant’s willingness to 1754 participate in the study or the LAR’s consent on behalf of a potential participant. The person 1755 obtaining informed consent needs to ensure that the participant’s/LAR’s signature follows 1756 applicable law(s), reviewing IRB/EC/RE requirements, institutional policies, CRS SOPs, and the 1757 IRB/EC/RE-approved protocol. In general, the signature must be the individuals’ legal name, but 1758 participants can use any designation he/she wishes to adopt as a signature for the duration of 1759 the study, as long as there is no local law or institutional standards that allows it (traditional 1760 signature, a mark, thumb print, or other method of “making their mark” as long as it meets local 1761 law or institutional standards). The written signature must be in ink. 1762

SEE: The Essential Documents Guidance, “Signature Documentation” section. 1763

A participant/LAR who speaks and understands the language of the ICF, but does not read and 1764 write the language can give consent/permission to be in a study by “making his/her mark” or by 1765 fingerprint/thumbprint on the ICF, when this is consistent with applicable law(s), etc. In this 1766 situation, the participant’s research record should indicate the reason for the lack of a signature. 1767

Traditionally, informed consent is obtained in a face-to-face interview using paper consent forms. 1768 It is permissible for an investigator to use an alternate method for the informed consent process, 1769 such as conducting the informed consent process through email, phone or video chat, and 1770 obtaining written informed consent or parental permission by facsimile, secure email, or eIC 1771 (electronic informed consent; SEE: Section 7.7). An investigator may obtain an electronic 1772 signature (e-signature) to document informed consent or parental permission, if e-signatures are 1773 legally valid within the local jurisdiction where the research is being conducted and the IRB/EC 1774 has approved this method to document informed consent. The investigator should be able to 1775 verify that the e-signature is legitimate. The CRS’s informed consent process SOP should include 1776 relevant information about this alternative process, as applicable. As per FDA guidance, an e-1777 signature is considered to be the “legally binding equivalent of the individual’s handwritten 1778 signature” (§ 11.3(b)(7)). 1779

In general, informed consent is documented by the use of an IRB/EC/RE-approved written ICF. 1780 The participant or LAR signs and dates the ICF and should receive a copy of the signed and dated 1781 written ICF as per ICH E6 (R2) (section 4.8.11). 1782

SEE: 1783

• 45 CFR 46.117(a)(c), 21 CFR 50.27 (a), 21 CFR 56.109(c); ICH E6 R2 section 4.8.11; 1784

• The Age and Identity Verification and Co-Enrollment Prevention Policy; 1785

• OHRP Informed Consent FAQs; 1786

• FDA Draft Guidance 7/2014: Informed Consent Information Sheet Guidance for IRBs, Clinical 1787 Investigators, and Sponsors; 1788

• FDA Draft Guidance 6/2017: Use of Electronic Records and Electronic Signatures in Clinical 1789 Investigations Under 21 CFR Part 11 – Questions and Answers Guidance for Industry 1790

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• OHRP and FDA Use of Electronic Informed Consent: Questions and Answers. Guidance for 1791 IRBs, Investigators, and Sponsors, December 2016 1792

7.2. Legally Authorized Representative (LAR) 1793

As per the current version of 45 CFR 46 part 102 (c) and 21 CFR 50.3 (l), a LAR or “legally 1794 authorized representative means an individual or judicial or other body authorized under 1795 applicable law to consent on behalf of a prospective subject to the subject's participation in the 1796 procedure(s) involved in the research”. ICH E6 (R2) has a similar definition for legally acceptable 1797 representative: “An individual or juridical or other body authorized under applicable law to 1798 consent, on behalf of a prospective subject, to the subject's participation in the clinical trial”. Who 1799 can act as the legally authorized/acceptable representatives is determined by the laws of the 1800 jurisdiction in which the research is conducted (e.g., local/in-country laws and guidance, 1801 institutional policies, etc.). Legally authorized/acceptable representatives should consider the 1802 individual’s previous preferences and values, if applicable, and the degree that study 1803 participation is in the participant’s best clinical interest. 1804

NOTE: The revised Common Rule, when implemented, expands the definition of a “legally 1805 authorized representative”. 1806

SEE: Section 8.2.1, Expanded definition of LAR. 1807

7.3. Impartial Witness 1808

An impartial witness must be present to observe the consent process when obtaining consent 1809 participants who do not speak/understand the language used to write the long ICF (section 6.3.5), 1810 illiterate/low literacy potential participants (section 6.6.6) and whenever the short form IC 1811 process is used (section 7.4). As per ICH E6 (R2), section 1.26, an impartial witness is “a person, 1812 who is independent of the trial, who cannot be unfairly influenced by people involved with the 1813 trial, who attends the informed consent process if the subject or the subject's legally acceptable 1814 representative cannot read, and who reads the informed consent form and any other written 1815 information supplied to the subject”. The purpose of the impartial witness is to corroborate the 1816 voluntariness of the participant’s/LAR’s consent and the adequacy of the consent process by 1817 ensuring that the information was accurately explained, and the participant’s/LAR’s questions 1818 were satisfactorily addressed. In order to fulfill this role, the impartial witness must be fluent in 1819 the language of the oral presentation. 1820

The witness must be an impartial third party, not otherwise connected with the research (i.e., 1821 not involved in the design, conduct, or reporting of the research study). The witness may be a 1822 family member or friend, “participant advocate”, staff member not involved in the trial or who 1823 does not work directly for the investigator, or anyone who can act in the best interest of the 1824 participant. The witness must be present (physically or by some other means, such as phone or 1825 video conference) during the entire consent discussion. 1826

A witness must be present when the participant/LAR is unable to read (e.g., illiterate, blind) and 1827 when the long ICF method is used and read to the participant or LAR. There must also be an 1828 impartial witness present when the short form ICF method is used (SEE: Section 7.4). 1829

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Under circumstances during which an interpreter is used during the informed consent discussion 1830 with the participant/LAR in the participant’s local language, the interpreter can also serve a dual 1831 role as the witness, if s/he is also an impartial third party to the research. 1832

SEE: 1833

• ICH E6 (R2) section 1.26; Sections 6.3.5, 6.3.6, and 7.4; 1834

• FDA Draft Guidance 7/2014: Informed Consent Information Sheet Guidance for IRBs, Clinical 1835 Investigators, and Sponsors; 1836

• DAIDS Clinical Trial Protocol Documents Manual sections 18.2.4 and 18.3.3 1837

7.4. Short Form ICF/Informed Consent Summary/Long Form ICF 1838

The regulations provide two different methods for obtaining written informed consent/parental 1839 permission: 1840

• Long form ICF: The long form ICF includes all the elements of informed consent as required 1841 under the HHS and FDA (when applicable) regulations and is written in a language and at a 1842 reading level that is understandable to the participant/LAR. The participant/LAR and the 1843 person obtaining consent sign the long form ICF. When the long ICF is used, the person 1844 obtaining consent will provide a copy of the long ICF to the participant/LAR. 1845

• Short Form ICF: The short form ICF states that the elements of informed consent as required 1846 under the HHS and FDA (when applicable) have been presented orally to the participant/LAR. 1847 A copy of the short form ICF and the written summary must be given to the participant/LAR. 1848 The participant/LAR must sign and date the short form. The witness must sign both the short 1849 form and the summary. The person obtaining consent/permission must sign the summary. 1850

The IRB/EC will approve which method(s) the investigator can use to obtain written 1851 consent/permission. Unless the IRB/EC waives the requirement to 1) obtain informed consent 1852 or 2) obtain written informed consent, a written IC document in a language that is 1853 understandable to the participant must be used. The consent document used can be either the 1854 IRB/EC-approved short form (accompanied by the written summary) or the IRB/EC-approved long 1855 form, as long as the short form or long form informed consent has been translated into a 1856 language understandable by the participant. 1857

If the participant/LAR cannot speak or read the language in the ICF, appropriate interpreter 1858 services need to be made available throughout the course of the research, since informed 1859 consent is a process that occurs throughout the course of the study. The interpreter may be a 1860 member of the research team, a family member, or friend of the participant/LAR. The person 1861 serving as the interpreter will interpret in the local language, the one understood by the 1862 participant, the consent document/written summary with the participant/LAR, explaining the 1863 study details in such a way that the participant/LAR understands the study, the required elements 1864 of informed consent, and his/her obligations as a participant part in the study. 1865

In this instance, informed consent is documented using an IRB/EC-approved short form ICF that 1866 has been translated into a language understandable to the prospective participant/LAR. 1867 Additionally, the IRB/EC needs to approve a written summary of what is to be said to the 1868

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participant/LAR; the IRB/EC-approved long form ICF can be used as this written summary (SEE: 1869 Section 6.6.5). 1870

SEE: 1871

• §46.116 and 117; §50.25 and 27;1872

• FDA Draft Guidance 7/2014: Informed Consent Information Sheet Guidance for IRBs, Clinical1873 Investigators, and Sponsors; 1874

• DAIDS Clinical Trial Protocol Documents Manual section 18.3.31875

• OHRP Guidance: Informed Consent of Subjects Who Do Not Speak English1876

7.5. Waiver and alteration of Some Elements of Informed Consent or Parental Permission for Non-1877 FDA Regulated Studies 1878

The HHS regulations at 45 CFR 46 allow an IRB/EC to waive the requirement for obtaining 1879 informed consent or parental permission, or to approve a consent procedure that leaves out or 1880 alters some or all of the elements of informed consent otherwise required under 45 CFR 1881 46.116(a) and (b). 1882

Waiving the requirement for obtaining informed consent or parental permission means that the 1883 IRB/EC has determined that investigators do not need to obtain the participant’s informed 1884 consent to participate in research. For example, some minimal risk, behavioral research in a clinic 1885 setting may require that participants be unaware that the research is taking place. 1886

SEE: 45 CFR 46.116(c) and (d) 1887 NOTE: FDA regulations do not contain an equivalent informed consent waiver process. 1888

7.6. Waiver of Documentation of Informed Consent or Parental Permission 1889

The HHS and FDA regulations allow an IRB/EC to waive the requirement to obtain a signed 1890 consent form for some or all of the participants. In cases in which the documentation 1891 requirement is waived, the IRB/EC may require the investigator to provide the participants with 1892 a written informed consent form or statement regarding the research (e.g., information sheet, 1893 written ICF). 1894

An IRB/EC may waive the requirement to obtain a signed consent form when either: “(1) That the 1895 only record linking the subject and the research would be the consent document and the principal 1896 risk would be potential harm resulting from a breach of confidentiality. Each subject will be asked 1897 whether the subject wants documentation linking the subject with the research, and the subject's 1898 wishes will govern; or (2) That the research presents no more than minimal risk of harm to subjects 1899 and involves no procedures for which written consent is normally required outside of the research 1900 context”. In these cases, the IRB/EC may determine that either the participant’s oral consent or, 1901 in the case of online survey research, the participant’s consent is implied by the completion of 1902 the survey instrument. 1903

During an informed consent process where the IRB/EC has waived the requirement to obtain a 1904 signed consent form, the investigator must provide the participant with all of the relevant 1905 information (e.g., review the eight basic elements of informed consent §46.116 and §50.25, if 1906

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applicable), answer the participant’s questions, and confirm that the participant understands the 1907 information provided before obtaining the participant’s verbal consent. The individual obtaining 1908 verbal consent must document the date that verbal consent was obtained and include a 1909 statement of what information was provided to the participant (e.g., information sheet) in the 1910 participant’s research record. 1911

NOTE: The revised Common Rule, when implemented, has an additional requirement for the 1912 IRB/EC approval of an informed consent documentation waiver request: “Where the participants 1913 are members of a cultural group in which signing forms is not a normal/acceptable practice.” 1914

SEE: 1915

• 45 CFR 46.117(c) and 21 CFR 56.109(c); 1916

• OHRP Informed Consent FAQs; 1917

• DAIDS Clinical Trial Protocol Documents Manual section 18.3.5 1918

7.7. Electronic Informed Consent Guidance 1919

Electronic informed consent (eIC) refers to the use of electronic systems and processes to convey 1920 study-related information and to obtain and document informed consent. Electronic systems and 1921 processes used must be in compliance with the FDA regulations at 21 CFR 11 and the DAIDS Policy 1922 on the Use of Electronic Information Systems in Clinical Research. eICs may include the use of, 1923 but not limited to, text, graphics, audios, podcasts, and interactive CRSs. 1924

7.7.1. eIC Process 1925

• The eIC must contain the required elements of informed consent, unless the IRB/EC has 1926 approved a process that alters or waives some or all of the elements. (add hyperlink to section 1927 7.5) _ 1928

• The information must be presented in a format that is understandable to the participants and 1929 all abbreviations should be spelled out the first time they are used. 1930

• Take steps to accommodate persons who have impairments such as poor vision or have 1931 difficulty with motor skills or are unfamiliar with electronic devices. 1932

• The eIC process must allow participants the opportunity to ask questions and receive answers 1933 by any means or combination of methods, such as messaging, telephone calls, or 1934 videoconferencing before signing the eIC. 1935

• If the eIC is interactive, it must be easy to use and allow the potential participant to go back 1936 and review information. 1937

7.7.2. Documenting eIC 1938

• If the consent is obtained at the research CRS, the participant's identity will be verified, the 1939 contents of the eIC will be reviewed with the participant, study related questions from 1940 participant and witness will be answered, and the witness will also signed the eIC. 1941

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• If the consent process is conducted remotely, all interactive responses and signatures by1942 participants, legally authorized representatives or other parties should be documented1943 electronically by the software system.1944

• The system must capture the date that consent was given, and a copy of the consent must be1945 provided to the person signing the form.1946

• The signed and dated hard copy of the eIC is given to the participant as per ICH E6 section1947 4.8.1948

7.7.3. eIC Confidentiality 1949

The copy of the consent may be a printed copy of the eIC or an electronic copy that is transmitted 1950 to the participant. If the eIC is transmitted using a personal electronic device such as an iPhone, 1951 the participant should be advised of the risk of loss of confidentiality. 1952

7.7.4. eIC Assent 1953

The eIC process may also be used to obtain assent from children. The language and presentation 1954 of the information must be understandable to the child and the documentation of assent would 1955 be the same as that used for adult participants. 1956

7.7.5. eIC IRB/EC Approval 1957

The IRB/EC must review and approve eICs and any amendments to the eIC. 1958

SEE: OHRP and FDA Use of Electronic Informed Consent: Questions and Answers. Guidance for 1959 IRBs, Investigators, and Sponsors, December 2016; OHRP Use of Electronic Informed Consent: 1960 Questions and Answers 1961

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8. INFORMED CONSENT CONSIDERATIONS UNDER THE REVISED COMMON RULE 1962

8.1. New Requirements upon implementation of the revised Final Rule/Common Rule (45 CFR 46) 1963

NOTE: anticipated effective date of January 21, 2019 1964

SEE: HHS -Revised Common Rule 1965

8.1.1. Expanded Definition of “Legally Authorized Representative” (LAR) 1966

The term legally authorized representative (LAR) has been expanded in the revised Common Rule 1967 and includes the following additional text: “If there is no applicable law addressing this issue, LAR 1968 means an individual recognized by institutional policy as acceptable for providing consent in the 1969 non-research context on behalf of the prospective subject to the subject’s participation in the 1970 procedure(s) involved in the research”. 1971

8.1.2. Concise Summary with “Key Information” 1972

Under the Final Rule, consent forms will now require a concise summary of study activities, risks, 1973 and benefits to be presented to research participants in advance of the main body of the consent 1974 document. “Key information" must be included to facilitate a potential participant's decision to 1975 participate or not. “Key Information” includes the following: 1976

• The project is research with voluntary participation 1977

• Summary of the research, including the purpose, duration, and procedures 1978

• Reasonably foreseeable risks or discomforts 1979

• Reasonable expected benefit 1980

• Any alternative procedures or course of treatment 1981

8.1.3. New Required Elements of Consent 1982

These elements are contained in the Final Rule but are not yet implemented. In the interim, 1983 investigators may still consider informing participants in IC documents of the following, when 1984 appropriate. 1985

New Basic Element to be included in IC documents: One of the following statements about any 1986 research that involves the collection of identifiable private information or identifiable 1987 biospecimens needs to be included: 1988

• A statement that identifiers might be removed from the identifiable private information or 1989 identifiable biospecimens and that, after such removal, the information or biospecimens 1990 could be used for future research studies or distributed to another investigator for future 1991 research studies without additional informed consent from the subject or the legally 1992 authorized representative, if this might be a possibility; or 1993

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• A statement that the subject’s information or biospecimens collect as part of the research, 1994 even if identifiers are removed, will not be used or distributed for future research studies 1995

Three new Additional Elements to be included in IC documents, if applicable: 1996

• “A statement that the subject’s biospecimens (even if identifiers are removed) may be used 1997 for commercial profit and whether the subject will or will not share in this commercial profit”; 1998

• “A statement regarding whether clinically relevant research results, including individual 1999 research results, will be disclosed to subjects, and if so, under what conditions”; and 2000

• “For research involving biospecimens, whether the research will (if known) or might include 2001 whole genome sequencing (i.e., sequencing of a human germline or somatic specimen with 2002 the intent to generate the genome or exome sequence of that specimen)”. 2003

8.1.4. Broad Consent and Secondary Research 2004

The revised Common rules proposes the use of broad consent for the storage and use of 2005 biospecimens in future research with the proactive request of describing the general types of 2006 possible future research that may be done under a primary research study. This optional use of 2007 broad consent would allow the implementation of secondary research using identifiable private 2008 information and/or identifiable biospecimens without requiring a new study-specific IC form. 2009 Investigators will be allowed to continue to use biospecimens in secondary research with, at 2010 most, a limited IRB/EC/RE review or involvement, if any, and as long as there are no plans to 2011 share individual research results (IRRs) or incidental findings (IFs) with the individuals who 2012 provided these biospecimens as participants in the primary research. 2013

Besides the specific broad consent elements described in the previous section, all basic elements 2014 of informed consent must be met as per §46.116(a), including informing participants that they 2015 are allowed to leave the research at any point, including secondary research studies, without 2016 penalty or loss of benefits. Furthermore, participants will also need to be reminded that the use 2017 of de-identified biospecimens in secondary research will be possible and that withdrawal of this 2018 permission may not be possible once the research has commenced. However, the Final Rule does 2019 prohibit IRBs/ECs/REs from waiving informed consent if participants were asked and declined to 2020 provide broad consent to the storage and use of their biospecimens and identifiable private 2021 information for secondary research. 2022

Moreover, for studies where biospecimens are being stored at a central location or a by third 2023 parties or collaborators, primary investigators working in association with these biobanks and 2024 each one of the new investigators conducting secondary studies will need to have clear plans for 2025 tracking the different levels of consent granted by participants. More importantly, primary 2026 investigators will need to ensure to honor the wishes of participants who declined consent for 2027 secondary research use, by disposing these biospecimens in a compliant and timely manner at 2028 the end of the primary research study. 2029

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8.1.5. Incidental Findings and Individual Research Results Disclosure from Secondary Research with 2030 Stored Biospecimens 2031

In the Final Rule, secondary research use of identifiable biospecimens and identifiable private 2032 information is exempt from the Common Rule, if “the investigator does not include returning 2033 individual research results to subjects as part of the study plan.” The Final Rule does not address 2034 if this exemption applies to not returning results or incidental findings to at least one participant 2035 or to systematically to all participants. If the exemption is not available, the proposed research 2036 would be subject to regular IRB/EC/RE review. It is understood that the return of general or 2037 aggregate research findings would not prevent the use of this exemption. 2038

HHS believes that returning individual research results may be beneficial not only to the 2039 participants, but to research in general by enhancing public trust and individuals’ willingness to 2040 participate. It is then recommended that when developing a study plan, sponsors and 2041 investigators carefully balance the utility of returning individual research results/incidental 2042 findings against the increased regulatory requirements resulting from not meeting the exemption 2043 criteria. 2044

As clearly stated by the Secretary’s Advisory Committee on Human Research Protections 2045 (SACHRP) in Attachment C - Recommendations for Broad Consent Guidance : “The return of 2046 individual research results could be made to a single subject, a subset of the subjects, or to all of 2047 the subjects. This exemption does not require that the return of individual research results 2048 actually occur, but rather that the intention to return individual research results be part of the 2049 study plan—that is, that the return of results is a planned. premeditated activity contemplated in 2050 the protocol” 2051

For example, if a study plan can forecast anticipatable incidental and significant findings from the 2052 primary and secondary research with identifiable biospecimens, that study plan should consider 2053 including these possible findings and their disclosure to the affected participants, which will make 2054 this research ineligible for an exemption from the Common Rule. However, even under this 2055 interpretation, a study plan would continue to meet the exemption criterion if it allows for 2056 reporting or disclosure to participants of incidental findings/individual research results that are 2057 clinically meaningful risks unrelated to the study’s design or endpoints (particularly and almost 2058 exclusive to primary research). 2059

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9. OTHER2060

9.1. DAIDS Informed Consent Templates 2061

DAIDS created informed consent templates as tools to assist protocol teams, DAIDS networks, 2062 clinical research site (CRS) staff and other relevant stakeholders when developing 2063 protocol/sample and site-specific ICF documents for DAIDS supported and/or sponsored clinical 2064 research. Although DAIDS does not require the use of a standard IC form format, protocol and 2065 site-specific informed consent forms need to address each of the issues included in these 2066 templates, when relevant. However, the template language is not mandated to be used 2067 verbatim. Investigators are responsible for ensuring that all IC forms and related documents 2068 adhere to all applicable in-country, local, and institutional laws, regulations, guidelines, and 2069 policies. These templates can be found on the RSC’s website. 2070

• DAIDS Sample Informed Consent Template for Stored Samples for Future Use and2071 Instructions Page2072

• DAIDS Protocol Specific Informed Consent Template—General Use and Instructions Page2073

NOTE: the approach is “mandated concepts” rather than “mandated language”. 2074

9.2. DAIDS Therapeutics Research Program (TRP) Guidance for the Development of Protocol 2075 Procedures to Address Reproductive Risk 2076

DAIDS TRP created guidance for investigators and protocol teams to consider when developing 2077

clinical trials that will potentially include females and males of reproductive potential, in which 2078

there may be reproductive risks from the study product(s), strategies, or procedures. This 2079

document provides guidance on protocol inclusion/exclusion criteria, pregnancy testing and 2080

contraception requirements, follow-up for unintended pregnancy, pregnancy registries, and 2081

informed consent. 2082

SEE: DAIDS Therapeutic Research Program Guidance for the Development of Protocol Procedures 2083 to Address Reproductive Risk 2084

9.3. Informed Consent Process SOP Examples 2085

DAIDS Informed Consent Process SOP examples are posted on the RSC’s website: Informed 2086 Consent Process Information. These documents are guidance resources; for use as reference 2087 only. 2088

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10. REFERENCES 2089

This section will be added to the Final Version for general release. 2090