GOOD CLINICAL PRACTICE (GCP) E6(R3)

INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL

REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE

ICH HARMONISED GUIDELINE

GOOD CLINICAL PRACTICE (GCP)

E6(R3)

Draft version

Endorsed on 19 May 2023

Currently under public consultation

At Step 2 of the ICH Process, a consensus draft text or guideline, agreed by the appropriate

ICH Expert Working Group, is transmitted by the ICH Assembly to the regulatory authorities

of the ICH regions for internal and external consultation, according to national or regional

procedures.

E6(R3)

Document History

Code

History

Date

Approval by the Steering Committee under Step 2

and release for public consultation.

27 April 1995

Approval by the Steering Committee under Step 4

and recommended for adoption to the three ICH

regulatory bodies.

1 May 1996

E6(R1)

Approval by the Steering Committee of Post-Step 4

editorial corrections.

10 June 1996

E6(R2)

Adoption by the Regulatory Members of the ICH

Assembly under Step 4. Integrated Addendum to

ICH E6(R1) document. Changes are integrated

directly into the following sections of the parental

Guideline: Introduction, 1.63, 1.64, 1.65, 2.10, 2.13,

4.2.5, 4.2.6, 4.9.0, 5.0, 5.0.1, 5.0.2, 5.0.3, 5.0.4,

5.0.5, 5.0.6, 5.0.7, 5.2.2, 5.5.3 (a), 5.5.3 (b), 5.5.3 (h),

5.18.3, 5.18.6 (e), 5.18.7, 5.20.1, 8.1

9 November 2016

E6(R3)

Endorsement by the Members of the ICH Assembly

under Step 2 and release for public consultation.

19 May 2023

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ICH E6(R3) Guideline 
 
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ICH HARMONISED GUIDELINE 
GOOD CLINICAL PRACTICE (GCP) 
E6(R3) 
ICH Consensus Guideline 
TABLE OF CONTENTS 
I.  INTRODUCTION........................................................................................................ 1 
Guideline Scope ........................................................................................................................ 1 
Guideline Structure ................................................................................................................. 1 
II.  PRINCIPLES OF ICH GCP ....................................................................................... 2 
III.  ANNEX 1 ...................................................................................................................... 7 
1.  INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
(IRB/IEC)...................................................................................................................... 7 
1.1  Responsibilities ............................................................................................................. 7 
1.2  Composition, Functions and Operations ................................................................... 9 
1.3  Procedures .................................................................................................................... 9 
1.4  Records........................................................................................................................ 10 
1.5  Submission and Communication .............................................................................. 11 
2.  INVESTIGATOR ...................................................................................................... 11 
2.1  Qualifications and Training ...................................................................................... 11 
2.2  Resources .................................................................................................................... 11 
2.3  Responsibilities ........................................................................................................... 11 
2.4  Communication with IRB/IEC ................................................................................. 12 
2.5  Compliance with Protocol ......................................................................................... 12 
2.6  Premature Termination or Suspension of a Trial ................................................... 13 
2.7  Participant Medical Care and Safety Reporting..................................................... 13 
2.7.1  Medical Care of Trial Participants ........................................................... 13 
2.7.2  Safety Reporting ........................................................................................ 14 
2.8  Informed Consent of Trial Participants .................................................................. 14 
2.9  End of Participation in a Clinical Trial ................................................................... 18 
2.10  Investigational Product Management ...................................................................... 19 
2.11  Randomisation Procedures and Unblinding ........................................................... 19 

ICH E6(R3) Guideline 
 
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12  Records........................................................................................................................ 20 
13  Clinical Trial/Study Reports ..................................................................................... 21 
 SPONSOR ................................................................................................................... 22 
1  Trial Design ................................................................................................................ 22 
2  Resources .................................................................................................................... 22 
3  Allocation of Activities ............................................................................................... 22 
4  Qualification and Training........................................................................................ 22 
4.1  Medical Expertise ...................................................................................... 22 
5  Financing .................................................................................................................... 23 
6  Agreements ................................................................................................................. 23 
7  Investigator Selection................................................................................................. 24 
8  Communication with IRB/IEC and Regulatory Authority(ies) ............................ 24 
8.1  Notification/Submission to Regulatory Authority(ies) .............................. 24 
8.2  Confirmation of Review by IRB/IEC ......................................................... 25 
9  Sponsor Oversight ...................................................................................................... 25 
10  Quality Management ................................................................................................. 26 
10.1  Risk Management ...................................................................................... 26 
11  Quality Assurance and Quality Control .................................................................. 27 
11.1  Quality Assurance ..................................................................................... 27 
11.2  Audit .......................................................................................................... 27 
11.3  Quality Control .......................................................................................... 28 
11.4  Monitoring ................................................................................................. 28 
12  Noncompliance ........................................................................................................... 33 
13  Safety Assessment and Reporting............................................................................. 33 
13.1  Sponsor Review of Safety Information ...................................................... 34 
13.2  Safety Reporting  ....................................................................................... 34 
13.3  Managingan Immediate Hazard ................................................................ 35 
14  Insurance/Indemnification/Compensation to Participants and Investigators ..... 35 
15  Investigational Product(s) ......................................................................................... 35 
15.1  Information on Investigational Product(s) ................................................ 35 
15.2  Manufacturing,  Packaging,  Labelling  and  Coding  Investigational 
Product(s) ............................................................................................................. 35 

ICH E6(R3) Guideline 
 
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15.3  Supplying and Handling Investigational Product(s) ................................. 36 
16  Data and Records ....................................................................................................... 37 
16.1  Data Handling ........................................................................................... 37 
16.2  Statistical Programming and Data Analysis ............................................. 41 
16.3  Record Keeping and Retention .................................................................. 41 
16.4  Record Access ............................................................................................ 42 
17  Reports ........................................................................................................................ 42 
17.1  Premature Termination or Suspension of a Trial ..................................... 42 
17.2  Clinical Trial/Study Reports ...................................................................... 42 
 DATA GOVERNANCE – INVESTIGATOR AND SPONSOR ............................ 43 
1  Safeguard Blinding in Data Governance ................................................................. 43 
2  Data Life Cycle Elements .......................................................................................... 44 
2.1  Data Capture ............................................................................................. 44 
2.2  Relevant Metadata, Including Audit Trails ............................................... 44 
2.3  Review of Data and Metadata ................................................................... 45 
2.4  Data Corrections ....................................................................................... 45 
2.5  Data Transfer, Exchange and Migration .................................................. 45 
2.6  Finalisation of Data Sets Prior to Analysis ............................................... 45 
3  Computerised Systems............................................................................................... 45 
3.1  Procedures for the Use of Computerised Systems ..................................... 46 
3.2  Training ..................................................................................................... 46 
4  Security of Computerised Systems ........................................................................... 46 
5  Validation of Computerised Systems ....................................................................... 46 
6  System Failure ............................................................................................................ 47 
7  Technical Support ...................................................................................................... 47 
8  User Management ...................................................................................................... 48 
GLOSSARY............................................................................................................................ 49 
APPENDICES ........................................................................................................................ 58 
Appendix A. INVESTIGATOR’S BROCHURE ................................................................ 58 
A.1  Introduction ................................................................................................................ 58 
A.2  General Considerations ............................................................................................. 59 
A.2.1  Title Page .................................................................................................. 59 

ICH E6(R3) Guideline 
 
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A.2.2  Confidentiality Statement .......................................................................... 59 
A.3  Contents of the Investigator’s Brochure .................................................................. 59 
A.3.1  Table of Contents ....................................................................................... 59 
A.3.2  Summary .................................................................................................... 59 
A.3.3  Introduction ............................................................................................... 59 
A.3.4  Physical, Chemical and Pharmaceutical Properties and Formulation .... 59 
A.3.5  Nonclinical Studies .................................................................................... 60 
A.3.6  Effects in Humans ...................................................................................... 61 
A.3.7  Summary of Data and Guidance for the Investigator ............................... 62 
Appendix B. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S)
...................................................................................................................................... 64 
B.1  General Information .................................................................................................. 64 
B.2  Background Information .......................................................................................... 64 
B.3  Trial Objectives and Purpose ................................................................................... 64 
B.4  Trial Design ................................................................................................................ 65 
B.5  Selection of Participants ............................................................................................ 65 
B.6  Withdrawal of Consent or Discontinuation of Participation ................................. 65 
B.7  Treatment and Interventions for Participants ........................................................ 66 
B.8  Assessment of Efficacy ............................................................................................... 66 
B.9  Assessment of Safety .................................................................................................. 66 
B.10  Statistical Considerations .......................................................................................... 66 
B.11  Direct Access to Source Records .............................................................................. 67 
B.12  Quality Control and Quality Assurance .................................................................. 67 
B.13  Ethics ........................................................................................................................... 67 
B.14  Data Handling and Record Keeping ........................................................................ 67 
B.15  Financing and Insurance ........................................................................................... 67 
B.16  Publication Policy....................................................................................................... 67 
Appendix C. ESSENTIAL RECORDS FOR THE CONDUCT OF A CLINICAL TRIAL
...................................................................................................................................... 68 
C.1  Introduction ................................................................................................................ 68 
C.2  Management of Essential Records ........................................................................... 68 
C.3  Essentiality of Trial Records ..................................................................................... 69 
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ICH E6(R3) Guideline

I. INTRODUCTION

Good Clinical Practice (GCP) is an international, ethical, scientific and quality standard for the

conduct of trials that involve human participants. Clinical trials conducted in accordance with

this standard will help to assure that the rights, safety and well-being of trial participants are

protected; that the conduct is consistent with the principles that have their origin in the

Declaration of Helsinki; and that the clinical trial results are reliable. The term “trial conduct”

in this document includes processes from planning to reporting, including planning, initiating,

performing, recording, oversight, evaluation, analysis and reporting activities as appropriate.

The objective of this ICH GCP Guideline is to provide a unified standard to facilitate the mutual

acceptance of clinical trial data for ICH member countries and regions by applicable regulatory

authorities.

This guideline builds on key concepts outlined in ICH E8(R1) General Considerations for

Clinical Studies. This includes fostering a quality culture and proactively designing quality into

clinical trials and drug development planning, identifying factors critical to trial quality, and

engaging stakeholders, as appropriate, using a proportionate risk-based approach.

Clinical trials vary widely in scale, complexity and cost. Careful evaluation of the priorities

involved in each trial and the risks associated with the priorities will help ensure efficiency by

focusing on activities critical to achieving the trial objectives.

Guideline Scope

This guideline applies to interventional clinical trials of investigational products

that are

intended to be submitted to regulatory authorities. This guideline may also be applicable to

other interventional clinical trials of investigational products that are not intended to support

marketing authorisation applications in accordance with local requirements.

Guideline Structure

This ICH GCP Guideline is composed of principles and annexes that expand on the principles,

with specific details for different types of clinical trials. The principles are intended to apply

across clinical trial types and settings and to remain relevant as technological and

methodological advances occur. The principles outlined in this guideline may be satisfied using

differing approaches and should be applied to fit the intended purpose of the clinical trial.

Annex-1 is intended to provide information on how the principles can be appropriately applied

to clinical trials. Additional annexes may be developed to respond to stakeholder needs and to

address emerging innovations in trial design and conduct. This guideline should be read in

conjunction with other ICH guidelines relevant to the design and conduct of clinical trials,

including multiregional trials.

For the purpose of this guideline, the term “investigational products” should be considered synonymous with

drugs, medicines, medicinal products, vaccines and biological products.

ICH E6(R3) Guideline

II. PRINCIPLES OF ICH GCP

Clinical trials are a fundamental part of clinical research that support the development of new

medicines or uses of existing medicines. Well-designed and conducted clinical trials help

answer key questions in healthcare and drug development. Their results are essential for

evidence-based healthcare decisions. Trials with inadequate design and/or poorly conducted

trials may place participant safety at risk and yield inadequate or unreliable evidence and are

unethical. They waste resources and the efforts and time of investigators and participants.

The principles of GCP are designed to be flexible and applicable to a broad range of clinical

trials. This guideline, along with ICH E8(R1), encourages thoughtful consideration and

planning to address specific and potentially unique aspects of an individual clinical trial. This

includes evaluation of trial characteristics, such as the design elements, the investigational

product being evaluated, the medical condition being addressed, the characteristics of the

participants, the setting in which the clinical trial is being conducted, and the type of data being

collected. Careful consideration of factors relevant to ensuring trial quality is needed for each

clinical trial.

The principles are intended to support efficient approaches to trial design and conduct. For

example, innovative digital health technologies, such as wearables and sensors, may expand

the possible approaches to trial conduct. Such technologies can be incorporated into existing

healthcare infrastructures and enable the use of a variety of relevant data sources in clinical

trials. This will aid in keeping clinical trial conduct in line with advancing science and

technological developments. The use of technology in the conduct of clinical trials should be

adapted to fit the participant characteristics and the particular trial design. This guideline is

intended to be media neutral to enable the use of different technologies for the purposes of

documentation.

The use of innovative clinical trial designs and technologies may help include diverse patient

populations, as appropriate, and enable wider participation. The design of the trial, to ensure

appropriate quality and meaningful trial outcomes, may be supported by the perspectives of

stakeholders; for example, patients and/or healthcare providers. Their input can increase the

likelihood of meaningful trial outcomes, which are relevant to both trial participants and future

patients. This input will also guide decisions on the feasibility of data collection and assure that

participation in the trial does not become unduly burdensome for those involved.

Clinical trials should be designed to protect the rights, safety and well-being of participants and

assure the reliability of results. Quality by design should be implemented to identify the factors

(i.e., data and processes) that are critical to ensuring trial quality and the risks that threaten the

integrity of those factors and ultimately the reliability of the trial results. Clinical trial processes

and risk mitigation strategies implemented to support the conduct of the trial should be

proportionate to the importance of the data being collected and the risks to trial participant

safety and data reliability. Trial designs should be operationally feasible and avoid unnecessary

complexities.

The overarching principles provide a flexible framework for clinical trial conduct. They are

structured to provide guidance throughout the life cycle of the clinical trial. These principles

are applicable to trials involving human participants. The principles are interdependent and

should be considered in their totality to assure ethical trial conduct and reliable results.

ICH E6(R3) Guideline

1. Clinical trials should be conducted in accordance with the ethical principles that

have their origin in the Declaration of Helsinki and that are consistent with GCP

and applicable regulatory requirement(s). Clinical trials should be designed and

conducted in ways that ensure the rights, safety and well-being of participants.

1.1 The rights, safety and well-being of the participants are the most important

considerations and should prevail over interests of science and society.

1.2 The safety of the participants should be reviewed periodically as new safety

information becomes available, which could have an impact on the participant

or the conduct of the trial.

1.3 Foreseeable risks and inconveniences should be weighed against the anticipated

benefits for the individual participants and society. A trial should be initiated

and continued only if the anticipated benefits justify the known and anticipated

risks.

1.4 When designing a clinical trial, the scientific goal and purpose should be

carefully considered so as not to unnecessarily exclude particular participant

populations. The participant selection process should be representative of the

anticipated population who is likely to use the medicinal product in future

clinical practice to allow for generalising the results across the broader

population. Certain trials (e.g., early phase, proof of concept trials,

bioequivalence studies) may not require a heterogeneous population.

1.5 A qualified physician or, when appropriate, a qualified dentist (or other

qualified healthcare professionals in accordance with local regulatory

100

requirements) should have the overall responsibility for the trial-related medical

101

care given to, and medical decisions made on behalf of, participants; however,

102

the practical interactions and the delivery of medical care and decisions can be

103

carried out by appropriately qualified healthcare professionals in accordance

104

with applicable regulatory requirements.

105

1.6 The confidentiality of information that could identify participants should be

106

protected in accordance with applicable privacy and data protection

107

requirements.

108

109

2. Informed consent is an integral feature of the ethical conduct of a trial. Clinical

110

trial participation should be voluntary and based on a consent process that

111

ensures participants (or their legally acceptable representatives, where

112

applicable) are well-informed.

113

114

2.1 Freely given informed consent should be obtained and documented from every

115

participant prior to clinical trial participation. For potential participants unable

116

to provide informed consent, their legally acceptable representative should

117

provide consent prior to clinical trial participation.

118

2.2 The process and information provided should be designed to achieve the

119

primary objective of enabling potential trial participants to evaluate the benefits

120

and risks of participating in the trial and to make an informed decision on

121

whether or not to participate in the trial. The information provided during the

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ICH E6(R3) Guideline

informed consent process should be clear and concise so as to be understandable

123

by potential participants or legally acceptable representatives.

124

2.3 The informed consent process should take into consideration relevant aspects

125

of the trial, such as the characteristics of the participants, the trial design, the

126

anticipated benefit and risk of medical intervention(s), the setting and context

127

in which the trial will be conducted (e.g., trials in emergency situations), and

128

the potential use of technology to inform participants (or their legally

129

acceptable representatives) and obtain informed consent.

130

131

3. Clinical trials should be subject to an independent review by an institutional

132

review board/independent ethics committee (IRB/IEC).

133

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3.1 A trial should always be conducted in compliance with the protocol that

135

receives prior IRB/IEC approval/favourable opinion.

136

3.2 Periodic review of the trial by the IRB/IEC should also be conducted in

137

accordance with applicable regulatory requirements.

138

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4. Clinical trials should be scientifically sound for their intended purpose and based

140

on robust and current scientific knowledge and approaches.

141

142

4.1 The available nonclinical and clinical information on an investigational

143

product(s) should be adequate to support the proposed clinical trial.

144

4.2 Clinical trials should be scientifically sound and reflect the state of knowledge

145

and experience with the investigational product(s), including, if applicable, the

146

condition to be treated, diagnosed or prevented; the current understanding of

147

the underlying biological mechanism (of both the condition and the treatment);

148

and the population for which the investigational product is intended.

149

4.3 There should be periodic review of current scientific knowledge and approaches

150

to determine whether modifications to the trial are needed, since new or

151

unanticipated information may arise once the trial has begun.

152

153

5. Clinical trials should be designed and conducted by qualified individuals.

154

155

5.1 Individuals with different expertise and training may be needed across all

156

phases of a clinical trial, such as physicians, scientists, ethicists, technology

157

experts, trial coordinators, monitors, auditors and statisticians. Individuals

158

involved in a trial should be qualified by education, training and experience to

159

perform their respective task(s).

160

161

6. Quality should be built into the scientific and operational design and conduct of

162

clinical trials.

163

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6.1 Quality of a clinical trial is considered in this guideline as fit for purpose. The

165

quality and amount of the information generated during a clinical trial should

166

support good decision making.

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ICH E6(R3) Guideline

6.2 Factors critical to the quality of the trial should be identified. These factors are

168

attributes of a trial that are fundamental to the protection of participants, the

169

reliability and interpretability of the trial results and the decisions made based

170

on those trial results. Quality by design involves focusing on the design of all

171

components of the trial in order to maximise the likelihood of trial success (i.e.,

172

that the trial will answer the research question).

173

6.3 Strategies should be implemented to avoid, detect and address serious non-

174

compliance with GCP, the trial protocol and applicable regulatory requirements

175

to prevent recurrence.

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7. Clinical trial processes, measures and approaches should be implemented in a

178

way that is proportionate to the risks to participants and to the importance of

179

the data collected.

180

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7.1 Trial processes should be proportionate to the risks inherent in the trial and the

182

importance of the information collected. Risks in this context include risks to

183

the rights, safety and well-being of trial participants as well as risks to the

184

reliability of the trial results.

185

7.2 The focus should be on the risks to participants beyond those associated with

186

standard medical care. The risks relating to investigational products that have a

187

marketing authorisation when used in the clinical trial context may differ from

188

the routine care of patients and should be taken into consideration.

189

7.3 Risks to critical to quality factors should be managed prospectively and

190

adjusted when new or unanticipated issues arise once the trial has begun.

191

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8. Clinical trials should be described in a clear, concise and operationally feasible

193

protocol.

194

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8.1 A well-designed trial protocol is fundamental to the protection of participants

196

and for the generation of reliable results.

197

8.2 The scientific objectives of any trial should be clear and explicitly stated in the

198

protocol.

199

8.3 The clinical trial protocol as well as the plans or documents for the protocol

200

execution (e.g., statistical analysis plan, data management plan, monitoring

201

plan) should be clear, concise and operationally feasible.

202

203

9. Clinical trials should generate reliable results.

204

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9.1 The quality and amount of the information generated in a clinical trial should

206

be sufficient to provide confidence in the trial’s results and support good

207

decision making.

208

9.2 Systems and processes that aid in data capture, management and analyses, as

209

well as those that help ensure the quality of the information generated from the

210

trial, should be fit for purpose, should capture the data required by the protocol

211

and should be implemented in a way that is proportionate to the risks to

212

participants and the importance of acquired data.

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ICH E6(R3) Guideline

9.3 Trial processes should be operationally feasible and avoid unnecessary

214

complexity, procedures and data collection. Trial processes should support the

215

key trial objectives.

216

9.4 Computerised systems used in clinical trials should be fit for purpose, and

217

factors critical to their quality should be addressed in their design or adaptation

218

for clinical trial purposes.

219

9.5 Clinical trials should incorporate efficient and well-controlled processes for

220

managing records through appropriate management of data integrity,

221

traceability and protection of personal information, thereby allowing the

222

accurate reporting, interpretation and verification of the clinical trial-related

223

information.

224

9.6 Clinical trial-related records should be retained securely by sponsors and

225

investigators for the required period of time and should be available to

226

regulatory authorities upon request to enable reconstruction of the trial conduct

227

and results in order to ensure the reliability of trial results.

228

9.7 The transparency of clinical trials in drug development includes registration on

229

publicly accessible and recognised databases and the public posting of clinical

230

trial results.

231

232

10. Roles and responsibilities in clinical trials should be clear and documented

233

appropriately.

234

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10.1 The sponsor may transfer or the investigator may delegate some or all their

236

tasks, duties or functions (hereafter referred to as activities), but they retain

237

overall responsibility for their respective activities.

238

10.2 Agreements should clearly define the roles, activities and responsibilities for

239

the clinical trial and be documented appropriately. Where activities have been

240

transferred or delegated to service providers, the responsibility for the conduct

241

of the trial, including quality and integrity of the trial data, resides with the

242

sponsor or investigator, respectively.

243

10.3 The sponsor or investigator should maintain appropriate oversight or

244

supervision of the aforementioned activities, respectively.

245

246

11. Investigational products used in a clinical trial should be manufactured in

247

accordance with applicable Good Manufacturing Practice (GMP) standards and

248

be stored, shipped, handled and disposed of in accordance with the product

249

specifications and the trial protocol.

250

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11.1 Investigational products used in a clinical trial should be manufactured in

252

accordance with applicable GMP standards.

253

11.2 Measures should be in place to ensure that the investigational product provided

254

to trial participants retains its quality.

255

11.3 Investigational products should be used in accordance with the protocol and

256

relevant trial documents.

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ICH E6(R3) Guideline

11.4 Manufacturing, handling and labelling of investigational products should be

258

undertaken in a manner that aligns with treatment assignment and maintains

259

blinding, where applicable.

260

11.5 Investigational product labelling should follow applicable regulatory

261

requirements.

262

11.6 Adequate measures to ensure that the investigational product is handled and

263

shipped appropriately should be implemented.

264

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III. ANNEX 1

266

1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE

267

(IRB/IEC)

268

The IRB/IEC is responsible for the ethical review of the trial. The requirements for

269

the IRB/IEC in this guideline should be read in conjunction with local regulatory

270

requirements.

271

1.1 Responsibilities

272

1.1.1 The purpose of an IRB/IEC is to safeguard the rights, safety and well-being of all trial

273

participants.

274

275

1.1.2 The IRB/IEC should review the following information, where applicable:

276

277

(a) protocol and any amendments;

278

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(b) informed consent material(s), assent form(s), where applicable, and any

280

updates, including the description of the process for how informed consent is

281

to be obtained;

282

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284

product information brochure (e.g., Summary of Product Characteristics

285

(SmPC), package leaflet or labelling), as appropriate, including their updates;

286

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(d) any other information to be provided to the trial participant(s), including a

288

description of the media through which such information will be provided;

289

290

(e) advertisement for participant recruitment (if used) and information on the

291

recruitment process;

292

293

(f) plans to compensate participants (if any);

294

295

(g) ongoing updates to safety information (dependent on requirements of the

296

IRB/IEC);

297

298

(h) investigator’s current curriculum vitae and/or other documentation evidencing

299

qualifications;

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ICH E6(R3) Guideline

(i) any other documents that the IRB/IEC may need to fulfil its responsibilities.

302

303

1.1.3 The IRB/IEC should review a proposed clinical trial within a reasonable time and

304

document its reviews clearly identifying the trial, the documents reviewed and the

305

dates for the following:

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307

(a) approval/favourable opinion;

308

309

(b) modifications required prior to its approval/favourable opinion;

310

311

312

313

(d) termination/suspension of any prior approval/favourable opinion.

314

315

1.1.4 The IRB/IEC should conduct continuing review of each ongoing trial at intervals

316

appropriate to the degree of risk to participants.

317

318

1.1.5 The IRB/IEC may request more information than is outlined in section 2.8.11 be given

319

to participants when, in the judgement of the IRB/IEC, the additional information

320

would add meaningfully to the protection of the rights, safety and/or well-being of the

321

participants.

322

323

1.1.6 Where the protocol indicates that prior consent of the trial participant or the

324

participant’s legally acceptable representative is not possible (see section 2.8.9), the

325

IRB/IEC should determine that the proposed protocol and/or other document(s)

326

adequately address relevant ethical concerns and meet applicable regulatory

327

requirements for such trials (e.g., in emergency situations).

328

329

1.1.7 If minors are to be included in a trial, the IRB/IEC should review the assent

330

information considering the age, maturity and psychological state of the minor, as

331

well as applicable regulatory requirements.

332

333

1.1.8 If the trial participants are compensated for their participation in the trial, the IRB/IEC

334

should review both the amount and method of payment to participants to assure that

335

neither presents problems of coercion or undue influence on the trial participants.

336

Payments to a participant should be prorated and not wholly contingent on completion

337

of the trial by the participant. Reasonable reimbursement of participants for travel and

338

lodging is not typically coercive.

339

340

1.1.9 The IRB/IEC should ensure that information regarding payment to participants,

341

including the methods, amounts and schedule of payment to trial participants, is set

342

forth in the informed consent material and any other information to be provided to

343

participants.

344

ICH E6(R3) Guideline

1.2 Composition, Functions and Operations

345

1.2.1 The IRB/IEC should consist of a reasonable number of members who collectively

346

have the qualifications and experience to review and evaluate the science, medical

347

aspects and ethics of the proposed trial. It is recommended that the IRB/IEC should

348

include:

349

350

(a) at least five members;

351

352

(b) at least one member whose primary area of interest is not in medical sciences;

353

354

355

356

Only those IRB/IEC members who are independent of the investigator and the sponsor

357

of the trial should vote/provide an opinion. A list of IRB/IEC members and their

358

qualifications should be maintained.

359

360

1.2.2 The IRB/IEC should perform its functions according to documented operating

361

procedures, should maintain records of its activities and minutes of its meetings, and

362

should comply with GCP and with the applicable regulatory requirement(s).

363

364

1.2.3 An IRB/IEC should make its decisions at announced meetings at which at least a

365

quorum, as stipulated in its documented operating procedures, is present.

366

367

1.2.4 Only members who participate in the IRB/IEC review and discussion should

368

vote/provide their opinion and/or advise.

369

370

1.2.5 The investigator, investigator site staff and/or sponsor, where appropriate, may

371

provide information on any aspect of the trial but should not participate in the decision

372

making of the IRB/IEC or in the vote/opinion of the IRB/IEC.

373

374

1.2.6 An IRB/IEC may invite non-members with expertise in special areas for assistance.

375

1.3 Procedures

376

The IRB/IEC should establish, document in writing or electronically, and follow its procedures,

377

which should include:

378

1.3.1 Determining its composition (names and qualifications of the members) and the

379

authority under which it is established;

380

381

1.3.2 Scheduling, notifying its members of and conducting its meetings;

382

383

1.3.3 Conducting initial and continuing review of trials;

384

385

1.3.4 Determining the frequency of continuing review, as appropriate;

386

387

ICH E6(R3) Guideline

1.3.5 Providing, according to the applicable regulatory requirements, expedited review and

388

approval/favourable opinion of minor change(s) in ongoing trials that have the

389

approval/favourable opinion of the IRB/IEC;

390

391

1.3.6 Specifying that no participant should be admitted to a trial before the IRB/IEC issues

392

its documented approval/favourable opinion of the trial;

393

394

1.3.7 Specifying that no deviations from the protocol should be initiated without prior

395

documented IRB/IEC approval/favourable opinion, except when necessary to

396

eliminate immediate hazards to the participants;

397

398

1.3.8 Specifying that the investigator/institution should promptly report to the IRB/IEC (see

399

section 1.5):

400

401

(a) deviations from the protocol to eliminate immediate hazards to the trial

402

participants (see sections 1.3.7, 2.5.3 and 2.5.4);

403

404

(b) changes increasing the risk to participants and/or significantly affecting the

405

conduct of the trial (see section 2.4.6);

406

407

408

applicable regulatory requirements;

409

410

(d) new information that may affect adversely the safety of the participants or the

411

conduct of the trial.

412

413

1.3.9 Ensuring that the IRB/IEC (see section 1.5) promptly notifies in writing or

414

electronically the investigator/institution or sponsor concerning:

415

416

(a) its trial-related decisions/opinions;

417

418

(b) the reasons for its decisions/opinions;

419

420

421

1.4 Records

422

1.4.1 The IRB/IEC should retain all relevant records (e.g., documented procedures,

423

membership lists, lists of occupations/affiliations of members, submitted documents,

424

minutes of meetings and correspondence) in accordance with applicable regulatory

425

requirements and make them available upon request from the regulatory

426

authority(ies).

427

428

1.4.2 The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to

429

provide its documented procedures and membership lists.

430

ICH E6(R3) Guideline

1.5 Submission and Communication

431

For the submission to or communication with the IRB/IEC, it is recognised that in most regions,

432

there is also a requirement to make a submission to the relevant regulatory authority, and these

433

may be combined, in line with applicable regulatory requirements, in a single submission in

434

some regions. In addition, applicable regulatory requirements may require that submissions to

435

the IRB/IEC are made in some regions by the investigator/institution and in others by the

436

sponsor.

437

438

2. INVESTIGATOR

439

2.1 Qualifications and Training

440

2.1.1 The investigator(s) should be qualified by education, training and experience to

441

assume responsibility for the proper conduct of the trial and should provide evidence

442

of such qualifications.

443

444

2.1.2 The investigator should be familiar with the appropriate use of the investigational

445

product(s) as described in the protocol, in the current Investigator’s Brochure, in the

446

product information and/or in other information sources provided by the sponsor.

447

2.2 Resources

448

2.2.1 The investigator should be able to demonstrate (e.g., based on retrospective or

449

currently available data) a potential for recruiting the proposed number of eligible

450

participants within the recruitment period as agreed with the sponsor.

451

452

2.2.2 The investigator should have sufficient time, an adequate number of available and

453

qualified staff, and adequate facilities for the foreseen duration of the trial to conduct

454

the trial properly and safely.

455

2.3 Responsibilities

456

2.3.1 The investigator may delegate trial-specific activities to other persons or parties.

457

The investigator may be supported by the sponsor to identify a suitable service

458

provider(s); however, the investigator retains the final decision on whether the service

459

provider intended to support the investigator is appropriate based on information

460

provided by the sponsor (see section 3.6.6).

461

The investigator retains the ultimate responsibility and maintains appropriate

462

supervision of the persons or parties undertaking the activities delegated to ensure the

463

rights, safety and well-being of the trial participants and data reliability.

464

465

2.3.2 The investigator should ensure that persons or parties to whom the investigator has

466

delegated trial-specific activities are appropriately qualified and supervised and are

467

adequately informed about the protocol, the investigational product(s) and their

468

assigned trial activities (including activities conducted by staff provided by other

469

parties, for example, home nurses arranged by the sponsor). Trial-related training to

470

ICH E6(R3) Guideline

persons assisting in the trial should correspond to what is necessary to enable them to

471

fulfil their delegated trial activities that go beyond their usual training and experience.

472

473

2.3.3 The investigator should ensure a record is maintained of the persons and parties to

474

whom the investigator has delegated significant trial-related activities. In situations

475

where the clinical trial activities are performed in accordance with routine clinical

476

care, delegation documentation may not be required.

477

478

2.3.4 Agreements made by the investigator/institution with service providers for trial-

479

related activities should be documented.

480

481

2.3.5 The investigator/institution should permit monitoring and auditing by the sponsor and

482

inspection by the appropriate regulatory authority(ies).

483

2.4 Communication with IRB/IEC

484

2.4.1 Submission to the IRB/IEC may be made by the investigator/institution or sponsor in

485

accordance with applicable regulatory requirements (see section 1.5).

486

487

2.4.2 Before initiating a trial, the investigator/institution should have a documented and

488

dated approval/favourable opinion from the IRB/IEC for the trial protocol, informed

489

consent material, participant recruitment procedures (e.g., advertisements) and any

490

other information to be provided to participants.

491

492

2.4.3 As part of the investigator’s/institution’s or sponsor’s (in accordance with applicable

493

regulatory requirements) submission to the IRB/IEC, a current copy of the

494

Investigator’s Brochure or basic product information brochure should be provided

495

(see section A.1.1 of Appendix A. Investigator’s Brochure). If the Investigator’s

496

Brochure is updated during the trial, the IRB/IEC should receive the current version

497

in accordance with applicable regulatory requirements.

498

499

2.4.4 As the trial progresses, the investigator/institution or sponsor should provide any

500

updates to the participant information according to applicable regulatory

501

requirements.

502

503

2.4.5 The investigator or the sponsor should submit documented summaries of the trial

504

status to the IRB/IEC in accordance with local regulatory requirements or upon

505

request.

506

507

2.4.6 The investigator or the sponsor should promptly communicate to the IRB/IEC (see

508

section 1.3.8) and, where applicable, the institution about any changes significantly

509

affecting the conduct of the trial and/or increasing the risk to participants.

510

2.5 Compliance with Protocol

511

2.5.1 The investigator should comply with the protocol and GCP and applicable regulatory

512

requirements. The investigator/institution should sign the protocol or an alternative

513

contract to confirm agreement with the sponsor.

514

ICH E6(R3) Guideline

2.5.2 The investigator should document all protocol deviations and review deviations

515

communicated to them by the sponsor. For important deviations, the investigator

516

should explain the deviation and implement appropriate measures to prevent a

517

recurrence, where applicable, see section 3.9.3.

518

519

2.5.3 The investigator should follow the protocol and deviate only where necessary to

520

eliminate an immediate hazard(s) to trial participants. In case of deviations undertaken

521

to eliminate immediate hazard to trial participants, the investigator should inform the

522

sponsor, IRB/IEC and/or regulatory authorities promptly.

523

524

2.5.4 The investigator should report information on the immediate hazard, the implemented

525

change and the subsequent proposed protocol amendment to the IRB/IEC and/or

526

regulatory authorities.

527

2.6 Premature Termination or Suspension of a Trial

528

2.6.1 If the trial is prematurely terminated or suspended for any reason, the

529

investigator/institution should promptly inform the trial participants and should assure

530

appropriate therapy and follow-up for the participants.

531

532

2.6.2 Where the investigator terminates or suspends their involvement in a trial without

533

prior agreement by the sponsor, the investigator should promptly inform the sponsor,

534

the IRB/IEC and the regulatory authorities in accordance with applicable regulatory

535

requirements and should provide a detailed explanation of the reasons.

536

537

2.6.3 If the sponsor terminates or suspends a trial, the investigator/institution, or the

538

sponsor, in accordance with applicable regulatory requirement(s), should promptly

539

inform the IRB/IEC and the regulatory authorities. See section 3.17.1.

540

541

2.6.4 If the IRB/IEC terminates or suspends its approval/favourable opinion of a trial (see

542

sections 1.1.3 and 1.3.9), the investigator should inform the institution, where

543

applicable, and the investigator/institution should promptly notify the sponsor.

544

2.7 Participant Medical Care and Safety Reporting

545

2.7.1 Medical Care of Trial Participants

546

(a) A qualified physician or, where appropriate, a qualified dentist (or other

547

qualified healthcare professionals in accordance with local regulatory

548

requirements) who is an investigator or a sub-investigator for the trial should

549

have the overall responsibility for trial-related medical care and decisions.

550

551

(b) Other appropriately qualified healthcare professionals may be involved in the

552

medical care of trial participants, in line with their normal activities and in

553

accordance with local regulatory requirements.

554

555

556

ensure that adequate medical care is provided to a participant for any adverse

557

events, including clinically significant laboratory values, related to the trial.

558

ICH E6(R3) Guideline

The investigator/institution should inform a participant when medical care is

559

needed for intercurrent illness(es) of which the investigator becomes aware.

560

561

(d) The investigator should inform the participant’s primary physician about the

562

participant’s involvement in the trial if the participant has a primary physician

563

and agrees to the primary physician being informed.

564

2.7.2 Safety Reporting

565

(a) Adverse events and/or laboratory abnormalities required for safety evaluations

566

(as outlined in the protocol) should be reported to the sponsor according to the

567

reporting requirements and within the time periods specified in the protocol.

568

569

(b) All serious adverse events (SAEs) should be reported immediately (after the

570

investigator reasonably becomes aware of the event) to the sponsor. In

571

accordance with applicable regulatory requirements, the protocol may identify

572

SAEs not requiring immediate reporting, for example, deaths or other events

573

that are endpoints. Subsequent information should be submitted as a follow-

574

up report, as necessary.

575

576

577

and, where applicable, the regulatory authority with any additional requested

578

information (e.g., autopsy reports and terminal medical reports) when they

579

become available.

580

581

(d) The investigator may delegate activities for safety reporting to qualified

582

investigator site staff but retains the overall responsibility for safety of

583

participants under their responsibility and compliance with the reporting

584

requirements.

585

2.8 Informed Consent of Trial Participants

586

2.8.1 In obtaining and documenting informed consent (paper or electronic format), the

587

investigator should comply with the applicable regulatory requirement(s) and should

588

adhere to GCP and to the ethical principles that have their origin in the Declaration of

589

Helsinki. See the glossary term “informed consent.” The informed consent process

590

should include the following:

591

592

(a) Prior to consenting and enrolling participants, the investigator should have the

593

IRB/IEC’s documented approval/favourable opinion of the informed consent

594

materials and process;

595

596

(b) The information should be as clear and concise as possible, use simple

597

language and avoid unnecessary volume and complexity. This is to ensure that

598

the trial participants or their legally acceptable representatives have an

599

adequate understanding of the objectives of the trial, alternative treatments,

600

the potential benefits and risks, burdens and their rights and obligations to be

601

able to make an informed decision as to their participation in the trial;

602

ICH E6(R3) Guideline

603

may be used in the informed consent process including for providing

604

information to the participant. Obtaining consent remotely may be considered

605

where appropriate.

606

607

2.8.2 The participant or the participant’s legally acceptable representative should be

608

informed in a timely manner if new information becomes available that may be

609

relevant to the participant’s willingness to continue trial participation. The

610

communication of this information and confirmation of the willingness to continue

611

trial participation should be documented.

612

613

New information that could impact a participant’s willingness to continue

614

participation should be assessed to determine if re-consent is needed (e.g., depending

615

on the stage of the trial, consideration should be given to whether the new information

616

is relevant only to new participants or to existing participants). If re-consent is needed

617

(e.g., information on emerging safety concerns), new information should be clearly

618

identified in the revised informed consent materials. Revised informed consent

619

materials should receive the IRB/IEC’s approval/favourable opinion in advance of

620

use.

621

622

2.8.3 Neither the investigator nor the investigator site staff should coerce or unduly

623

influence a participant to participate or to continue their participation in the trial.

624

625

2.8.4 None of the information provided to the participant during the informed consent

626

process should contain any language that causes the participant or the participant’s

627

legally acceptable representative to waive or to appear to waive any legal rights, or

628

that releases or appears to release the investigator, the institution, the sponsor or their

629

service providers from liability for negligence.

630

631

2.8.5 The informed consent process should be conducted by the investigator or other

632

investigator site staff delegated by the investigator, in accordance with applicable

633

regulatory requirements. If the participant is unable to provide consent themselves,

634

the participant’s legally acceptable representative should provide their consent on

635

behalf of the participant.

636

637

2.8.6 The information provided during the informed consent process and translations should

638

be relevant, clear, simple, concise and understandable to the participant or the

639

participant’s legally acceptable representative and the impartial witness, where

640

applicable.

641

642

2.8.7 Before informed consent may be obtained, the investigator or investigator site staff

643

delegated by the investigator, in accordance with the protocol and conditions of

644

IRB/IEC favourable opinions/approvals, should provide the participant or the

645

participant’s legally acceptable representative ample time unless justified (e.g., in an

646

emergency situation) and opportunity to enquire about trial details and to decide

647

whether or not to participate in the trial. Questions about the trial should be answered

648

ICH E6(R3) Guideline

to the satisfaction of the participant or the participant’s legally acceptable

649

representative.

650

651

2.8.8 Prior to trial participation, the informed consent form should be signed and dated by

652

the participant or by the participant’s legally acceptable representative and, where

653

appropriate, impartial witness and by the investigator or delegated investigator site

654

staff who conducted the informed consent discussion. The informed consent process

655

may involve a physical signature or an electronic signature.

656

657

2.8.9 In emergency situations, when prior consent of the participant is not possible, the

658

consent of the participant’s legally acceptable representative, if present, should be

659

requested. When prior consent of the participant is not possible and the participant’s

660

legally acceptable representative is not available, enrolment of the participant should

661

require measures described in the protocol and/or elsewhere, with documented

662

approval/favourable opinion by the IRB/IEC, to protect the participant’s rights, safety

663

and well-being and to ensure compliance with applicable regulatory requirements.

664

The participant or the participant’s legally acceptable representative should be

665

informed about the trial as soon as possible, and consent as appropriate (see section

666

2.8.10) should be requested.

667

668

2.8.10 If a participant or the legally acceptable representative is unable to read, an impartial

669

witness should be present (remotely or in-person) during the entire informed consent

670

discussion. After the informed consent form and any other information is read and

671

explained to the participant or the participant’s legally acceptable representative and

672

they have orally consented to the participant’s trial participation and, if capable of

673

doing so, have signed and personally dated the informed consent form, the witness

674

should contemporaneously sign and personally date the consent form. By signing the

675

consent form, the witness attests that the consent information was accurately

676

explained to and apparently understood by the participant or the participant’s legally

677

acceptable representative and that informed consent was freely given by the

678

participant or the participant’s legally acceptable representative.

679

680

2.8.11 The informed consent discussion and the informed consent materials to be provided

681

to participants should explain the following as applicable:

682

683

(a) the purpose of the trial;

684

685

(b) that the trial involves research and summary of the experimental aspects of the

686

trial;

687

688

689

assignment to the investigational product, if applicable;

690

691

(d) the trial procedures to be followed including all invasive procedures;

692

693

(e) the participant’s obligations;

694

ICH E6(R3) Guideline

(f) the reasonably foreseeable risks or inconveniences to the participant and, when

695

applicable, the participant’s partner, to an embryo, foetus or nursing infant;

696

697

(g) the reasonably expected benefits. When there is no intended clinical benefit to

698

the participant, the participant should be made aware of this;

699

700

(h) the alternative procedure(s) or course(s) of treatment that may be available to

701

the participant and their important potential benefits and risks;

702

703

(i) the compensation and/or treatment available to the participant in the event of

704

trial-related injury;

705

706

(j) any anticipated prorated compensation to the participant for trial participation;

707

708

(k) any anticipated expenses to the participant for trial participation;

709

710

(l) that the participant’s trial participation is voluntary, and the participant may

711

refuse to participate or may withdraw, at any time, without penalty or loss of

712

benefits to which the participant is otherwise entitled;

713

714

(m) the process by which the participant’s data will be handled, including in the

715

event of the withdrawal of participation in accordance with regulatory

716

requirements;

717

718

(n) that by agreeing to participate in the trial, the participant or their legally

719

acceptable representative allows direct access to original medical records, per

720

applicable regulatory requirements, while safeguarding the confidentiality of

721

the participant. This access is limited for the purpose of reviewing trial

722

activities and/or reviewing or verifying data and records by the IRB/IEC(s),

723

regulatory authority(ies) and the sponsor’s representatives, for example,

724

monitor(s) or auditor(s);

725

726

(o) that records identifying the participant will be kept confidential and, to the

727

extent permitted by the applicable regulatory requirements, will not be made

728

publicly available. If the trial results are published, the participant’s identity

729

will remain confidential. The trial may be registered on publicly accessible

730

and recognised databases, per applicable regulatory requirements;

731

732

(p) that the participant or the participant’s legally acceptable representative will

733

be informed in a timely manner if information becomes available that may be

734

relevant to the participant’s willingness to continue trial participation;

735

736

(q) the person(s) to contact for further trial information and the trial participant’s

737

rights, and whom to contact in the event of suspected trial-related injury;

738

739

ICH E6(R3) Guideline

(r) the foreseeable circumstances and/or reasons under which the participant’s

740

trial participation may be terminated;

741

742

(s) the expected duration of the participant’s trial participation;

743

744

(t) the approximate number of participants involved in the trial;

745

746

(u) that trial results and information on the participant’s actual treatment, if

747

appropriate, will be made available to them should they desire it.

748

749

2.8.12 Prior to participation, the participant or the participant’s legally acceptable

750

representative should receive a copy (paper or electronic) of the signed informed

751

consent form and any other informed consent materials provided to the participants,

752

or in accordance with applicable regulatory requirements. During trial participation,

753

the participant or the participant’s legally acceptable representative should receive a

754

copy of the consent form updates and any other updated informed consent materials

755

provided to participants.

756

757

2.8.13 Where a minor is to be included as a participant, age-appropriate assent information

758

should be provided and discussed with the minor as part of the consent process, and

759

assent from the minor to enrol in the trial should be obtained as appropriate. A process

760

for re-consent should be considered if, during the course of the trial, the minor reaches

761

the age of legal consent, in accordance with applicable regulatory requirements.

762

763

2.8.14 When a clinical trial includes participants who may only be enrolled in the trial with

764

the consent of the participant’s legally acceptable representative (e.g., minors, patients

765

with severe impaired decision-making capacity), the participant should be informed

766

about the trial to the extent compatible with the participant’s understanding and, if

767

capable, the participant should sign and personally date the informed consent form or

768

assent form as appropriate.

769

770

2.8.15 In exceptional circumstances (e.g., public health emergencies), when the usual

771

methods to obtain and document informed consent are not possible, the use of

772

alternative measures and technologies in accordance with local IRBs/IECs and

773

applicable regulatory requirements should be considered.

774

2.9 End of Participation in a Clinical Trial

775

2.9.1 When a participant decides to stop treatment with the investigational product, stop

776

trial visits or completely withdraw from a trial; is discontinued from the trial; or

777

reaches routine end of trial, the investigator should follow the protocol and other

778

sponsor instructions to determine appropriate follow-up measures. This may include

779

instructions to avoid unnecessary loss of already collected critical data in accordance

780

with applicable regulatory requirements.

781

782

2.9.2 Although a participant is not obliged to provide a reason(s) for withdrawing

783

prematurely from a trial, the investigator should make a reasonable effort to ascertain

784

ICH E6(R3) Guideline

the reason(s), while fully respecting the participant’s rights. The investigator should

785

consider discussing with the participant or the participant’s legally acceptable

786

representative the reasons for withdrawal to determine if there are ways to address the

787

concerns. The investigator site staff should make an effort to explain to the participant

788

the value and importance of continuing their participation to minimise trial

789

participants withdrawal.

790

791

2.9.3 Where relevant, the investigator should inform the participant about the trial results

792

and treatment received when this information is available from the sponsor after

793

unblinding, with due respect to the participant’s preference to be informed.

794

2.10 Investigational Product Management

795

2.10.1 Responsibility for investigational product(s) accountability rests with the

796

investigator/institution. The sponsor may facilitate this process.

797

798

2.10.2 When the investigator/institution assigns some or all of their activities for

799

investigational product(s) accountability to a pharmacist or another individual, they

800

should be under the supervision of the investigator/institution.

801

802

2.10.3 The investigator/institution and/or a pharmacist or other appropriate individual should

803

maintain records of the product’s delivery, the inventory, the use by each participant

804

(including documenting that the participants were provided the doses specified by the

805

protocol) and the return to the sponsor and destruction or alternative disposition of

806

unused product(s). These records should include dates, quantities, batch/serial

807

numbers, expiration dates (if applicable) and the unique code numbers assigned to the

808

investigational product(s) and trial participants. For authorised medicinal products,

809

alternative approaches to the aforementioned may be considered, in accordance with

810

local regulatory requirements.

811

812

2.10.4 The investigational product(s) should be stored as specified by the sponsor and in

813

accordance with applicable regulatory requirement(s).

814

815

2.10.5 The investigator should ensure that the investigational product(s) are used only in

816

accordance with the approved protocol.

817

818

2.10.6 Where applicable, the investigator or a person designated by the

819

investigator/institution should explain the correct use of the investigational product(s)

820

to each participant and should check, at intervals appropriate for the trial, that each

821

participant is following the instructions properly.

822

2.11 Randomisation Procedures and Unblinding

823

The investigator should follow the trial’s randomisation procedures, if any, and, in the case of

824

an investigator-blinded trial, should ensure that the identification code is broken only in

825

accordance with the protocol. In the case of an emergency, to protect patient safety, the

826

investigator should be prepared and capable from the start of the trial to perform unblinding

827

without undue delay and hinderance. The investigator should promptly document and explain

828

ICH E6(R3) Guideline

to the sponsor any premature unblinding (e.g., accidental unblinding, emergency unblinding to

829

protect trial participant, unblinding due to an SAE) of the investigational product(s).

830

2.12 Records

831

2.12.1 In generating, recording and reporting trial data, the investigator should ensure the

832

integrity of data under their responsibility, irrespective of the media used.

833

834

2.12.2 The investigator/institution should maintain adequate source records that include

835

pertinent observations on each of the trial participants under their responsibility.

836

Source records should be attributable, legible, contemporaneous, original, accurate

837

and complete. Changes to source records should be traceable, should not obscure the

838

original entry and should be explained if necessary (via an audit trail). The

839

investigator should define what is considered to be a source record(s), the methods of

840

data capture and their location prior to starting the trial and should update this

841

definition when needed. Unnecessary transcription steps in between the source record

842

and the data acquisition tool should be avoided.

843

844

2.12.3 The investigator should have timely access to and be responsible for the timely review

845

of data, including relevant data from external sources (e.g., central laboratory data,

846

centrally read imaging data, other institution’s records and, if appropriate, electronic

847

patient-reported outcome (ePRO) data) which can have an impact on, for example,

848

participant eligibility, treatment or safety. The protocol may provide exceptions for

849

access, for instance, to protect blinding.

850

851

2.12.4 The investigator should ensure that data acquisition tools and other systems deployed

852

by the sponsor for clinical trial purposes are used as specified in the protocol or trial-

853

related instructions.

854

855

2.12.5 The investigator should ensure the accuracy, completeness, legibility and timeliness

856

of the data reported to the sponsor in the data acquisition tools completed by the

857

investigator site (e.g., case report form (CRF)) and in all required reports. The

858

investigator should review and endorse the reported data at milestones agreed upon

859

with the sponsor (e.g., interim analysis).

860

861

2.12.6 Data reported to the sponsor should be consistent with the source records or the

862

discrepancies explained. Changes or corrections in the reported data should be

863

traceable, should be explained (if necessary) and should not obscure the original entry.

864

865

2.12.7 The investigator/institution should implement appropriate measures to protect the

866

privacy and confidentiality of personal information of trial participants in accordance

867

with applicable regulatory requirements on personal data protection. Data reported to

868

the sponsor should be identified by an unambiguous participant code that can be traced

869

back to the identity of the participant by the investigator/institution.

870

871

2.12.8 For systems deployed by the investigator/institution that maintain and retain trial

872

data/information, the investigator/institution should ensure that such data are

873

ICH E6(R3) Guideline

protected from unauthorised access, disclosure, dissemination or alteration and from

874

inappropriate destruction or accidental loss.

875

876

2.12.9 When using computerised systems in a clinical trial, the investigator/institution should

877

do the following:

878

879

(a) for systems deployed by the investigator/institution, ensure that appropriate

880

individuals have secure and attributable access;

881

882

(b) for systems deployed by the investigator/institution specifically for the

883

purposes of clinical trials, ensure that the requirements for computerised

884

systems in section 4 are addressed;

885

886

887

investigator, ensure that traceability is maintained and participants are

888

provided with appropriate training;

889

890

(d) ensure that incidents in the use and operation of computerised systems, which

891

in their judgement may have a significant and/or persistent impact on the trial

892

data, are reported to the sponsor and, where applicable, to the IRB/IEC.

893

894

2.12.10 The investigator/institution should maintain the trial records as specified in Appendix

895

C. Essential Records for the Conduct of a Clinical Trial and as required by the

896

applicable regulatory requirement(s). The investigator/institution should have control

897

of all essential records generated by the investigator/institution before, during and

898

after the trial. The investigator/institution should take measures to prevent accidental

899

or premature destruction of these records. If the investigator closes a site or leaves a

900

site during or after the end of the clinical trial, the sponsor should be notified of the

901

appropriate individual responsible for retention of the site’s essential records.

902

903

2.12.11 The investigator/institution should retain the essential records for the required

904

retention period in accordance with applicable regulatory requirements or until the

905

sponsor informs the investigator/institution that these records are no longer needed,

906

whichever is the longer (see Appendix C).

907

908

2.12.12 Upon request of the monitor, auditor, IRB/IEC or regulatory authority, the

909

investigator/institution should make available for direct access all requested trial-

910

related records.

911

2.13 Clinical Trial/Study Reports

912

2.13.1 Upon completion of the trial, the investigator, where applicable, should inform the

913

institution. The investigator/institution should provide the IRB/IEC with a summary

914

of the trial’s outcome and, if applicable, the regulatory authority(ies) with any

915

required reports.

916

917

ICH E6(R3) Guideline

2.13.2 Where a coordinating investigator is involved in a trial, consideration should be given

918

to them being a signatory on the clinical trial report; see ICH E3 Structure and Content

919

of Clinical Study Reports.

920

921

3. SPONSOR

922

The responsibility of the sponsor entails the implementation of risk-proportionate processes to

923

ensure the safety of the trial participants and the reliability of the trial results throughout the

924

clinical trial life cycle.

925

3.1 Trial Design

926

3.1.1 When planning trials, the sponsor should ensure that sufficient safety and efficacy

927

data from nonclinical studies and/or clinical trials and/or real-world data are available

928

to support human exposure by the route, at the dosages, for the duration and in the

929

trial population to be studied.

930

931

3.1.2 Sponsors should incorporate quality into the design of the clinical trial by identifying

932

factors that are critical to the quality of the trial and by managing risks to those factors.

933

934

3.1.3 Sponsors should consider inputs from a wide variety of stakeholders, for example,

935

healthcare professionals and patients, to support the development plan and clinical

936

trial protocols as described in ICH E8(R1) and when developing the informed consent

937

material and any other participant-facing information.

938

939

3.1.4 The sponsor should ensure that all aspects of the trial are operationally feasible and

940

should avoid unnecessary complexity, procedures and data collection. Protocols, data

941

acquisition tools and other operational documents should be fit for purpose, clear,

942

concise and consistent, when applicable.

943

3.2 Resources

944

The sponsor should ensure that sufficient resources are available to appropriately conduct the

945

trial.

946

3.3 Allocation of Activities

947

Prior to initiating clinical trial activities, the sponsor should determine the roles and allocate

948

trial-related activities accordingly.

949

3.4 Qualification and Training

950

The sponsor should utilise appropriately qualified individuals for the activities to which they

951

are assigned (e.g., biostatisticians, clinical pharmacologists, physicians, data scientists/data

952

managers, auditors and monitors) throughout the trial process.

953

3.4.1 Medical Expertise

954

The sponsor should have medical personnel readily available who will be able to

955

advise on specific trial-related medical questions or problems.

956

ICH E6(R3) Guideline

3.5 Financing

957

The financial aspects of the trial should be documented in an agreement between the sponsor

958

and the investigator/institution.

959

3.6 Agreements

960

3.6.1 Agreements made by the sponsor with the investigator/institution, service providers

961

and any other parties (e.g., independent data monitoring committee (IDMC),

962

adjudication committee) involved with the clinical trial should be documented prior

963

to initiating the activities.

964

965

3.6.2 Agreements should be updated when necessary to reflect significant changes in the

966

activities delegated.

967

968

3.6.3 The sponsor should obtain the investigator’s/institution’s and, where applicable,

969

service provider’s agreement:

970

971

(a) to conduct the trial in accordance with the approved protocol and in

972

compliance with GCP and applicable regulatory requirement(s);

973

974

(b) to comply with procedures for data recording/reporting;

975

976

977

accordance with applicable regulatory requirements or until the sponsor

978

informs the investigator/institution or, where applicable, the service provider,

979

that these documents are no longer needed, whichever is longer;

980

981

(d) to permit monitoring, auditing and inspections by sponsors, IRB/IECs and

982

regulatory authorities (domestic and foreign) including providing direct access

983

to source records and facilities, including to those of service providers.

984

985

3.6.4 The responsibilities of coordinating investigator(s) and the other participating

986

investigators should be documented prior to the start of the trial.

987

988

3.6.5 Any of the sponsor’s trial-related activities that are transferred to and assumed by a

989

service provider should be documented in an agreement. The sponsor’s trial-related

990

activities that are not specifically transferred to and assumed by a service provider are

991

retained by the sponsor.

992

993

3.6.6 The sponsor should provide information to the investigator on any service provider

994

identified by the sponsor to undertake any activities under the responsibility of the

995

investigator. The responsibility for such activities remains with the investigator.

996

997

3.6.7 A sponsor may transfer any or all of the sponsor’s trial-related activities to a service

998

provider; however, the ultimate responsibility for the sponsor’s trial-related activities,

999

including protection of participants’ rights, safety and well-being and reliability of the

1000

trial data, resides with the sponsor. Any service provider used for clinical trial

1001

ICH E6(R3) Guideline

activities should implement appropriate quality management and report to the sponsor

1002

any incidents that might have an impact on the safety of trial participants or/and trial

1003

results.

1004

1005

3.6.8 The sponsor is responsible for assessing the suitability of and selecting the service

1006

provider to ensure that they can adequately undertake the activities transferred to

1007

them. The sponsor should provide the service providers with the protocol where

1008

necessary as well as any other documents required for them to perform their activities.

1009

1010

3.6.9 The sponsor should have access to relevant information (e.g., SOPs and performance

1011

metrics) for selection and oversight of service providers.

1012

1013

3.6.10 The sponsor should ensure appropriate oversight of important trial-related activities

1014

that are transferred to service providers and further subcontracted.

1015

1016

3.6.11 Trial-related activities performed by service providers should be conducted in

1017

accordance with relevant GCP requirements, which may be fulfilled by a service

1018

provider’s existing processes.

1019

1020

3.6.12 A clinical trial may have one or several sponsors where permitted under applicable

1021

regulatory requirements. In trials with more than one sponsor, the sponsors should

1022

have a documented agreement that sets out their respective responsibilities, in

1023

accordance with local regulatory requirements and/or practice. Where the documented

1024

agreement does not specify to which sponsor a given responsibility is attributed, that

1025

responsibility lies with all sponsors.

1026

3.7 Investigator Selection

1027

3.7.1 The sponsor is responsible for selecting the investigator(s)/institution(s). Each

1028

investigator should be qualified by education, training and experience and should

1029

demonstrate they have adequate resources and facilities to properly conduct the trial.

1030

If organisation of a coordinating committee and/or selection of coordinating

1031

investigator(s) are to be utilised in multicentre trials, their organisation and/or

1032

selection are the sponsor’s responsibility, and their roles should be documented prior

1033

to their involvement in the trial.

1034

1035

3.7.2 The sponsor should provide the investigator(s)/institution(s) with the protocol and an

1036

up-to-date Investigator’s Brochure as well as sufficient time for the review of the

1037

protocol and the information provided.

1038

3.8 Communication with IRB/IEC and Regulatory Authority(ies)

1039

3.8.1 Notification/Submission to Regulatory Authority(ies)

1040

In accordance with applicable regulatory requirement(s), before initiating the clinical

1041

trial(s), the sponsor (or the sponsor and the investigator) should submit any required

1042

application(s) to the appropriate regulatory authority(ies) for review, acceptance

1043

and/or permission to begin the trial(s). Any notification/submission should be dated

1044

and contain sufficient information to identify the protocol.

1045

ICH E6(R3) Guideline

3.8.2 Confirmation of Review by IRB/IEC

1046

(a) Where reference is made to a submission to the IRB/IEC, this can be made by

1047

the investigator/institution or sponsor in accordance with applicable regulatory

1048

requirements (see section 1.5).

1049

1050

(b) The sponsor should ensure that the following is obtained:

1051

1052

(i) The name and address of the relevant IRB/IEC along with:

1053

1054

(aa) a statement that it is organised and operates according to GCP

1055

and the applicable regulatory requirements;

1056

1057

(bb) documented initial and subsequent IRB/IEC

1058

approval/favourable opinion as well as any termination of the

1059

trial or the suspension of approval/favourable opinion.

1060

3.9 Sponsor Oversight

1061

3.9.1 The sponsor should ensure that the trial design and trial conduct, the processes

1062

undertaken, and the information and data generated are of sufficient quality to ensure

1063

reliable trial results, trial participant’s safety and appropriate decision making.

1064

1065

3.9.2 The sponsor should ensure that trial processes are conducted in compliance with the

1066

trial protocol and related documents as well as with applicable regulatory

1067

requirements and ethical standards.

1068

1069

3.9.3 The sponsor should determine necessary trial-specific criteria for classifying protocol

1070

deviations as important (i.e., those that impact the rights, safety and well-being of trial

1071

participants and the reliability of results).

1072

1073

3.9.4 Decisions related to the trial should be appropriately assessed for their impact on

1074

participant’s rights, safety and well-being and the reliability of trial results. Risks

1075

related to such decisions should be suitably managed throughout the planning,

1076

conduct and reporting of the trial.

1077

1078

3.9.5 The range and extent of oversight measures should be fit for purpose and tailored to

1079

the complexity of and risks associated with the trial. The selection and oversight of

1080

investigators and service providers are fundamental features of the oversight process.

1081

Oversight by the sponsor includes quality assurance and quality control processes

1082

relating to the trial-related activities of investigators and service providers.

1083

1084

3.9.6 The sponsor should ensure appropriate and timely escalation and follow-up of issues

1085

to allow the implementation of appropriate actions in a timely manner.

1086

1087

3.9.7 The sponsor may consider establishing an IDMC to assess the progress of a clinical

1088

trial including the safety data and the efficacy endpoints at intervals and to recommend

1089

to the sponsor whether to continue, modify or stop a trial.

1090

ICH E6(R3) Guideline

3.9.8 Where appropriate, sponsors may also establish an endpoint assessment/adjudication

1091

committee in certain trials to review important endpoints reported by investigators to

1092

determine whether the endpoints meet protocol-specified criteria. Such committees

1093

should typically be blinded to the assigned treatments when performing their

1094

assessments, regardless of whether the trial itself is conducted in a blinded manner, to

1095

ensure that the data reviewed by committee are as free of bias as possible.

1096

1097

3.9.9 Committees established for purposes that could impact participant safety or the

1098

reliability of trial results should include members with relevant expertise and with

1099

managed conflicts of interest, have written operating procedures (e.g., charters) and

1100

document their decisions.

1101

3.10 Quality Management

1102

The sponsor should implement an appropriate system to manage quality throughout all stages

1103

of the trial process. Quality management includes the design and implementation of efficient

1104

clinical trial protocols including tools and procedures for trial conduct (including for data

1105

collection and management) in order to support participant’s rights, safety and well-being and

1106

the reliability of trial results. The sponsor should adopt a proportionate and risk-based approach

1107

to quality management, which involves incorporating quality into the design of the clinical trial

1108

(i.e., quality by design) and identifying those factors that are likely to have a meaningful impact

1109

on participant’s rights, safety and well-being and the reliability of the results (i.e., critical to

1110

quality factors as described in ICH E8(R1)). The sponsor should describe the quality

1111

management approach implemented in the trial in the clinical trial report (see ICH E3).

1112

3.10.1 Risk Management

1113

A proportionate approach to the identification and management of risk is described below:

1114

3.10.1.1 Risk Identification

1115

The sponsor should identify risks that may have a meaningful impact on critical to

1116

quality factors. Risks should be considered across the processes used in the clinical

1117

trial (e.g., patient selection, informed consent process, randomisation and

1118

investigational product administration, data handling, and service provider activities).

1119

3.10.1.2 Risk Evaluation

1120

The sponsor should evaluate potential risks by considering:

1121

(a) the likelihood of harm/hazard occurring;

1122

1123

(b) the extent to which such harm/hazard would be detectable;

1124

1125

1126

reliability of trial results.

1127

3.10.1.3 Risk Control

1128

(a) Risk control should be proportionate to the importance of the risk to

1129

participants’ rights, safety and well-being and the reliability of trial results.

1130

ICH E6(R3) Guideline

Risk mitigation activities may be incorporated in protocol design and

1131

implementation, monitoring plans, agreements between parties defining roles

1132

and responsibilities, systematic safeguards to ensure adherence to SOPs, and

1133

training in processes and procedures.

1134

1135

(b) The sponsor should set acceptable ranges to support this process within which

1136

variation can be accepted. Where deviation beyond these ranges is detected,

1137

an evaluation should be performed to determine if there is a possible systemic

1138

issue and if action is needed.

1139

3.10.1.4 Risk Communication

1140

The sponsor should communicate the identified risks and mitigating activities, if

1141

applicable, to those who are involved in taking action or are affected by such activities.

1142

Communication also facilitates risk review and continual improvement during clinical

1143

trial conduct.

1144

3.10.1.5 Risk Review

1145

The sponsor should periodically review risk control measures to ascertain whether the

1146

implemented quality management activities remain effective and relevant, taking into

1147

account emerging knowledge and experience.

1148

3.10.1.6 Risk Reporting

1149

The sponsor should summarise and report the risks and the remedial actions taken in

1150

relation to important deviations from the acceptable ranges as detailed in section

1151

3.10.1.3(b) and document them in the clinical trial report (ICH E3).

1152

3.11 Quality Assurance and Quality Control

1153

The sponsor is responsible for establishing, implementing and maintaining

1154

appropriate quality assurance and quality control processes and documented

1155

procedures to ensure that trials are conducted and data are generated, recorded and

1156

reported in compliance with the protocol, GCP and the applicable regulatory

1157

requirement(s).

1158

3.11.1 Quality Assurance

1159

Quality assurance should be applied throughout the clinical trial and includes

1160

implementing strategies to identify potential or actual causes of serious non-

1161

compliance with the protocol, GCP and/or applicable regulatory requirements to

1162

enable their corrective and/or preventive actions.

1163

3.11.2 Audit

1164

When performed, audits should be conducted in a manner that is proportionate to the

1165

risks associated with the conduct of the trial.

1166

The purpose of a sponsor’s audit, which is independent of and separate from routine

1167

monitoring or quality control functions, is to evaluate whether the processes put in

1168

place to manage and conduct the trial are effective and compliant.

1169

ICH E6(R3) Guideline

3.11.2.1 Selection and Qualification of Auditors

1170

(a) The sponsor should appoint individuals who are independent of the clinical

1171

trial being audited.

1172

1173

(b) The sponsor should ensure that the auditors are qualified by training and

1174

experience to conduct audits properly.

1175

3.11.2.2 Auditing Procedures

1176

(a) The sponsor should ensure that the auditing of clinical trials/processes is

1177

conducted in accordance with the sponsor’s documented procedures on what

1178

to audit, how to audit (i.e., on-site or remote), the frequency of audits and the

1179

form and content of audit reports.

1180

1181

(b) The sponsor’s audit plan, program and procedures for a trial audit should be

1182

guided by the importance of the trial to submissions to regulatory authorities,

1183

the number of participants in the trial, the type and complexity of the trial, the

1184

level of risks to the trial participants and any identified problem(s).

1185

1186

1187

1188

(d) To preserve the independence and value of the audit function, the regulatory

1189

authority(ies) should not routinely request the audit reports. Regulatory

1190

authority(ies) may seek access to an audit report on a case-by-case basis when

1191

evidence of serious GCP non-compliance exists or in the course of legal

1192

proceedings.

1193

1194

(e) When required by applicable regulatory requirements, the sponsor should

1195

provide an audit certificate.

1196

3.11.3 Quality Control

1197

Quality control should be applied to each stage of the data handling to ensure that data

1198

are reliable and have been processed correctly. Within clinical trials, monitoring and

1199

data management processes are the main quality control activities.

1200

1201

The quality control of sites (other than investigator sites, such as centralised imaging

1202

reading facilities), including on site and/or centralised activities, may be undertaken

1203

and reported using a risk-based approach.

1204

3.11.4 Monitoring

1205

The aim of monitoring is to ensure the participants’ rights, safety and well-being and

1206

the reliability of trial results as the trial progresses. Monitoring is one of the principal

1207

quality control activities.

1208

Monitoring involves a broad range of activities including, but not limited to,

1209

communication with investigator sites, verification of the investigator and investigator

1210

site staff qualifications and site resources, training and review of trial documents and

1211

ICH E6(R3) Guideline

information using a range of approaches including source data review, source data

1212

verification, data analytics and visits to institutional facilities undertaking trial-related

1213

activities. Some of these monitoring activities may be conducted by different methods

1214

and persons with different roles. However, monitoring should be performed by

1215

persons not involved in the clinical conduct of the trial being monitored. The

1216

monitoring approach should consider the activities and services involved, including

1217

decentralised settings, and be included in the monitoring plan. Monitors and other trial

1218

staff should adhere to data protection and confidentiality requirements in accordance

1219

with applicable regulatory requirements, institution policy and established data

1220

security standards.

1221

Monitoring activities may include site monitoring (performed on-site or remotely) and

1222

centralised monitoring, depending on the monitoring strategy and the design of the

1223

clinical trial.

1224

The sponsor should determine the appropriate extent and nature of monitoring, based

1225

on identified risks. Factors such as the objective, purpose, design, complexity,

1226

blinding, number of trial participants, investigational product, current knowledge of

1227

the safety profile and endpoints of the trial should be considered.

1228

3.11.4.1 Investigator Site Monitoring

1229

(a) Monitoring may be performed in relation to the clinical trial activities at the

1230

investigator sites (e.g., including their pharmacies and local laboratories, as

1231

appropriate). The frequency of monitoring activities should also be determined

1232

based on identified risks. Monitoring activities and their frequency should be

1233

modified as appropriate using knowledge gained.

1234

1235

(b) This monitoring activity may be performed on-site or remotely depending on

1236

the nature of the activity and its objectives.

1237

1238

1239

records, other data acquisition tools and essential record retention systems.

1240

3.11.4.2 Centralised Monitoring

1241

(a) Centralised monitoring is an evaluation of accumulated data, performed in a

1242

timely manner, by the sponsor’s qualified and trained persons (e.g., medical

1243

monitor, data scientist/data manager, biostatistician).

1244

1245

(b) Centralised monitoring processes provide additional monitoring capabilities

1246

that can complement and reduce the extent and/or frequency of site monitoring

1247

or be used on its own. Use of centralised data analytics can help identify

1248

systemic or site-specific issues, including protocol non-compliance and

1249

potentially unreliable data.

1250

1251

1252

targeted site monitoring.

1253

ICH E6(R3) Guideline

3.11.4.3 Monitoring Plan

1254

The sponsor should develop a monitoring plan that is tailored to the identified

1255

potential safety risks, the risks to data quality and/or other risks to the reliability of

1256

the trial results. Particular attention should be given to procedures relevant to

1257

participant safety and to trial endpoints. The plan should describe the monitoring

1258

strategy, the monitoring activities of all the parties involved, the various monitoring

1259

methods and tools to be used, and the rationale for their use. The monitoring strategy

1260

should ensure appropriate oversight of trial conduct and consider site capabilities and

1261

the potential burden. The plan should focus on aspects that are critical to quality. The

1262

monitoring plan should reference the sponsor’s applicable policies and procedures.

1263

Monitoring of key data and processes (e.g., those related to primary endpoints and key

1264

secondary endpoints and processes intended to assure patient safety) performed

1265

outside the investigator site (e.g., central reading facilities, central laboratories) should

1266

be addressed in the monitoring plan.

1267

3.11.4.4 Monitoring Procedures

1268

Persons performing monitoring should follow the sponsor’s monitoring plan and

1269

applicable monitoring procedures.

1270

3.11.4.5 Monitoring Activities

1271

Monitoring in accordance with the sponsor’s requirements and monitoring plan

1272

should generally include the following activities across the clinical trial life cycle, as

1273

applicable.

1274

3.11.4.5.1 Communication with Parties Conducting the Trial

1275

(a) Establishing and maintaining a line of communication between the

1276

sponsor and the investigator and other parties and individuals involved

1277

in the trial conduct (e.g., centrally performed activities). In general, each

1278

site should have an assigned monitor as their contact point.

1279

1280

(b) Informing the investigator or other parties and individuals involved in

1281

the trial conduct of identified deviations from the protocol, GCP and the

1282

applicable regulatory requirements and taking appropriate action

1283

designed to prevent recurrence of the detected deviations. Important

1284

deviations should be highlighted and should be the focus of remediation

1285

efforts as appropriate.

1286

1287

1288

the trial conduct of source record(s) or entry errors or omissions in data

1289

acquisition tools and ensuring that corrections, additions or deletions are

1290

made as appropriate, dated, explained (if necessary) and that approval

1291

of the change is properly documented.

1292

1293

(d) Actions taken in relation to the deviations, errors or omissions should be

1294

proportionate to their importance.

1295

ICH E6(R3) Guideline

3.11.4.5.2 Investigator Site Selection, Initiation, Management and Close-out

1296

(a) Selecting the site and confirming that the investigator and individuals or

1297

parties involved in the trial conduct have adequate qualifications,

1298

resources (see sections 3.1, 3.2, and 4.7) and facilities, including

1299

laboratories, equipment and investigator site staff, to safely and properly

1300

conduct the trial.

1301

1302

(b) Confirming that the investigator, investigator site staff and other parties,

1303

and individuals involved in the trial conduct are adequately informed

1304

about the trial and follow the current approved protocol and other

1305

protocol-related documents, such as the current Investigator’s Brochure

1306

and relevant information related to the investigational product and

1307

instructions related to their delegated activities.

1308

1309

1310

Appendix C).

1311

1312

(d) Confirming that informed consent was obtained before participation in

1313

the trial (see section 2.8) for all enrolled participants at the site.

1314

1315

(e) Determining whether adverse events are appropriately reported within

1316

the time periods required by the protocol, GCP and the applicable

1317

regulatory requirement(s).

1318

1319

(f) Clarifying the sponsor’s protocol requirements for source records and

1320

the site’s location of such data.

1321

1322

(g) Verifying that the blinding is maintained, where applicable.

1323

1324

(h) Reviewing and reporting the participant recruitment and retention rates.

1325

1326

(i) Confirming that the investigator provides the required reports,

1327

notifications or other information in accordance with the protocol and

1328

trial procedures.

1329

1330

(j) Confirming the arrangement for the retention of the essential records and

1331

the final accountability of the investigational product (e.g., return and

1332

destruction or alternative disposition, if appropriate) during site close-

1333

out activity.

1334

3.11.4.5.3 Monitoring of Investigational Product Management

1335

(a) Confirming, for the investigational product(s):

1336

1337

(i) that storage conditions are acceptable and in accordance with the

1338

storage requirement specified in the protocol;

1339

1340

ICH E6(R3) Guideline

(ii) that supplies are sufficient throughout the trial and are used

1341

within their shelf-life;

1342

1343

(iii) that the correct investigational product(s) are supplied only to

1344

participants who are eligible to receive it at the protocol-

1345

specified dose(s) and, where appropriate, in accordance with the

1346

randomisation procedures;

1347

1348

(iv) that the participants, investigator, investigator site staff and other

1349

relevant parties and individuals involved in the trial conduct are

1350

provided with necessary instruction on properly using, handling,

1351

storing, returning and destroying, or alternative disposition of the

1352

investigational product(s);

1353

1354

(v) that the receipt, use, return and destruction, or alternative

1355

disposition of the investigational product(s) are controlled and

1356

documented adequately;

1357

1358

(vi) that the disposition of unused investigational product(s)

1359

complies with applicable regulatory requirement(s) and is in

1360

accordance with the sponsor requirements;

1361

1362

(vii) where product available on the market is dispensed and used in

1363

accordance with applicable regulatory requirements, some of the

1364

previously outlined considerations may not be applicable.

1365

3.11.4.5.4 Monitoring of Clinical Trial Data

1366

(a) Verifying that the investigator is enrolling only eligible trial participants.

1367

1368

(b) Checking the accuracy, completeness and consistency of the reported

1369

trial data against the source records and other trial-related records and

1370

whether these were reported in a timely manner. This can be done on the

1371

basis of using samples and supported by data analytics, as appropriate.

1372

The sample size may need adjustment based on previous monitoring

1373

results or other indications of insufficient data quality. Monitoring

1374

should:

1375

1376

(i) verify that the data required by the protocol and identified as

1377

critical in the monitoring plan are consistent with the source;

1378

1379

(ii) identify missing data, inconsistent data, data outliers,

1380

unexpected lack of variability and protocol deviations;

1381

1382

(iii) examine data trends, such as the range, consistency and

1383

variability of data within and across sites;

1384

1385

ICH E6(R3) Guideline

1386

across sites, potential data manipulation and data integrity problems.

1387

3.11.4.6 Monitoring Report

1388

(a) Reports of monitoring activities should include a summary of what was

1389

reviewed, a description of significant findings, conclusions and actions

1390

required to resolve them and follow-up on their resolution including those not

1391

resolved in previous reports. The requirements of monitoring reports

1392

(including their content and frequency) should be described in the sponsor’s

1393

procedures.

1394

1395

(b) Reports of investigator site and/or centralised monitoring should be provided

1396

to the appropriate sponsor staff as described in the sponsor’s procedures in a

1397

timely manner for review and follow-up.

1398

1399

1400

action and resolution. The sponsor should decide on the appropriate action to

1401

be taken, and these decisions and the resolution of the actions involved, where

1402

needed, should be recorded.

1403

3.12 Noncompliance

1404

3.12.1 Noncompliance with the protocol, SOPs, GCP and/or applicable regulatory

1405

requirement(s) by an investigator/institution or by member(s) of the sponsor’s staff

1406

should lead to appropriate and proportionate action by the sponsor to secure

1407

compliance.

1408

1409

3.12.2 If noncompliance that significantly affects or has the potential to significantly affect

1410

trial participant’s rights, safety or well-being or the reliability of trial results is

1411

discovered, the sponsor should perform a root cause analysis, implement appropriate

1412

corrective and preventive actions and confirm their adequacy unless otherwise

1413

justified. Where the sponsor identifies issues that could significantly impact

1414

participant’s rights, safety and well-being or the reliability of trial results, the sponsor

1415

should notify the regulatory authority and/or IRB/IEC in line with applicable

1416

regulatory requirements.

1417

1418

3.12.3 If the monitoring and/or auditing identifies serious noncompliance on the part of an

1419

investigator/institution that persists despite efforts at remediation, the sponsor should

1420

terminate the investigator’s/institution’s participation in the trial. When an

1421

investigator’s/institution’s participation is terminated because of noncompliance, the

1422

sponsor should promptly notify the regulatory authority(ies) and IRB/IEC as

1423

appropriate.

1424

3.13 Safety Assessment and Reporting

1425

The sponsor is responsible for the ongoing safety evaluation of the investigational product(s).

1426

ICH E6(R3) Guideline

The Investigator’s Brochure or, where applicable, the current scientific information such as a

1427

basic product information brochure, forms the basis of safety assessment and reporting for the

1428

clinical trial. For further information, see Appendix A.

1429

3.13.1 Sponsor Review of Safety Information

1430

The sponsor should aggregate, as appropriate, and periodically review relevant safety

1431

information. This may result in the update of the protocol, Investigator’s Brochure,

1432

informed consent materials and related documents.

1433

The sponsor should review the available emerging safety information to assess

1434

whether there is any new data that may affect the participant’s willingness to continue

1435

in the trial, impact the conduct of the trial, or alter the approval/favourable opinion of

1436

the IRB/IEC and/or regulatory authority(ies), as applicable. Any information of this

1437

nature should be communicated to the participants, investigator, IRB/IEC and

1438

regulatory authorities, as applicable, in a timely manner.

1439

3.13.2 Safety Reporting

1440

(a) The sponsor should submit to the regulatory authority(ies) safety updates and

1441

periodic reports, including changes to the Investigator’s Brochure, as required

1442

by applicable regulatory requirements.

1443

1444

(b) The sponsor should, in accordance with the applicable regulatory

1445

requirement(s) and with ICH E2A Clinical Safety Data Management:

1446

Definitions and Standards for Expedited Reporting, expedite the reporting to

1447

the regulatory authority(ies) of all adverse drug reactions (ADRs) that meet

1448

three criteria: suspected, unexpected and serious (i.e., SUSARs).

1449

1450

1451

the expectedness of the reaction in relation to the applicable product

1452

information (e.g., the reference safety information (RSI) contained within the

1453

Investigator’s Brochure or alternative documents) in accordance with

1454

applicable regulatory requirements. Refer to ICH E2F Development Safety

1455

Update Report for more information about RSI.

1456

1457

(d) The reporting of SUSARs to investigator(s)/institutions(s) and to the

1458

IRB(s)/IEC(s) should be undertaken in a manner that reflects the urgency of

1459

action required and should take into consideration the evolving knowledge of

1460

the safety profile of the product. Reporting of SUSARs to the

1461

investigators/institutions should be made in accordance with regulatory

1462

requirements. In some regions, periodic reporting of line listings with an

1463

overall safety assessment may be appropriate.

1464

1465

(e) Urgent safety issues requiring immediate attention or action should be

1466

reported to the IRB/IEC and/or regulatory authority(ies) and investigators

1467

without undue delay and as specified in regulatory requirements.

1468

1469

ICH E6(R3) Guideline

(f) Alternative arrangements for safety reporting to regulatory authorities,

1470

IRBs/IECs, and investigators and for reporting by investigators to the sponsor

1471

should be prospectively agreed upon with the regulatory authority(ies) and the

1472

IRB/IEC if applicable, and described in the clinical trial protocol, (e.g., SAEs

1473

considered efficacy or safety endpoints, which would not be subject to

1474

unblinding and expedited reporting; see ICH E2A). See ICH E19.

1475

3.13.3 Managing an Immediate Hazard

1476

The sponsor should take prompt action to address immediate hazards to participants.

1477

The sponsor should determine the causes of the hazard and based on this, take

1478

appropriate remedial actions.

1479

The sponsor should consider whether the protocol requires amendment in response to

1480

an immediate hazard. The information on the immediate hazard, if required, and any

1481

subsequent protocol amendment should be submitted to the IRB/IEC and/or

1482

regulatory authorities by the investigator/institution or sponsor (in accordance with

1483

applicable regulatory requirements).

1484

3.14 Insurance/Indemnification/Compensation to Participants and Investigators

1485

3.14.1 If required by the applicable regulatory requirement(s), the sponsor should provide

1486

insurance or should indemnify (legal and financial coverage) the investigator/the

1487

institution against claims arising from the trial except for claims that arise from

1488

malpractice and/or negligence.

1489

1490

3.14.2 The sponsor’s policies and procedures should address the costs of treatment of trial

1491

participants in the event of trial-related injuries in accordance with the applicable

1492

regulatory requirement(s).

1493

1494

3.14.3 The approach to compensating trial participants should comply with applicable

1495

regulatory requirement(s).

1496

3.15 Investigational Product(s)

1497

3.15.1 Information on Investigational Product(s)

1498

1499

The sponsor should ensure that an Investigator’s Brochure is developed and updated

1500

as significant new information on the investigational product becomes available.

1501

Alternatively, for authorised medicinal products, the sponsor should identify the basic

1502

product information to be used in the trial (see Appendix A).

1503

3.15.2 Manufacturing, Packaging, Labelling and Coding Investigational Product(s)

1504

(a) The sponsor should ensure that the investigational product(s) (including active

1505

control(s) and placebo, if applicable) is characterised as appropriate to the

1506

stage of development of the product(s), is manufactured in accordance with

1507

any applicable GMP and is coded and labelled in a manner that protects the

1508

blinding, if applicable. In addition, the labelling should comply with

1509

applicable regulatory requirement(s).

1510

1511

ICH E6(R3) Guideline

(b) The sponsor should determine acceptable storage temperatures and other

1512

storage conditions (e.g., protection from light) for the investigational

1513

product(s), appropriate reconstitution fluids and procedures, and devices for

1514

product infusion, if any. The sponsor should inform all involved parties (e.g.,

1515

monitors, investigators, pharmacists, storage managers) of these

1516

determinations.

1517

1518

1519

and unacceptable deterioration during transport and storage.

1520

1521

(d) In blinded trials, the sponsor should implement:

1522

1523

(i) a process to blind the sponsor staff, trial participant and/or investigator

1524

as appropriate to the investigational product identity and assignment to

1525

prevent and detect inappropriate unblinding;

1526

1527

(ii) a procedure and mechanism that permits the investigator to rapidly

1528

identify the product(s) in case of a medical emergency where

1529

unblinding is considered necessary, while protecting the identity of the

1530

treatment assignment of the other trial participants;

1531

1532

(iii) a mechanism that protects the blinding of the trial where a participant’s

1533

treatment assignment is unblinded for the purpose of safety reporting

1534

to regulatory authorities and/or IRB/IEC, where appropriate.

1535

1536

(e) If significant formulation changes are made in the investigational product(s)

1537

(including active control(s) and placebo, if applicable) during the course of

1538

clinical development, the results of any additional studies of the formulated

1539

product(s) (e.g., stability, dissolution rate, bioavailability) needed to assess

1540

whether these changes would significantly alter the pharmacokinetic profile

1541

of the product should be available prior to the use of the new formulation in

1542

clinical trials.

1543

3.15.3 Supplying and Handling Investigational Product(s)

1544

(a) The sponsor is responsible for supplying the investigator(s)/institution(s) with

1545

the investigational product(s) or, where appropriate, supplying trial

1546

participants in accordance with applicable regulatory requirements and after

1547

obtaining the required approval/favourable opinion from the IRB/IEC and the

1548

regulatory authority(ies) for the trial.

1549

1550

(b) The sponsor should ensure that instructions are available for the

1551

investigator/institution or trial participants on the handling and storage of

1552

investigational product(s). The procedures should consider adequate and safe

1553

receipt, handling, storage, dispensing, retrieval of unused product from

1554

participants and return of unused investigational product(s) to the sponsor (or

1555

ICH E6(R3) Guideline

alternative disposition if authorised by the sponsor and in compliance with the

1556

applicable regulatory requirement(s)).

1557

1558

1559

1560

(i) ensure timely delivery of investigational product(s) to the

1561

investigator(s) or, where appropriate, to trial participants in accordance

1562

with applicable regulatory requirements to avoid any interruption to

1563

the trial as well as for the continuation of treatment for participants.

1564

1565

(ii) maintain records that document the identity, shipment, receipt, return

1566

and destruction, or alternative disposition of the investigational

1567

product(s) (see Appendix C);

1568

1569

(iii) maintain a system for retrieving investigational products and

1570

documenting this retrieval (e.g., for deficient product recall, return and

1571

destruction, or alternative disposition after trial completion, or expired

1572

product reclaim);

1573

1574

(iv) maintain a system for the disposition of unused investigational

1575

product(s) and for the documentation of this disposition;

1576

1577

(v) take steps to ensure that the investigational product(s) are stable over

1578

the period of use and only used within the current shelf-life;

1579

1580

(vi) maintain sufficient quantities of the investigational product(s) used in

1581

the trials to reconfirm specifications should this become necessary and

1582

maintain records of batch sample analyses and characteristics. The

1583

samples should be retained either until the analyses of the trial data are

1584

complete or as required by the applicable regulatory requirement(s),

1585

whichever represents the longer retention period. The samples do not

1586

need to be kept by the sponsor in trials where an authorised medicinal

1587

product is used as an investigational product unmodified from its

1588

authorised state, since samples are kept by the manufacturer.

1589

3.16 Data and Records

1590

3.16.1 Data Handling

1591

(a) The sponsor should ensure the integrity and confidentiality of data generated

1592

and managed.

1593

1594

(b) The sponsor should apply quality control to the relevant stages of data

1595

handling to ensure that the data are of sufficient quality to generate reliable

1596

results. The sponsor should focus their quality assurance and quality control

1597

activities and data review on critical data, including its relevant metadata.

1598

1599

ICH E6(R3) Guideline

1600

collection in the protocol (see Appendix B. Clinical Trial Protocol and

1601

Protocol Amendment(s)). Where necessary, additional details, including a

1602

data flow diagram, should be contained in a protocol-related document (e.g.,

1603

a data management plan).

1604

1605

(d) The sponsor should ensure that data acquisition tools are fit for purpose and

1606

designed to capture the information required by the protocol. They should be

1607

validated and ready for use prior to their required use in the trial.

1608

1609

(e) The sponsor should ensure that documented processes are implemented to

1610

ensure the data integrity for the full data life cycle.

1611

1612

(f) The sponsor should implement measures to ensure the safeguarding of the

1613

blinding, if any (e.g., maintain the blinding during data entry and processing).

1614

1615

(g) The sponsor should provide guidance to investigators/institutions, service

1616

providers and trial participants, where relevant, on the expectations for data

1617

capture, data changes, data retention and data disposal.

1618

1619

(h) The sponsor should not make changes to data entered by the investigator or

1620

trial participants unless justified and documented by the sponsor and agreed

1621

upon by the investigator.

1622

1623

(i) The sponsor should allow correction of errors to data, including data entered

1624

by participants, where requested by the investigators/participants. Such data

1625

corrections should be justified and supported by source records around the

1626

time of original entry.

1627

1628

(j) The sponsor should ensure that the investigator has access to data collected in

1629

accordance with the protocol during the course of the trial including relevant

1630

data from external sources, for example, central laboratory data, centrally read

1631

imaging data and, if appropriate, ePRO data that are necessary to enable the

1632

investigators to make decisions (e.g., on eligibility, treatment, continuing

1633

participation in the trial and care for the safety of the individual trial

1634

participants). The sponsor should pay special attention to data that may

1635

unblind the investigator and include the appropriate provisions in the protocol.

1636

1637

(k) The sponsor should not have exclusive control of data captured in data

1638

acquisition tools.

1639

1640

(l) The sponsor should ensure that the investigator has access to the required data

1641

for retention purposes.

1642

1643

ICH E6(R3) Guideline

(m) The sponsor should ensure that the investigator receives instructions on how

1644

to navigate systems, data and relevant metadata for the trial participants under

1645

their responsibility.

1646

1647

(n) The sponsor should seek investigator endorsement of their data at

1648

predetermined milestones.

1649

1650

(o) The sponsor should document the data management steps to be undertaken

1651

prior to data analysis. These steps may vary depending on the purpose of the

1652

analysis to be conducted (e.g., data for IDMC, for interim analysis or the final

1653

analysis).

1654

1655

(p) Prior to provision of the data for analysis, edit access to the data acquisition

1656

tools should be restricted as appropriate to the purpose of the analysis; for

1657

example, for interim analysis, the restriction may only be temporary or

1658

managed differently compared to the final analysis.

1659

1660

(q) Deviations from the planned statistical analysis or changes made to the data

1661

analysis set after the trial has been unblinded (where applicable) should be

1662

clearly documented and justified and should only occur in exceptional

1663

circumstances (e.g., data discrepancies that must be resolved for the reliability

1664

of the trial results). Data changes should be authorised by the investigator and

1665

reflected in an audit trail. Post-unblinding data changes and deviations from

1666

the planned statistical analyses should be reported in the clinical trial report.

1667

1668

(r) The sponsor should use an unambiguous trial participant identification code

1669

(see glossary term) that allows identification of all the data reported for each

1670

participant.

1671

1672

(s) The sponsor should implement appropriate measures to protect the privacy and

1673

confidentiality of personal information of trial participants, in accordance with

1674

applicable regulatory requirements on personal data protection.

1675

1676

(t) In accordance with applicable regulatory requirements, the sponsor should

1677

document what happens to data when a participant withdraws or discontinues

1678

from the trial.

1679

1680

(u) The sponsor should ensure that trial data are protected from unauthorised

1681

access, disclosure, dissemination or alteration and from inappropriate

1682

destruction or accidental loss.

1683

1684

(v) The sponsor should have processes and procedures in place for reporting

1685

incidents (including security breaches) that have a significant impact on the

1686

trial data to relevant parties, including regulatory authorities, where relevant.

1687

1688

1689

ICH E6(R3) Guideline

(w) When using computerised systems in a clinical trial, the sponsor should:

1690

1691

(i) have a record of the computerised systems used in a clinical trial. This

1692

should include the use, functionality, interfaces and validation status

1693

of each computerised system, and who is responsible for its

1694

management should be described. The record should also include a

1695

description of implemented access controls and internal and external

1696

security measures;

1697

1698

(ii) ensure that the requirements for computerised systems deployed by the

1699

sponsor (e.g., requirements for validation, audit trails, user

1700

management, backup, disaster recovery and IT security) are addressed

1701

and implemented and that documented procedures and adequate

1702

training are in place to ensure the correct development, maintenance

1703

and use of computerised systems in clinical trials (see section 4). These

1704

requirements should be proportionate to the importance of the

1705

computerised system and the data or activities they are expected to

1706

process;

1707

1708

(iii) maintain a record of the individual users who are authorised to access

1709

the system, their roles and their access privileges:

1710

1711

(iv) ensure that access rights granted to investigator site staff are in

1712

accordance with delegations by the investigator and visible to the

1713

investigator;

1714

1715

(v) for systems deployed by the investigator/institution, assess whether

1716

such systems, if identified as containing source records in the trial,

1717

(e.g., electronic health records and other record keeping systems for

1718

source data collection and investigator site files) are fit for purpose or

1719

whether the known issue(s) can be appropriately mitigated. This

1720

assessment should occur during the process of selecting clinical trial

1721

sites and should be documented;

1722

1723

(vi) ensure that there is a process in place for service providers and

1724

investigators to inform the sponsor of system defects identified or

1725

incidents that could potentially constitute a serious non-compliance

1726

with the clinical trial protocol, trial procedures or GCP in accordance

1727

with section 3.13.

1728

ICH E6(R3) Guideline

3.16.2 Statistical Programming and Data Analysis

1729

This section concerning documentation of operational aspects of clinical trial

1730

statistical activities should be read in conjunction with ICH E9 Statistical Principles

1731

for Clinical Trials, which provides detailed guidance on statistical principles for

1732

clinical development, trial design, conduct, analysis and reporting.

1733

(a) The sponsor should ensure that appropriate and documented quality control of

1734

statistical programming and data analysis is implemented (e.g., for sample size

1735

calculations, results for IDMC, outputs for clinical trial report, statistical or

1736

centralised monitoring).

1737

1738

(b) The sponsor should ensure the traceability of data transformations and

1739

derivations during data processing and analysis.

1740

1741

1742

participant from any analysis set is predefined (e.g., in the protocol or the

1743

statistical analysis plan). The rationale for inclusion or exclusion for any

1744

participant (or particular data point) should be clearly described and

1745

documented.

1746

1747

(d) Procedures should be in place to describe unblinding; these descriptions

1748

should include:

1749

1750

(i) who was unblinded, at what timepoint and for what purpose they were

1751

unblinded;

1752

1753

(ii) who should remain blinded;

1754

1755

(iii) the safeguards in place to preserve the blinding.

1756

1757

(e) The sponsor should retain the statistical programming records that relate to the

1758

output contained or used in reports of the trial results, including quality

1759

control/validation activities performed. Outputs should be traceable to the

1760

statistical software programs, and they should be dated and time stamped and

1761

protected against any changes.

1762

3.16.3 Record Keeping and Retention

1763

(a) The sponsor (or subsequent owners of the data) should retain all of the

1764

sponsor-specific essential records pertaining to the trial in conformance with

1765

the applicable regulatory requirement(s).

1766

1767

(b) The sponsor should inform the investigator(s)/institution(s) and service

1768

providers, when appropriate, in writing of the need for essential records

1769

retention and should notify the investigator(s)/institution(s) and service

1770

providers, when appropriate, in writing when the trial-related records are no

1771

longer needed.

1772

ICH E6(R3) Guideline

1773

to the appropriate authority(ies) as required by the applicable regulatory

1774

requirement(s).

1775

3.16.4 Record Access

1776

(a) The sponsor should ensure that it is specified in the protocol or other

1777

documented agreement that the investigator(s)/institution(s) provide direct

1778

access to source records for trial-related monitoring, audits, IRB/IEC review

1779

and regulatory inspection.

1780

1781

(b) The sponsor should ensure that trial participants have consented to direct

1782

access to their original medical records and other participant-related trial

1783

documents for trial-related monitoring, audit, IRB/IEC review and regulatory

1784

inspection as part of the informed consent.

1785

3.17 Reports

1786

3.17.1 Premature Termination or Suspension of a Trial

1787

If a trial is prematurely terminated or suspended, the sponsor should promptly inform

1788

the investigators/institutions and the regulatory authority(ies) of the termination or

1789

suspension and the reason(s) for the termination or suspension. The IRB/IEC should

1790

also be informed promptly and provided with the reason(s) for the termination or

1791

suspension by the sponsor or by the investigator/institution, in accordance with

1792

applicable regulatory requirement(s).

1793

3.17.2 Clinical Trial/Study Reports

1794

(a) Whether the trial is completed or prematurely terminated or an interim analysis

1795

is undertaken for regulatory submission, the sponsor should ensure that the

1796

clinical trial reports, including interim reports, are prepared and provided to

1797

the regulatory agency(ies) as required by the applicable regulatory

1798

requirement(s). The sponsor should also ensure that the clinical trial reports in

1799

marketing applications meet the standards of ICH E3 or are otherwise in

1800

accordance with applicable regulatory requirements. (Note: ICH E3 specifies

1801

that abbreviated study reports may be acceptable in certain cases.)

1802

1803

(b) Investigators should be provided with a summary of the trial results.

1804

1805

1806

about the final treatment taken by their participants for blinded trials and a

1807

brief summary of the overall outcome of the trial. Where this information is

1808

provided to participants, the language should be non-technical, understandable

1809

to a layperson and non-promotional. The sponsor should only supply this

1810

information after the trial has been unblinded and all relevant

1811

analyses/conclusions have been completed and finalised.

1812

ICH E6(R3) Guideline

4. DATA GOVERNANCE – INVESTIGATOR AND SPONSOR

1813

This section provides guidance to investigators and sponsors (i.e., the responsible parties) on

1814

appropriate management of data integrity, traceability and security, thereby allowing the

1815

accurate reporting, verification and interpretation of the clinical trial-related information. This

1816

section should be read in conjunction with corresponding responsibilities for the investigator

1817

and the sponsor as defined in sections 2 and 3, along with ICH E8(R1) and ICH E9.

1818

The quality and amount of the information generated in a clinical trial should be sufficient to

1819

address trial objectives, provide confidence in the trial’s results and support good decision

1820

making.

1821

The systems and processes that help ensure this quality should be designed and implemented

1822

in a way that is proportionate to the risks to participants and the reliability of trial results.

1823

The following key processes should address the full data life cycle with a focus on the criticality

1824

of the data and should be implemented proportionately and documented appropriately:

1825

(a) processes to ensure data protection of trial participants’ confidential data;

1826

1827

(b) processes for managing computerised systems to ensure that they are fit for

1828

purpose and used appropriately;

1829

1830

1831

randomisation, dose escalation and blinding;

1832

1833

(d) processes to support key decision making, such as data finalisation prior to

1834

analysis, unblinding, allocation to analysis data sets, changes in clinical trial

1835

design and, where applicable, the activities of, for example, an IDMC.

1836

4.1 Safeguard Blinding in Data Governance

1837

4.1.1 Maintaining the integrity of the blinding is important in particular in the design of

1838

systems, management of users’ account, delegation of responsibilities with respect to

1839

data handling and provision of data access at sites, data transfers, database review

1840

prior to planned unblinding and statistical analysis across all appropriate stages of the

1841

trial.

1842

1843

4.1.2 Roles, responsibilities and procedures for access to unblinded information should be

1844

defined and documented by all relevant parties according to the protocol; this

1845

information may also be included in the data management plans and statistical

1846

analysis plans. For example, in blinded trials, sponsor staff or designated third parties

1847

who are involved in operation of the trial and directly or indirectly interact with site

1848

investigator staff should not have access to unblinding information.

1849

1850

4.1.3 The potential for unblinding should be part of the risk assessment of a blinded trial.

1851

Any planned or unplanned unblinding, including accidental or emergency unblinding,

1852

should be documented and assessed for impact to trial results.

1853

ICH E6(R3) Guideline

4.2 Data Life Cycle Elements

1854

Procedures should be in place to cover the full data life cycle.

1855

4.2.1 Data Capture

1856

(a) The requirements for and extent of data verification, when data captured on

1857

paper or in an electronic health record are manually transcribed into a

1858

computerised system, should take the criticality of the data into account. Refer

1859

to section 4.2.3 for data entered directly in data acquisition tools.

1860

(b) Acquired data from any source should be accompanied by relevant metadata.

1861

At the point of data capture, automated data validation checks should be

1862

considered as required based upon risk, and their implementation should be

1863

controlled and documented.

1864

1865

4.2.2 Relevant Metadata, Including Audit Trails

1866

The approach used by the responsible party for implementing, evaluating, accessing,

1867

managing and reviewing relevant metadata associated with critical data should entail:

1868

1869

(a) Evaluating the system for the types and content of metadata available to ensure

1870

that:

1871

(i) computerised systems maintain logs of user account creation, changes

1872

to user roles and permissions and user access;

1873

1874

(ii) systems are designed to permit data changes in such a way that the

1875

initial data entry and any subsequent changes or deletions are

1876

documented, including, where appropriate, using a risk-based

1877

evaluation, the reason for the change if it is not implicit;

1878

1879

(iii) systems record and maintain workflow actions in addition to direct

1880

data entry/changes into the system.

1881

(b) Ensuring that audit trails, reports and logs are not disabled or modified except

1882

in rare circumstances and only if a log of such action and justification is

1883

maintained;

1884

1885

1886

1887

(d) Ensuring that the automatic capture of date and time of data entries or transfer

1888

using data acquisition tools are unambiguous (e.g., coordinated universal time

1889

(UTC));

1890

1891

(e) Determining which of the identified metadata require review and retention.

1892

ICH E6(R3) Guideline

4.2.3 Review of Data and Metadata

1893

Procedures for review of trial-specific data, audit trails and other relevant metadata

1894

should be in place. It should be a planned activity, and the extent and nature should

1895

be adapted to the individual trial and adjusted based on experience during the trial.

1896

4.2.4 Data Corrections

1897

There should be processes to correct data errors that could impact the reliability of the

1898

trial results. Corrections should be attributed to the entity making the correction,

1899

justified and supported by source records around the time of original entry, and

1900

performed in a timely manner.

1901

4.2.5 Data Transfer, Exchange and Migration

1902

Validated processes or other appropriate processes such as reconciliation should be in

1903

place to ensure that electronic data transferred between computerised systems retains

1904

its integrity and preserves its confidentiality. The transfer process should be

1905

documented to ensure traceability, and data reconciliation should be implemented as

1906

appropriate.

1907

4.2.6 Finalisation of Data Sets Prior to Analysis

1908

(a) Data of sufficient quality for interim and final analysis are achieved by

1909

implementing timely and reliable processes for data capture, verification,

1910

validation, review and rectification of errors and omissions that have a

1911

meaningful impact on the safety of trial participants and/or the reliability of

1912

the trial results.

1913

1914

(b) Activities undertaken to finalise the data sets prior to analysis should be

1915

confirmed and documented in accordance with pre-specified procedures.

1916

These activities may include reconciliation of entered data and data sets or

1917

reconciliation of relevant databases, correction of data errors and omissions,

1918

medical coding, compilation and addressing the impact of non-compliance

1919

including protocol deviations.

1920

1921

1922

accordance with the planned statistical analysis and should be documented.

1923

4.3 Computerised Systems

1924

As described in sections 2 and 3, the responsibilities of the sponsor, investigator and

1925

the activities of other parties with respect to a computerised system used in clinical

1926

trials should be clear and documented. In summary, the sponsor is responsible for

1927

ensuring that for computerised systems which they put in place, the expectations for

1928

computerised systems as described in this section are addressed in a risk proportionate

1929

manner. The sponsor should review whether the systems used by the

1930

investigator/institution (e.g., electronic health records and other record keeping

1931

systems for source data collection) are fit for purpose in the context of the trial. In the

1932

event that the investigator/institution deploys systems specifically for the purposes of

1933

ICH E6(R3) Guideline

conducting clinical trials, the investigator/institution should ensure that the

1934

expectations are proportionately addressed and implemented.

1935

The responsible party should ensure that those developing computerised systems for

1936

clinical trials are aware of the intended purpose and the regulatory requirements that

1937

apply to them.

1938

It is recommended that representatives of intended participant populations and

1939

healthcare professionals are involved in the design of the system, where relevant, to

1940

ensure that computerised systems are suitable for use by the intended user population.

1941

4.3.1 Procedures for the Use of Computerised Systems

1942

Documented procedures should be in place to ensure the appropriate use of

1943

computerised systems in clinical trials for essential activities related to data collection,

1944

handling and management.

1945

4.3.2 Training

1946

The responsible party should ensure that those using computerised systems are

1947

appropriately trained in their use.

1948

4.4 Security of Computerised Systems

1949

4.4.1 The security of the trial data and records should be managed throughout the data life

1950

cycle.

1951

1952

4.4.2 The responsible party should ensure that security controls are maintained for

1953

computerised systems. These controls should include user management and ongoing

1954

measures to prevent, detect and/or mitigate security breaches. Aspects such as user

1955

authentication requirements and password management, firewall settings, antivirus

1956

software, security patching, system monitoring and penetration testing should be

1957

considered.

1958

1959

4.4.3 The responsible party should maintain adequate backup of the data.

1960

1961

4.4.4 Procedures should cover the following: system security measures, data backup and

1962

disaster recovery.

1963

4.5 Validation of Computerised Systems

1964

4.5.1 The responsible party is responsible for the validation status of the system throughout

1965

its life cycle. The approach to validation of computerised systems should be based on

1966

a risk assessment that considers the intended use of the system; the purpose and

1967

importance of the data/record that is collected/generated, maintained and retained in

1968

the system; and the potential of the system to affect the well-being, rights and safety

1969

of trial participants and the reliability of trial results.

1970

1971

4.5.2 Validation should demonstrate that the system conforms to the established

1972

requirements for completeness, accuracy, and reliability and is consistent with

1973

intended performance.

1974

ICH E6(R3) Guideline

4.5.3 Systems should be appropriately validated prior to use with adequate change control

1975

procedures implemented.

1976

1977

4.5.4 Validation of changes should be based on risk and consider both previously collected

1978

and new data.

1979

1980

4.5.5 Both basic system functionality and protocol specific configurations and

1981

customisations, including automated data entry checks and calculations, should be

1982

validated. Interfaces between systems should also be defined and validated. Different

1983

degrees of qualification/validation may be needed for bespoke systems, systems

1984

designed to be configured or systems where no alterations are needed.

1985

1986

4.5.6 Where relevant, procedures should cover the following: system design, validation,

1987

and functionality testing; release; setup; installation and change control until

1988

decommissioning.

1989

1990

4.5.7 The responsible party should ensure that the computerised systems used in clinical

1991

trial processes are qualified and validated, including those developed by other parties.

1992

They should ensure that qualification and validation documentation is maintained and

1993

retained.

1994

1995

4.5.8 Validation should generally include defining the requirements and specifications for

1996

the system and their testing, along with the associated documentation, to ensure the

1997

system is fit for purpose, especially for critical functionality, such as randomisation,

1998

dosing and dose titrations and reductions, and collection of endpoint data.

1999

2000

4.5.9 Unresolved issues, if any, should be justified and, where relevant, addressed by

2001

mitigations prior to and/or during the continued use of the system.

2002

2003

4.5.10 The trial-specific systems (including updates resulting from protocol amendments)

2004

should only be implemented to enable the conduct of the trial by the investigator after

2005

all necessary approvals for the clinical trial have been received.

2006

4.6 System Failure

2007

Contingency procedures should be in place to prevent loss or lack of accessibility to data

2008

essential to participant safety, trial decisions or trial outcomes.

2009

4.7 Technical Support

2010

4.7.1 Where appropriate, there should be mechanisms (e.g., help desk support) in place to

2011

document, evaluate and manage issues with the computerised systems (e.g., raised by

2012

users), and there should be periodic review of these cumulative issues to identify those

2013

that are repeated and/or systemic.

2014

2015

4.7.2 Defects and issues should be resolved according to their criticality. Issues with high

2016

criticality should be resolved in a timely manner.

2017

ICH E6(R3) Guideline

4.8 User Management

2018

4.8.1 Access controls are integral to computerised systems used in clinical trials to limit

2019

system access to authorised users and to ensure attributability to an individual. The

2020

security measures should be selected in such a way that they achieve the intended

2021

security and do not unduly impact user-friendliness.

2022

4.8.2 Procedures should be in place to ensure that user access rights are appropriately

2023

assigned based on a user’s duties and functions, blinding arrangements and the

2024

organisation to which users belong. Access rights should be revoked when they are

2025

no longer needed.

2026

4.8.3 Authorised users and access privileges should be clearly documented, maintained and

2027

retained. These records should include any updates to a user’s roles, access rights and

2028

permissions, and time of access privileges given (e.g., time stamp).

2029

ICH E6(R3) Guideline

GLOSSARY

2030

Adverse Events and Adverse Reaction-related definitions:

2031

Adverse Event (AE): Any unfavourable medical occurrence in a trial participant. The

2032

adverse event does not necessarily have a causal relationship with the treatment.

2033

Adverse Drug Reaction (ADR):

2034

• in the pre-approval clinical experience with a new investigational product or its new

2035

usages (particularly as the therapeutic dose(s) may not be established):

2036

unfavourable and unintended responses, such as a sign (e.g., laboratory results),

2037

symptoms or disease related to any dose of a medicinal product where a causal

2038

relationship between a medicinal product and an adverse event is a reasonable

2039

possibility. The level of certainty about the relatedness of the adverse drug reaction

2040

to an investigational product will vary. If the ADR is suspected to be medicinal

2041

product-related with a high level of certainty, it should be included in the reference

2042

safety information (RSI) and/or the Investigator’s Brochure (IB).

2043

2044

• for marketed medicinal products: a response to a drug that is noxious and

2045

unintended and that occurs at doses normally used in humans for prophylaxis,

2046

diagnosis or therapy of diseases or for modification of physiological function.

2047

(See ICH E2A Clinical Safety Data Management: Definitions and Standards for

2048

Expedited Reporting).

2049

Serious Adverse Event (SAE): Any unfavourable medical occurrence that is considered

2050

serious at any dose if it:

2051

• results in death

2052

• is life-threatening

2053

• requires inpatient hospitalisation or prolongation of existing hospitalisation

2054

• results in persistent or significant disability/incapacity

2055

• is a congenital anomaly/birth defect (see ICH E2A)

2056

Suspected Unexpected Serious Adverse Reaction (SUSAR): an adverse reaction that

2057

meets three criteria: suspected, unexpected and serious.

2058

• Suspected: There is a reasonable possibility that the drug caused the adverse drug

2059

reaction.

2060

2061

• Unexpected: An adverse reaction, the nature or severity of which is not consistent

2062

with the applicable product information (e.g., the RSI, see glossary term contained

2063

within the Investigator’s Brochure or alternative documents according to applicable

2064

regulatory requirements. Refer to ICH E2F Development Safety Update Report for

2065

more information about RSI.

2066

2067

• Serious: See above for SAE.

2068

2069

ICH E6(R3) Guideline

Agreement

2070

A document or set of documents describing the details of any arrangements on delegation or

2071

transfer, distribution and/or sharing of activities and, if appropriate, on financial matters

2072

between two or more parties. This could be in the form of a contract. The protocol may serve

2073

as the basis of an agreement.

2074

Applicable Regulatory Requirement(s)

2075

Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational

2076

products.

2077

Assent

2078

Affirmative agreement of a minor to participate in clinical trial. The absence of expression of

2079

agreement or disagreement should not be interpreted as assent.

2080

Audit

2081

A systematic and independent examination of trial-related activities and records performed by

2082

the sponsor, service provider (including contract research organisation (CRO)) or institution to

2083

determine whether the evaluated trial-related activities were conducted and the data were

2084

recorded, analysed and accurately reported according to the protocol, applicable standard

2085

operating procedures (SOPs), Good Clinical Practice (GCP) and the applicable regulatory

2086

requirement(s).

2087

Audit Certificate

2088

A declaration of confirmation by the auditor that an audit has taken place.

2089

Audit Report

2090

A record describing the conduct and outcome of the audit.

2091

Audit Trail

2092

Metadata records that allow reconstruction of the course of events by capturing details on

2093

actions (manual or automated) performed relating to information and data collection and, where

2094

applicable, to activities in computerised systems. The audit trail should show activities, initial

2095

entry, and changes to data fields or records, by whom, when and, where applicable, why. In

2096

computerised systems, the audit trail should be secure, computer generated and timestamped.

2097

Blinding/Masking

2098

A procedure in which one or more parties to the trial are kept unaware of the treatment

2099

assignment(s). Single-blinding usually refers to the participant(s) being unaware, and double-

2100

blinding usually refers to the participant(s), investigator(s) or other trial staff, as appropriate,

2101

being unaware of the treatment assignment(s).

2102

Case Report Form (CRF)

2103

A tool designed to record protocol-required information to be reported by the investigator to

2104

the sponsor on each trial participant (see Data Acquisition Tool).

2105

2106

ICH E6(R3) Guideline

Certified Copy

2107

A copy (irrespective of the type of media used) of the original record that has been verified

2108

(i.e., by a dated signature or by generation through a validated process) to have the same

2109

information as the original, including relevant metadata, where applicable.

2110

Clinical Trial

2111

Any interventional investigation in human participants intended to discover or verify the

2112

clinical, pharmacological and/or other pharmacodynamic effects of an investigational

2113

product(s); and/or to identify any adverse reactions to an investigational product(s); and/or to

2114

study absorption, distribution, metabolism and excretion of an investigational product(s) with

2115

the object of ascertaining its safety and/or efficacy.

2116

Clinical Trial/Study Report (CSR)

2117

A documented description of a trial of any investigational product conducted in human

2118

participants, in which the clinical and statistical description, presentations and analyses are

2119

fully integrated into a single report (see ICH E3 Structure and Content of Clinical Study

2120

Reports).

2121

Comparator

2122

An investigational or authorised medicinal product (i.e., active control), placebo or standard of

2123

care used as a reference in a clinical trial.

2124

Compliance (in relation to trials)

2125

Adherence to the trial-related requirements, GCP requirements and the applicable regulatory

2126

requirements.

2127

Confidentiality

2128

Prevention of disclosure to other than authorised individuals of a sponsor’s proprietary

2129

information or of a participant’s identity or their confidential information.

2130

Coordinating Investigator

2131

An investigator assigned the responsibility for the coordination of investigators at different

2132

investigator sites participating in a multicentre trial (if appropriate).

2133

Computerised Systems Validation

2134

A process of establishing and documenting that the specified requirements of a computerised

2135

system can be consistently fulfilled from design until decommissioning of the system or

2136

transition to a new system. The approach to validation should be based on a risk assessment

2137

that takes into consideration the intended use of the system and the potential of the system to

2138

affect trial participant protection and the reliability of trial results.

2139

Contract Research Organisation (CRO)

2140

See Service Provider.

2141

2142

ICH E6(R3) Guideline

Data Acquisition Tool (DAT)

2143

A paper or electronic tool designed to collect data and associated metadata from a data

2144

originator in a clinical trial according to the protocol and to report the data to the sponsor.

2145

The data originator may be a human (e.g., the participant or trial staff), a machine (e.g.,

2146

wearables and sensors) or an electronic transfer of data from one system to another (e.g.,

2147

extraction of data from an electronic health record or laboratory system).

2148

Examples of DATs include but are not limited to CRFs, interactive response technologies

2149

(IRTs), patient-reported outcomes (PROs), clinical outcome assessments (COAs) and wearable

2150

devices, irrespective of the media used.

2151

Direct Access

2152

Permission to examine, analyse and verify records that are important to the evaluation of a

2153

clinical trial and may be performed in person or remotely. Any party (e.g., domestic and foreign

2154

regulatory authorities, sponsor’s monitors and auditors) with direct access should take

2155

reasonable precautions within the constraints of the applicable regulatory requirement(s) to

2156

maintain the confidentiality of participants’ identities and their data and sponsor’s proprietary

2157

information.

2158

Essential Records

2159

Essential records are the documents and data (and relevant metadata), in any format, associated

2160

with a clinical trial that facilitate the ongoing management of the trial and collectively allow

2161

the evaluation of the methods used, the factors affecting a trial and the actions taken during the

2162

trial conduct to determine the reliability of the trial results produced and the verification that

2163

the trial was conducted in accordance with GCP and applicable regulatory requirements (see

2164

Appendix C. Essential Records for the Conduct of a Clinical Trial).

2165

Good Clinical Practice (GCP)

2166

A standard for the planning, initiating, performing, recording, oversight, evaluation, analysis

2167

and reporting of clinical trials that provides assurance that the data and reported results are

2168

reliable and that the rights, safety and well-being of trial participants are protected.

2169

Impartial Witness

2170

A person who is independent of the trial who cannot be unfairly influenced by people involved

2171

with the trial, who attends the informed consent process if the participant or the participant’s

2172

legally acceptable representative cannot read, and who reads the informed consent form and

2173

any other documented information supplied or read to the participant and/or their legally

2174

acceptable representative.

2175

Independent Data Monitoring Committee (IDMC)

2176

An independent data monitoring committee (e.g., data safety monitoring board) that may be

2177

established by the sponsor to assess at intervals the progress of a clinical trial, the safety data

2178

and the critical efficacy endpoints, and to recommend to the sponsor whether to continue,

2179

modify or stop a trial.

2180

2181

ICH E6(R3) Guideline

Informed Consent

2182

A process by which a participant or their legally accepted representative voluntarily confirms

2183

their willingness to participate in a trial after having been informed and been provided with the

2184

opportunity to discuss all aspects of the trial that are relevant to the participant’s decision to

2185

participate. Varied approaches to the provision of information and the discussion about the trial

2186

can be used. This can include, for example, providing text in different formats, images and

2187

videos and using telephone or video conferencing with investigator site staff. Informed consent

2188

is documented by means of a written or electronic, signed and dated informed consent form.

2189

Obtaining consent remotely may be considered when appropriate.

2190

Inspection

2191

The act by a regulatory authority(ies) of conducting an official review of documents, facilities,

2192

records and any other resources that are deemed by the authority(ies) to be related to the clinical

2193

trial and that may be accessed at the investigator site, at the sponsor’s and/or service provider’s

2194

(including CRO’s) facilities, or at other establishments deemed appropriate by the regulatory

2195

authority(ies). Some aspects of the inspection may be conducted remotely.

2196

Institution

2197

Any public or private entity or agency or medical or dental organisation in whose remit clinical

2198

trials are conducted.

2199

Institutional Review Board (IRB)/Independent Ethics Committee (IEC)

2200

An independent body (a review board or a committee, institutional, regional, national or

2201

supranational) constituted of medical professionals and non-medical members whose

2202

responsibility it is to ensure the protection of the rights, safety and well-being of human

2203

participants involved in a trial and to provide public assurance of that protection by, among

2204

other things, reviewing and approving/providing favourable opinion on the trial protocol, the

2205

suitability of the investigator(s), the facilities, and the methods and material to be used in

2206

obtaining and documenting informed consent of the trial participants. The legal status,

2207

composition, function, operations and regulatory requirements pertaining to IRBs/IECs may

2208

differ among countries but should allow the IRB/IEC to act in agreement with GCP as

2209

described in this guideline.

2210

Interim Clinical Trial/Study Report

2211

A report of intermediate results and their evaluation based on analyses performed during the

2212

course of a trial.

2213

Investigational Product

2214

A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in

2215

a clinical trial, including a product with a marketing authorisation when used or assembled

2216

(formulated or packaged) in a way different from the approved form, or when used for an

2217

unapproved indication, or when used to gain further information about an approved use.

2218

2219

2220

ICH E6(R3) Guideline

Investigator

2221

A person responsible for the conduct of the clinical trial, including the trial participants for

2222

whom that person has responsibility during the conduct of the trial. If a trial is conducted by a

2223

team of individuals, the investigator is the responsible leader of the team and may be called the

2224

principal investigator. Where an investigator/institution is referenced in this guideline, it

2225

describes expectations that may be applicable to the investigator and/or the institution in some

2226

regions. Where required by the applicable regulatory requirements, the “investigator” should

2227

be read as “investigator and/or the institution.”

2228

Investigator’s Brochure (IB)

2229

A compilation of the clinical and nonclinical data on the investigational product(s) that is

2230

relevant to the study of the investigational product(s) in human participants (see Appendix A.

2231

Investigator’s Brochure).

2232

Investigator Site

2233

The location(s) at or from where trial-related activities are conducted under the

2234

investigator’s/institution’s supervision.

2235

Legally Acceptable Representative

2236

An individual or juridical or other body authorised under applicable law to consent, on behalf

2237

of a prospective participant, to the participant’s participation in the clinical trial.

2238

Metadata

2239

The contextual information required to understand a given data element. Metadata is structured

2240

information that describes, explains or otherwise makes it easier to retrieve, use or manage

2241

data. For the purpose of this guideline, relevant metadata are those needed to reconstruct the

2242

trial conduct.

2243

Monitoring

2244

The act of overseeing the progress of a clinical trial and of ensuring that the clinical trial is

2245

conducted, recorded and reported in accordance with the protocol, SOPs, GCP and the

2246

applicable regulatory requirement(s).

2247

Monitoring Plan

2248

A document that describes the strategy, methods, responsibilities and requirements for

2249

monitoring the trial.

2250

Monitoring Report

2251

A documented report following site and/or centralised monitoring activities.

2252

Multicentre Trial

2253

A clinical trial conducted according to a single protocol but at more than one investigator site.

2254

Nonclinical Study

2255

Biomedical studies not performed on human participants.

2256

ICH E6(R3) Guideline

Original Medical Record

2257

See Source Records.

2258

Protocol

2259

A document that describes the objective(s), design, methodology, statistical considerations and

2260

organisation of a trial. The protocol usually also gives the background and rationale for the

2261

trial, but these could be provided in other protocol referenced documents. Throughout the ICH

2262

GCP Guideline, the term protocol refers to protocol and protocol amendments.

2263

Protocol Amendment

2264

A documented description of a change(s) to a protocol.

2265

Quality Assurance (QA)

2266

All those planned and systematic actions that are established to ensure that the trial is performed

2267

and the data are generated, documented (recorded) and reported in compliance with GCP and

2268

the applicable regulatory requirement(s).

2269

Quality Control (QC)

2270

The operational techniques and activities undertaken to verify that the requirements for quality

2271

of the trial-related activities have been fulfilled.

2272

Randomisation

2273

The process of deliberately including an element of chance when assigning participants to

2274

groups that receive different treatments in order to reduce bias.

2275

Reference Safety Information (RSI)

2276

Contains a cumulative list of ADRs that are expected for the investigational product being

2277

administered to participants in a clinical trial. The RSI is included in the Investigator’s

2278

Brochure.

2279

Regulatory Authorities

2280

Bodies having the power to regulate, including those that review submitted protocols and

2281

clinical data and those that conduct inspections. These bodies are sometimes referred to as

2282

competent authorities.

2283

Service Provider

2284

A person or organisation (commercial, academic or other) providing a service used during the

2285

conduct of a clinical trial to either the sponsor or the investigator to fulfil one or more of their

2286

trial-related activities.

2287

Signature

2288

A unique mark, symbol or entry in line with applicable regulatory requirements and/or practice

2289

to show expression of will and allow authentication of the signatory.

2290

2291

ICH E6(R3) Guideline

Source Records

2292

Original documents or data (which includes relevant metadata) or certified copies of the

2293

original documents or data, irrespective of the media used. This may include trial participants’

2294

medical/health records/notes/charts; data provided/entered by trial participants (e.g., electronic

2295

patient-reported outcome (ePROs)); healthcare providers’ records from pharmacies,

2296

laboratories and other facilities involved in the clinical trial; and data from automated

2297

instruments, such as wearables and sensors.

2298

Sponsor

2299

An individual, company, institution, or organisation that takes responsibility for the initiation,

2300

management and arrangement of the financing of a clinical trial. A clinical trial may have one

2301

or several sponsors where permitted under regulatory requirements. All sponsors have the

2302

responsibilities of a sponsor set out in this guideline. In accordance with regulatory

2303

requirements, sponsors may decide in a documented agreement setting out their respective

2304

responsibilities. Where the agreement does not specify to which sponsor a given responsibility

2305

is attributed, that responsibility lies with all sponsors.

2306

Sponsor-Investigator

2307

An individual who both initiates and conducts, alone or with others, a clinical trial, and under

2308

whose immediate direction the investigational product is administered to, dispensed to or used

2309

by a participant. The term does not include any person other than an individual (e.g., the term

2310

does not include a corporation or an agency). The obligations of a sponsor-investigator include

2311

both those of a sponsor and those of an investigator.

2312

Standard Operating Procedures (SOPs)

2313

Detailed, documented instructions to achieve uniformity of the performance of a specific

2314

activity.

2315

Sub-investigator

2316

Any individual member of the clinical trial team designated and supervised by the investigator

2317

to perform critical trial-related procedures and/or to make important trial-related decisions

2318

(e.g., associates, residents, research fellows).

2319

Trial Participant

2320

An individual who participates in a clinical trial, either as a recipient of the investigational

2321

product(s) or as a control.

2322

Trial Participant Identification Code

2323

A unique identifier assigned to each trial participant to protect the participant’s identity and

2324

used in lieu of the participant’s name when the investigator reports adverse events and/or other

2325

trial-related data.

2326

Vulnerable Participants

2327

Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the

2328

expectation, whether justified or not, of benefits associated with participation or of a retaliatory

2329

ICH E6(R3) Guideline

response from senior members of a hierarchy in case of refusal to participate. Examples are

2330

members of a group with a hierarchical structure, such as medical, pharmacy, dental and

2331

nursing students; subordinate hospital and laboratory personnel; employees of the

2332

pharmaceutical industry; members of the armed forces and persons kept in detention. Other

2333

vulnerable participants may include persons in nursing homes, unemployed or impoverished

2334

persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads,

2335

refugees, minors and those incapable of giving consent.

2336

ICH E6(R3) Guideline

APPENDICES

2337

Appendix A. INVESTIGATOR’S BROCHURE

2338

A.1 Introduction

2339

The Investigator’s Brochure (IB) is a compilation of the clinical and nonclinical data on the

2340

investigational product(s)

that are relevant to the study of the product(s) in human participants.

2341

Its purpose is to provide the investigators and others involved in the trial with the information

2342

to facilitate their understanding of the rationale for and their compliance with many key

2343

features of the protocol, such as the dose, dose frequency/interval, methods of administration

2344

and safety monitoring procedures.

2345

2346

A.1.1 Development of the Investigator’s Brochure

2347

Generally, the sponsor is responsible for ensuring that an up-to-date IB is developed.

2348

In the case of an investigator-initiated trial, the sponsor-investigator should determine

2349

whether a brochure is available from the product license/marketing authorisation

2350

holder. If the investigational product is provided by the sponsor-investigator, then they

2351

should provide the necessary information to the investigator site staff. Where

2352

permitted by regulatory authorities, the current scientific information such as a basic

2353

product information brochure (e.g., summary of product characteristics package

2354

leaflet, or labelling) may be an appropriate alternative, provided that it includes

2355

current, comprehensive and detailed information on all aspects of the investigational

2356

product that might be of importance to the investigator. If an authorised medicinal

2357

product is being studied for a new use (i.e., a new indication), an IB specific to that

2358

new use should be prepared unless there is a rationale for only one IB. The IB should

2359

be reviewed at least annually and revised as necessary in compliance with a sponsor’s

2360

documented procedures. More frequent revision may be appropriate depending on the

2361

stage of development and the generation of relevant new information. Relevant new

2362

information may be so important that it needs to be communicated to the investigators

2363

and possibly to the IRBs/IECs and/or regulatory authorities before it is included in a

2364

revised IB.

2365

2366

A.1.2 Reference Safety Information and Risk-Benefit Assessment

2367

The reference safety information (RSI) contained in the IB provides an important

2368

reference point for expedited reporting of suspected unexpected serious adverse

2369

reactions (SUSARs) in the clinical trial. The IB also provides insight to support the

2370

clinical management of the participants during the course of the clinical trial. The

2371

information should be presented in a concise, simple, objective, balanced and non-

2372

promotional form that enables a clinician or potential investigator to understand it and

2373

make their own unbiased risk-benefit assessment of the appropriateness of the

2374

proposed trial. For this reason, a medically qualified person should be involved in the

2375

generation of an IB, but the contents of the IB should be approved by the disciplines

2376

that generated the described data.

2377

For the purpose of this guideline, the term “investigational products” should be considered synonymous with

drugs, medicines, medicinal products, vaccines and biological products.

ICH E6(R3) Guideline

A.2 General Considerations

2378

These considerations delineate the minimum information that should be included in an IB. It is

2379

expected that the type and extent of information available will vary with the stage of

2380

development of the investigational product.

2381

The IB should include;

2382

A.2.1 Title Page

2383

This should provide the sponsor’s name, the identity of each investigational product

2384

(i.e., research number, chemical or approved generic name and trade name(s) where

2385

legally permissible and desired by the sponsor) and the release date. It is also

2386

suggested that an edition number and a reference to the number and date of the edition

2387

it supersedes be provided along with the cut-off date for data inclusion in the version.

2388

Where appropriate, a signature page may be included.

2389

A.2.2 Confidentiality Statement

2390

The sponsor may wish to include a statement instructing the investigator and other

2391

recipients to treat the IB as a confidential document for the sole information and use

2392

of the investigator/institution, investigator site staff, regulatory authorities and the

2393

institutional review board/independent ethics committee (IRB/IEC).

2394

A.3 Contents of the Investigator’s Brochure

2395

The IB should contain the following sections, each with literature references (publications or

2396

reports) included at the end of each chapter, where appropriate;

2397

A.3.1 Table of Contents

2398

A.3.2 Summary

2399

A brief summary (preferably not exceeding two pages) should be given, highlighting

2400

the significant physical, chemical, pharmaceutical, pharmacological, toxicological,

2401

pharmacokinetic, metabolic and clinical information available that is relevant to the

2402

stage of clinical development of the investigational product.

2403

A.3.3 Introduction

2404

A brief introductory statement should be provided that contains the chemical name

2405

(and generic and trade name(s) when approved) of the investigational product(s); all

2406

active ingredients; the pharmacological class of the investigational product(s) and its

2407

expected position within this class (e.g., advantages); the rationale for performing

2408

research with the investigational product(s); and the anticipated prophylactic,

2409

therapeutic or diagnostic indication(s). Finally, the introductory statement should

2410

provide the general approach to be followed in evaluating the investigational product.

2411

A.3.4 Physical, Chemical and Pharmaceutical Properties and Formulation

2412

A description should be provided of the investigational product substance(s)

2413

(including the chemical and/or structural formula(e)), and a brief summary should be

2414

given of the relevant physical, chemical and pharmaceutical properties.

2415

ICH E6(R3) Guideline

To permit appropriate safety measures to be taken in the course of the trial, a

2416

description of the formulation(s) to be used, including excipients, should be provided

2417

and justified if clinically relevant. Instructions for the storage and handling of the

2418

dosage form(s) should also be given.

2419

Any structural similarities to other known compounds should be mentioned.

2420

A.3.5 Nonclinical Studies

2421

Introduction

2422

The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic and

2423

investigational product metabolism studies should be provided in summary form. This

2424

summary should address the methodology used, the results and a discussion of the

2425

relevance of the findings to the investigated therapeutic and the possible unfavourable

2426

and unintended effects in humans.

2427

The information provided may include the following, as appropriate, if

2428

known/available:

2429

• species tested

2430

• number and sex of animals in each group

2431

• unit dose (e.g., milligram/kilogram (mg/kg))

2432

• dose interval

2433

• route of administration

2434

• duration of dosing

2435

• information on systemic distribution

2436

• duration of post-exposure follow-up

2437

• results, including the following aspects:

2438

- nature and frequency of pharmacological or toxic effects

2439

- severity or intensity of pharmacological or toxic effects

2440

- time to onset of effects

2441

- reversibility of effects

2442

- duration of effects

2443

- dose response

2444

Tabular format/listings should be used whenever possible to enhance the clarity of the

2445

presentation.

2446

The following sections should discuss the most important findings from the studies,

2447

including the dose response of observed effects, the relevance to humans and any

2448

aspects to be studied in humans. If applicable, the effective and nontoxic dose findings

2449

in the same animal species should be compared (i.e., the therapeutic index should be

2450

discussed). The relevance of this information to the proposed human dosing should

2451

be addressed. Whenever possible, comparisons should be made in terms of

2452

blood/tissue levels rather than on a mg/kg basis.

2453

(a) Nonclinical Pharmacology

2454

A summary of the pharmacological aspects of the investigational product and, where

2455

appropriate, its significant metabolites studied in animals should be included. Such a

2456

ICH E6(R3) Guideline

summary should incorporate studies that assess potential therapeutic activity (e.g.,

2457

efficacy models, receptor binding and specificity) as well as those that assess safety

2458

(e.g., special studies to assess pharmacological actions other than the intended

2459

therapeutic effect(s)).

2460

(b) Pharmacokinetics and Product Metabolism in Animals

2461

A summary of the pharmacokinetics and biological transformation and disposition of

2462

the investigational product in all species studied should be given. The discussion of

2463

the findings should address the absorption and the local and systemic bioavailability

2464

of the investigational product and its metabolites and their relationship to the

2465

pharmacological and toxicological findings in animal species.

2466

2467

A summary of the toxicological effects found in relevant studies conducted in

2468

different animal species should be described under the following headings where

2469

appropriate:

2470

• single dose

2471

• repeated dose

2472

• carcinogenicity

2473

• special studies (e.g., irritancy and sensitisation)

2474

• reproductive toxicity

2475

• genotoxicity (mutagenicity)

2476

A.3.6 Effects in Humans

2477

Introduction

2478

A thorough discussion of the known effects of the investigational product(s) in

2479

humans should be provided, including information on pharmacokinetics, metabolism,

2480

pharmacodynamics, dose response, safety, efficacy and other pharmacological

2481

activities. Where possible, a summary of each completed clinical trial and ongoing

2482

trials where interim results are available that may inform the safety evaluation should

2483

be provided. Information should also be provided regarding results of any use of the

2484

investigational product(s) other than from in clinical trials, such as from experience

2485

during marketing.

2486

(a) Pharmacokinetics and Product Metabolism in Humans

2487

A summary of information on the pharmacokinetics of the investigational product(s)

2488

should be presented, including the following, if available:

2489

• pharmacokinetics (including metabolism, as appropriate, and absorption,

2490

plasma protein binding, distribution and elimination)

2491

• bioavailability of the investigational product (absolute, where possible, and/or

2492

relative) using a reference dosage form

2493

• population subgroups (e.g., sex, age and impaired organ function)

2494

• interactions (e.g., product-product interactions and effects of food)

2495

ICH E6(R3) Guideline

• other pharmacokinetic data (e.g., results of population studies performed within

2496

clinical trial(s))

2497

2498

(b) Safety and Efficacy

2499

A summary of information should be provided about the investigational

2500

product’s/products’ (including metabolites, where appropriate) safety,

2501

pharmacodynamics, efficacy and dose response that was obtained from preceding

2502

trials in humans (healthy volunteers and/or patients). The implications of this

2503

information should be discussed. In cases where a number of clinical trials have been

2504

completed, the use of summaries of safety and efficacy across multiple trials by

2505

indications in subgroups may provide a clear presentation of the data. Tabular

2506

summaries of adverse drug reactions for all the clinical trials (including those for all

2507

the studied indications) would be useful. Important differences in adverse drug

2508

reaction patterns/incidences across indications or subgroups should be discussed.

2509

The IB should provide a description of the possible risks and adverse drug reactions

2510

to be anticipated on the basis of prior experiences with the product under investigation

2511

and with related products. There should be a list of adverse reactions, clearly identified

2512

as the reference safety information section, including information on their frequency

2513

and nature. This list should be used for determining the expectedness of a suspected

2514

serious adverse reaction and subsequently whether it needs to be expedited in

2515

accordance with regulatory requirements. A description should also be provided of

2516

the precautions or special monitoring to be done as part of the investigational use of

2517

the product(s).

2518

2519

The IB should identify countries where the investigational product has been marketed

2520

or approved. Any significant information arising from the marketed use should be

2521

summarised (e.g., formulations, dosages, routes of administration, adverse drug

2522

reactions). The IB should also identify all the countries where the investigational

2523

product did not receive approval/registration for marketing or was withdrawn from

2524

marketing/registration.

2525

A.3.7 Summary of Data and Guidance for the Investigator

2526

This section should provide an overall discussion of the nonclinical and clinical data

2527

and should summarise the information from various sources on different aspects of

2528

the investigational product(s), wherever possible. In this way, the investigator can be

2529

provided with the most informative interpretation of the available data and with an

2530

assessment of the implications of the information for future clinical trials.

2531

Where appropriate, the published reports on related products should be discussed.

2532

This could help the investigator to anticipate adverse drug reactions or other problems

2533

in clinical trials.

2534

The overall aim of this section is to provide the investigator with a clear understanding of the

2535

possible risks and adverse reactions and of the specific tests, observations and precautions that

2536

may be needed for a clinical trial. This understanding should be based on the available physical,

2537

ICH E6(R3) Guideline

chemical, pharmaceutical, pharmacological, toxicological and clinical information on the

2538

investigational product(s). Guidance should also be provided to the clinical investigator on the

2539

recognition and treatment of possible overdose and adverse drug reactions that is based on

2540

previous human experience and on the pharmacology of the investigational product.

2541

ICH E6(R3) Guideline

Appendix B. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S)

2542

Clinical trials should be described in a clear, concise and operationally feasible protocol. The

2543

protocol should be designed in such a way as to minimise unnecessary complexity and to

2544

mitigate or eliminate important risks to the rights, safety, and wellbeing of trial participants

2545

and the reliability of data. Protocol development processes should incorporate input from

2546

relevant stakeholders, where appropriate. Building adaptability into the protocol, for example,

2547

by including acceptable ranges for specific protocol provisions, can reduce the number of

2548

deviations or in some instances the requirement for a protocol amendment. Such adaptability

2549

should not adversely affect participant safety or the scientific validity of the trial. For additional

2550

information, refer to ICH E8(R1) General Considerations for Clinical Studies and ICH E9

2551

Statistical Principles for Clinical Trials.

2552

The contents of a trial protocol should generally include the following topics, which may vary

2553

depending on the trial design. Investigator site-specific information may be provided on

2554

separate protocol page(s) or addressed in a separate agreement, and some of the information

2555

listed below may be contained in other protocol referenced documents, such as an

2556

Investigator’s Brochure.

2557

B.1 General Information

2558

B.1.1 Protocol title, unique protocol identifying number, and date. Any amendment(s)

2559

should also bear the amendment number(s) and date(s).

2560

B.1.2 Name and address of the sponsor.

2561

B.1.3 Name and title of the person(s) authorised to sign the protocol and the protocol

2562

amendment(s) for the sponsor.

2563

B.2 Background Information

2564

B.2.1 Name and description of the investigational product(s).

2565

B.2.2 A summary of findings from nonclinical studies that potentially have clinical

2566

significance and from clinical trials that are relevant to the trial.

2567

B.2.3 Summary of the known and potential risks and benefits, if any, to human participants.

2568

B.2.4 Description of and justification for the route of administration, dosage, dosage

2569

regimen and treatment period(s).

2570

B.2.5 A statement that the trial will be conducted in compliance with the protocol, Good

2571

Clinical Practice (GCP) and the applicable regulatory requirement(s).

2572

B.2.6 Description of the population to be studied.

2573

B.2.7 References to literature and data that are relevant to the trial and that provide

2574

background for the trial.

2575

B.3 Trial Objectives and Purpose

2576

A clear description of the scientific objectives and the purpose of the trial. Information on

2577

estimands, where appropriate, if not included in any other trial-related document, see ICH

2578

ICH E6(R3) Guideline

E9(R1) Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the Guideline

2579

on Statistical Principles for Clinical Trials.

2580

B.4 Trial Design

2581

The scientific integrity of the trial and the reliability of the results from the trial depend

2582

substantially on the trial design. A description of the trial design should include:

2583

B.4.1 A specific statement of the primary endpoints and the secondary endpoints, if any, to

2584

be measured during the trial.

2585

B.4.2 A description of the type and design of trial to be conducted (e.g., double-blind,

2586

placebo-controlled, parallel design, adaptive design, platform/umbrella/basket, trials

2587

with decentralised elements) and a schematic diagram of trial design, procedures and

2588

stages.

2589

B.4.3 A description of the measures taken to minimise/avoid bias, including:

2590

(a) Randomisation

2591

(b) Blinding

2592

B.4.4 A description of the trial treatment(s) and the dosage and dosage regimen of the

2593

investigational product(s), including a description of the dosage form, packaging and

2594

labelling.

2595

B.4.5 The expected duration of the participant’s involvement in the trial and a description

2596

of the sequence and duration of all trial periods, including follow-up, if any.

2597

B.4.6 A description of the “stopping rules” or “discontinuation criteria” and “dose

2598

adjustment” or “dose interruption” for individual participants, parts of trial and entire

2599

trial.

2600

B.4.7 Accountability procedures for the investigational product(s), including the placebo(s)

2601

and other comparator(s), if any.

2602

B.4.8 Maintenance of treatment randomisation codes and procedures for breaking codes.

2603

B.5 Selection of Participants

2604

B.5.1 Participant inclusion criteria.

2605

B.5.2 Participant exclusion criteria.

2606

B.5.3 Mechanism for pre-screening, where appropriate, and screening of participants.

2607

B.6 Withdrawal of Consent or Discontinuation of Participation

2608

The investigator may choose to discontinue the participant, or the participant may

2609

withdraw their consent. The protocol should specify:

2610

(a) when and how to discontinue participants from the trial/investigational product

2611

treatment;

2612

ICH E6(R3) Guideline

(b) the type and timing of the data to be collected for withdrawn/discontinued

2613

participants, including the process by which the data are handled, in accordance

2614

with applicable regulatory requirements;

2615

2616

(d) the follow-up for participants who have discontinued the use of the

2617

investigational product.

2618

B.7 Treatment and Interventions for Participants

2619

B.7.1 The treatment(s) to be administered, including the name(s) of all the product(s), the

2620

dose(s), the dosing schedule(s), the criteria for dose adjustment(s), the route/mode(s)

2621

of administration and the treatment period(s), including the follow-up period(s) for

2622

participants for each investigational product treatment/trial treatment group/arm of the

2623

trial.

2624

B.7.2 Medication(s)/treatment(s) permitted (including concomitant and rescue medication)

2625

and not permitted before and/or during the trial.

2626

B.7.3 Strategies to monitor the participant’s adherence to treatment.

2627

B.8 Assessment of Efficacy

2628

B.8.1 Specification of the efficacy parameters, where applicable.

2629

B.8.2 Methods and timing for assessing, recording and analysing of efficacy parameters.

2630

Where any trial-related committees (e.g., independent data monitoring committee

2631

(IDMC)/adjudication committees) are utilised for the purpose of assessing efficacy

2632

data, procedures, timing and activities should be described in the protocol or a separate

2633

document.

2634

B.9 Assessment of Safety

2635

B.9.1 Specification of safety parameters.

2636

B.9.2 The methods, extent and timing for recording and assessing safety parameters. Where

2637

any trial-related committees (e.g., IDMC) are utilised for the purpose of assessing

2638

safety data, procedures, timing and activities should be described in the protocol or a

2639

separate document.

2640

B.9.3 Procedures for obtaining reports of and for recording and reporting adverse event and

2641

intercurrent events; see ICH E9(R1).

2642

B.9.4 The type and duration of the follow-up of participants after adverse events.

2643

B.10 Statistical Considerations

2644

B.10.1 A description of the statistical methods to be employed, including timing and purpose

2645

of any planned interim analysis(ses) and the criteria for the stopping of the trial.

2646

B.10.2 The number of participants planned to be enrolled and the reason for the choice of

2647

sample size, including reflections on or calculations of the power of the trial and

2648

clinical justification.

2649

ICH E6(R3) Guideline

B.10.3 The level of significance to be used or the threshold for success on the posterior

2650

probability in a Bayesian design.

2651

B.10.4 The criteria for the termination of the trial and the criteria for the stopping of the trial.

2652

B.10.5 The selection of participants to be included in the planned analyses (e.g., all

2653

randomised participants, all dosed participants, all eligible participants, all evaluable

2654

participants).

2655

B.10.6 Procedures for accounting for missing, unused and spurious data.

2656

B.10.7 Statement that any deviation(s) from the statistical analysis plan will be described and

2657

justified in the clinical study report.

2658

B.11 Direct Access to Source Records

2659

The sponsor should ensure that it is specified in the protocol or other documented agreement

2660

that the investigator(s)/institution(s)/service provider(s) will permit trial-related monitoring,

2661

audits, institutional review board/independent ethics committee (IRB/IEC) review and

2662

regulatory inspection(s), providing direct access to source records.

2663

B.12 Quality Control and Quality Assurance

2664

B.12.1 Description of identified quality factors and associated risks in the trial unless

2665

documented elsewhere.

2666

B.12.2 Description of the monitoring approaches that are part of the quality control process

2667

for the clinical trial.

2668

B.12.3 Description of the process for the handling of non-compliance with the protocol or

2669

GCP.

2670

B.13 Ethics

2671

Description of ethical considerations relating to the trial.

2672

B.14 Data Handling and Record Keeping

2673

B.14.1 Specification of data to be collected and the method of its collection. Where necessary,

2674

additional details should be contained in a clinical trial-related document.

2675

B.14.2 The identification of records to be recorded directly into the data acquisition tools

2676

(i.e., no prior written or electronic record of data) and considered to be source data.

2677

B.14.3 A statement that records should be retained in accordance with applicable regulatory

2678

requirements.

2679

B.15 Financing and Insurance

2680

Financing and insurance, if not addressed in a separate agreement.

2681

B.16 Publication Policy

2682

Publication policy, if not addressed in a separate agreement.

2683

ICH E6(R3) Guideline

Appendix C. ESSENTIAL RECORDS FOR THE CONDUCT OF A CLINICAL TRIAL

2684

C.1 Introduction

2685

C.1.1 Many records are generated before and during the conduct of a clinical trial. The

2686

nature and extent of those records generated and maintained are dependent upon the

2687

trial design, its conduct, application of proportional approaches and the importance

2688

and relevance of that record to the trial.

2689

2690

C.1.2 Determining which records are essential will be based upon consideration of the

2691

guidance in this appendix.

2692

2693

C.1.3 The essential records permit and contribute to the evaluation of the conduct of a trial

2694

and the reliability of the results produced. They serve to demonstrate the compliance

2695

of the investigator and sponsor with the standards of Good Clinical Practice (GCP)

2696

and applicable regulatory requirements. The essential records are used as part of the

2697

sponsor oversight or investigator supervision of the trial. These records are used by

2698

the sponsor’s independent audit function and during inspections by regulatory

2699

authority(ies) to assess the trial conduct and the reliability of the trial results. The

2700

investigator/institution should have access to and the ability to maintain and retain the

2701

essential records generated by the investigator/institution before, during and after the

2702

trial.

2703

C.2 Management of Essential Records

2704

C.2.1 Records should be identifiable and version controlled, and should include authors,

2705

reviewers and approvers as appropriate, along with date and signature (electronic or

2706

wet ink), where necessary.

2707

2708

C.2.2 For activities that are transferred or delegated to service providers by the sponsor or

2709

investigator/institution respectively, arrangements should be made for the access and

2710

management of the essential records throughout the trial and for their retention

2711

following completion of the trial.

2712

2713

C.2.3 These essential records should be maintained in or referred to from repositories,

2714

including, for example, the trial master file (TMF) or investigator site file (ISF). The

2715

TMF is held by the sponsor or by the investigator; in the latter case, it is often called

2716

the ISF.

2717

2718

C.2.4 The sponsor and investigator/institution should maintain a record of where essential

2719

records are located, including source records. The storage system(s) used during the

2720

trial and for archiving (irrespective of the type of media used) should provide for

2721

appropriate identification, version history, search and retrieval of trial records.

2722

2723

C.2.5 The sponsor and investigator/institution should ensure that the essential records are

2724

collected and filed in a timely manner, including those required to be in place prior to

2725

the trial start, which can greatly assist in the successful management of a trial.

2726

ICH E6(R3) Guideline

C.2.6 The sponsor and investigator/institution should retain the essential records in a way

2727

that ensures that they remain complete, readable and readily available and are directly

2728

accessible upon request by regulatory authorities. Alteration to the essential records

2729

should be traceable.

2730

2731

C.2.7 The original version of the essential record should be retained by the responsible party

2732

(sponsor or investigator). When a copy is used to permanently replace the original

2733

essential record, the copy should fulfil the requirements for certified copies.

2734

2735

C.2.8 In order to fulfil their responsibilities in the conduct of the trial, the sponsor and

2736

investigator/institution may need access to or copies of one another’s relevant

2737

essential records before, during and after the trial is completed. This will determine

2738

whether the record resides in the repositories of the sponsor, the

2739

investigator/institution, or both. There should be careful consideration of sharing of

2740

records subject to data protection legislation and blinding considerations in line with

2741

applicable regulatory requirements. For the sharing of essential records with service

2742

providers, see section C.2.2.

2743

2744

C.2.9 Certain essential records may not be specific to a trial but may be related to the

2745

systems and processes involved in running multiple trials and retained outside the

2746

trial-specific repositories (e.g., standard operating procedures validation records,

2747

master services agreements).

2748

C.3 Essentiality of Trial Records

2749

C.3.1 Whether a specific clinical trial record generated before, during and after the trial is

2750

essential and needs to be retained should be based on the following criteria:

2751

(a) Is a document that is submitted to or issued by the regulatory authority or

2752

IRB/IEC, including related correspondence and those documenting regulatory

2753

decisions or approvals/favourable opinions;

2754

(b) Is a trial-specific procedure or plan;

2755

2756

discussions and/or trial-related decisions that have been made related to the

2757

conduct of the trial and the processes being used;

2758

(d) Documents the conduct of relevant trial procedures;

2759

(e) Documents the arrangements between parties and insurance/indemnity

2760

arrangements;

2761

(f) Documents the compliance with the requirements and any conditions of

2762

approval from the regulatory authority or the favourable opinion of the

2763

institutional review board/independent ethics committee (IRB/IEC);

2764

(g) Documents the composition and, where appropriate, the functions,

2765

correspondence and decisions of any committees involved in the trial approval

2766

or its conduct.

2767

ICH E6(R3) Guideline

(h) Demonstrates that a trial-specific computerised system is validated and that

2768

non-trial-specific systems have been assessed as fit for purpose for their

2769

intended use in the trial;

2770

(i) Is a document that has been authorised/signed by the sponsor and/or

2771

investigator to confirm review or approval;

2772

(j) Is, where necessary, documentation that demonstrates signatures/initials of staff

2773

undertaking trial-specific activities; for example, completing data acquisition

2774

tools;

2775

(k) Documents what information was provided to potential trial participants and

2776

that participants’ informed consent was appropriately obtained and maintained;

2777

(l) Documents that sponsor personnel involved in the trial conduct and individuals

2778

performing trial-specific activities on their behalf are qualified by education,

2779

training and experience to undertake their activities;

2780

(m) Documents that the investigator and those individuals delegated trial-specific

2781

activities by the investigator are qualified by education, training and experience

2782

to undertake their activities, particularly where the activities are not part of their

2783

normal role;

2784

(n) Contains the data as well as relevant metadata that would be needed to be able

2785

to reconstruct the trial;

2786

(o) Are documents related to the sponsor and investigator oversight of safety of

2787

trial participants during the trial, including compliance with safety reporting

2788

requirements between sponsors and investigators, regulatory authorities and

2789

IRBs/IECs and informing trial participants of safety information as necessary;

2790

(p) Documents that service providers are suitably qualified for conducting their

2791

delegated or transferred activities;

2792

(q) Documents that laboratory activities and other tests used in the trial are fit for

2793

purpose;

2794

(r) Documents sponsor oversight of investigator site selection and monitoring and

2795

audit of the trial, where appropriate, and provides information on arising

2796

issues/non-compliance and deviations detected and implementation of

2797

corrective and preventative actions;

2798

(s) Documents the compliance with the protocol and/or procedures for

2799

management and statistical analysis of the data and production of any interim

2800

report and the final report;

2801

(t) Documents the collection, chain of custody, analysis and retention or

2802

destruction of biological samples;

2803

(u) Provides relevant information on the investigational product and its labelling;

2804

(v) Provides information about the shipment, storage, packaging, dispensing,

2805

randomisation and blinding of the investigational product;

2806

(w) Provides, where appropriate, traceability and accountability information about

2807

the investigational product from release from the manufacturer to dispensation,

2808

ICH E6(R3) Guideline

administration to trial participants, and return and destruction, or alternative

2809

disposition;

2810

(x) Provides information on the identity and quality of the investigational product

2811

used in the trial;

2812

(y) Documents processes and activities relating to unblinding;

2813

(z) Documents the recruitment, pre-trial screening and consenting process of trial

2814

participants and their identity and chronological enrolment as appropriate;

2815

(aa) Documents the existence of the trial participants and substantiates the integrity

2816

of trial data collected. Includes source records related to the trial and medical

2817

treatments and history of the trial participants;

2818

(bb) Defines processes/practices in place in the event of a security breach in order to

2819

protect participants’ rights, safety and well-being and the integrity of the data.

2820

C.3.2 Applying the criteria in section C.3.1, the trial records for every trial that are

2821

considered essential, except in justifiable and documented exceptional circumstances,

2822

are set out in Table 1, and these should be retained.

2823

2824

C.3.3 For other trial records, their presence and nature are dependent upon the trial design,

2825

its conduct and risk proportional management. Table 2 lists potential trial records that

2826

when generated, would be considered essential by applying the criteria in section

2827

C.3.1 and should be retained. This is not an exhaustive list, and other trial records may

2828

also be considered essential by the sponsor or the investigator.

2829

2830

Table 1 – Essential Records for All Trials

1.1

Investigator’s Brochure or basic product information brochure (e.g., summary of

product characteristic, package leaflet or labelling) and relevant updates

1.2

signed protocol and amendments during the trial

1.3

dated, documented approval/favourable opinion of IRB/IEC of information provided

to them before and during the trial

1.4

IRB/IEC composition

1.5

regulatory authority(ies) authorisation, approval and/or notification of the protocol

and subsequent protocol amendments during the trial (where required)

1.6

completed signed and dated informed consent forms

1.7

completed participant identification code list and enrolment log

1.8

- notification by originating investigator to sponsor of serious adverse events (SAEs)

and related reports, where required

- notification by sponsor and/or investigator, where required, to regulatory

authority(ies) and IRB(s)/IEC(s) of suspected unexpected serious adverse reactions

(SUSARs) and of other safety information

- notification by sponsor to investigators of safety information, where required

1.9

interim or annual reports to IRB/IEC and regulatory authority(ies)

1.10

source records

ICH E6(R3) Guideline

Table 1 – Essential Records for All Trials

1.11

data and relevant metadata (including documentation of data corrections) in the data

acquisition tools

1.12

final report by investigator to IRB/IEC and regulatory authority(ies), where required

1.13

interim (where applicable) and final clinical trial reports

2831

Table 2 – Potential Essential Records

2.1

sample of data acquisition tools (e.g., case report forms (CRFs), diaries, clinical

outcome assessments, patient-reported outcomes) that are provided to the investigator

and/or IRB/IEC

2.2

sample of information given to trial participants and revisions during the trial

- informed consent materials (including all applicable translations)

- any other documented information, e.g., instructions for use of an investigational

product or a device

- advertisement for participant recruitment

2.3

financial aspects of the trial

2.4

insurance statement

2.5

signed agreement between involved parties, e.g.,

- investigator/institution and sponsor

- investigator/institution and service providers

- sponsor and service providers

- sponsor and independent data monitoring committee (IDMC) members

2.6

curriculum vitae and/or other relevant documents evidencing qualifications of

investigator(s) and sub-investigator(s) involved in conducting the trial

2.7

trial-specific training records

2.8

documentation of delegation of activities by the investigator to investigator site staff

2.9

signature sheet documenting signatures and initials of delegated investigator site staff

2.10

normal value(s)/range(s) for medical/laboratory/technical procedure(s) and/or test(s)

included in the protocol and updates during the trial conduct

2.11

certification or accreditation or established quality control and/or external quality

assessment or other validation (where required) of medical/laboratory/technical

procedures/tests used during the trial conduct and any updates

2.12

documentation of collection, processing and shipment of body fluids/tissue samples

2.13

documentation of body fluids/tissue samples storage conditions

2.14

record of retained body fluids/tissue samples at the end of the trial

2.15

sample of label(s) attached to investigational product container(s)

2.16

instructions for handling of investigational product(s) and trial-related materials (if

not included in protocol or Investigator’s Brochure), for example, pharmacy manual

2.17

shipping records for investigational product(s) and trial-related materials

2.18

certificate(s) of analysis of investigational product(s) shipped

ICH E6(R3) Guideline

Table 2 – Potential Essential Records

2.19

investigational product(s) accountability at investigator site

2.20

documentation of investigational product storage conditions during shipment and at

the trial site

2.21

records of relabelling of investigational product at trial site

2.22

documentation of investigational product destruction

2.23

emergency decoding procedures for blinded trials

2.24

master randomisation list

2.25

instructions for use for critical trial-specific systems (e.g., interactive response

technologies (IRT) user manual, electronic CRF (eCRF) manual)

2.26

maintenance and calibration records for critical trial-specific equipment

2.27

treatment allocation and decoding documentation

2.28

completed participants screening log

2.29

site monitoring reports (including site selection, initiation, routine and close-out)

2.30

centralised monitoring reports

2.31

records and reports of protocol and GCP non-compliance/deviations and corrective

and preventative actions

2.32

documentation of relevant communications and meetings

2.33

audit certificate

2.34

documentation relating to data finalisation for analysis (e.g., query resolutions, SAE

reconciliation, quality control reports, coding completion, output data sets)

2.35

documentation of trial-specific computerised system validation (e.g., specifications,

testing, validation report, change control)

2.36

documentation relating to the statistical considerations and analysis (e.g., sample size

calculations, analysis sets decisions, analysis datasets, analysis programs, quality

control records and output)

2.37

trial-specific plans (e.g., risk management, monitoring, safety, data management, data

validation and statistical analysis) and procedures

2.38

procedures, meeting minutes and submissions to the IDMC

2832