E2F Development Safety Update Report 

This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) 

current thinking on this topic. It does not create or confer any rights for or on any person and does not 

operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the 

requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, 

contact the FDA staff responsible for implementing this guidance. If you cannot identify the 

appropriate FDA staff, call the appropriate number listed on the title page of this guidance. 

For questions regarding this draft document contact (CDER) Ellis F. Unger 301-796-2240 or 

(CBER) Peter F. Bross at 301-827-5102
8413dft.doc page of 34 1

1 INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL 

2 REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN 

3 USE 

4 

5 

6 

7 

8 ICH HARMONISED TRIPARTITE GUIDELINE 

9 

10 

11 DRAFT 

12 

13 

14 DEVELOPMENT SAFETY UPDATE REPORT

15 E2F 

16 

17 

18 Current Step 2 version 

19 05 June 2008
8413dft.doc page of 34 2

20 

21 1 INTRODUCTION ..............................................................................................4

22 1.1 OBJECTIVE OF THE GUIDELINE...................................................................4

23 1.2 SCOPE OF THE DSUR....................................................................................5

24 2 GUIDANCE ......................................................................................................6

25 2.1 WHEN SHOULD A DSUR BE PREPARED?...................................................6

26 2.2 PERIODICITY AND DSUR DATA LOCK POINT.............................................6

27 2.3 CHANGE OF DSUR DATA LOCK POINT.......................................................7

28 2.4 INTERRUPTION OR DISCONTINUATION OF CLINICAL TRIALS.................7

29 2.5 FINAL DSUR....................................................................................................7

30 2.6 RESPONSIBILITIES FOR PREPARING AND SUBMITTING A DSUR...........7

31 2.8 REFERENCE SAFETY INFORMATION ..........................................................9

32 2.9 FORMAT AND PRESENTATION OF DSUR .................................................10

33 2.10 GUIDANCE ON CONTENTS OF DSUR ........................................................11

34 3. UPDATE ON ACTIONS TAKEN IN THE REPORTING PERIOD FOR 

35 SAFETY REASONS.......................................................................................13

36 7 PRESENTATION OF SAFETY DATA FROM CLINICAL TRIALS ................17

37 8 SIGNIFICANT FINDINGS FROM CLINICAL TRIALS DURING THE 

38 REPORTING PERIOD....................................................................................19

39 9 RELEVANT FINDINGS FROM NON-INTERVENTIONAL STUDIES.............20

40 10 RELEVANT FINDINGS FROM OTHER SOURCES.......................................21

41 11 SAFETY FINDINGS FROM MARKETING EXPERIENCE .............................21

42 12 OTHER INFORMATION.................................................................................21

43 12.1 NON-CLINICAL DATA...................................................................................21

44 12.2 LONG-TERM FOLLOW UP ...........................................................................21

45 12.3 LITERATURE.................................................................................................21

46 12.4 OTHER DSURS .............................................................................................22

47 12.5 SIGNIFICANT MANUFACTURING CHANGES.............................................22

48 12.6 LACK OF EFFICACY.....................................................................................22

49 13 LATE BREAKING INFORMATION................................................................22

50 14 OVERALL SAFETY ASSESSMENT..............................................................23

51 14.1 EVALUATION OF THE RISKS ......................................................................23

52 14.2 BENEFIT-RISK CONSIDERATIONS .............................................................24

53 14.3 CONCLUSIONS .............................................................................................24

54 15 SUMMARY OF IMPORTANT RISKS.............................................................24
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55 APPENDICES TO THE DSUR .......................................................................25

56 16 TABLE OF GLOSSARY TERMS ...................................................................26
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57 

58 1 INTRODUCTION 

59 1.1 Objective of the Guideline 

60 The periodic analysis of safety information is crucial to the ongoing assessment of 

risk to trial subjects during the clinical development of an investigational drug.1,2,3 61 It is 

62 also important to notify regulators and other interested parties (e.g. ethics 

63 committees) at regular intervals of the evolving safety profile of an investigational 

64 drug and actions proposed or being taken to address safety concerns. Currently, 

65 regulations in some countries or regions require submission of a periodic report to 

66 regulatory authorities to address these issues. However, significant differences in the 

67 content and format of these reports highlight the importance of a common standard to 

68 promote a consistent approach, and enhance efficiency. The Development Safety 

69 Update Report (DSUR) proposed in this guideline is intended to be the common 

70 standard for annual clinical trial safety reporting among the ICH regions and can be 

71 submitted instead of existing reports including the US IND Annual Report and the EU 

72 Annual Safety Report. This comprehensive, thoughtful annual review can provide an 

73 additional level of assurance of protection for subjects in clinical trials. In addition, by 

74 harmonising the format, content and timing of annual safety reports, regulators in the 

75 three ICH regions can receive the same information at the same time, thereby 

76 reducing the number of reports generated. 

77 

78 The main objective of a DSUR is to present an annual review and evaluation of 

79 pertinent safety information collected during the reporting period to: (1) summarise 

80 the current understanding and management of identified and potential risks; (2) 

81 describe new safety issues that could have an impact on the protection of clinical trial 

82 subjects; (3) examine whether the information obtained by the sponsor during the 

 

1 The term investigational drug is used in this guideline to indicate only the experimental product under 

study or development.

2

 For detailed discussion see: The Development Safety Update Report (DSUR): Harmonizing the 

Format and Content for Periodic Safety Reporting During Clinical Trials: Report of CIOMS Working 

Group VII, Geneva 2007. 

 

3 ICH Topic E6(R1). Guideline for Good Clinical Practice. http://www.ich.org/LOB/media/MEDIA482.pdf 
8413dft.doc Page5 of 34 

83 reporting period is in accord with previous knowledge of the product’s safety; and (4) 

84 provide an update on the status of the clinical investigation/development programme. 

85 This guideline defines the content and format of a DSUR and provides an outline of 

86 points to be considered in its preparation and submission. 

87 1.2 Scope of the DSUR 

88 The main focus of the DSUR is data from interventional clinical trials (referred to in 

89 this document as “clinical trials”) of investigational drugs including biologicals, with or 

90 without a marketing approval, whether conducted by commercial or non-commercial 

91 sponsors. However, other findings that impact the safety and welfare of clinical trial 

92 subjects, (e.g. significant safety findings from non-clinical studies, safety findings 

93 from clinical trials conducted by a co-development partner in a licensing agreement, 

94 or relevant findings from non-interventional studies/compassionate use) should also 

95 be included where appropriate. Some of the information contained in the DSUR, such 

96 as safety findings, inclusion of serious adverse reactions in line listings, and 

97 discussion of relevant articles from published literature can also be provided in 

98 Periodic Safety Update Reports (PSURs) for marketed products that are the subject 

99 of ongoing clinical trials. Therefore, some overlap is expected between the DSUR 

100 and PSUR because of the different periodicities for submission and objectives. 

101 

102 The DSUR should provide safety information from all ongoing clinical trials that the 

103 sponsor is conducting or has completed during the review period including: 

104 • clinical trials conducted using an investigational drug whether with or without a 

105 marketing approval, i.e., human pharmacology, therapeutic exploratory and 

therapeutic confirmatory trials (Phase I – III);4 106 

107 • clinical trials conducted using marketed drugs in approved indications, i.e., 

108 therapeutic use trials (Phase IV); 

109 • other therapeutic use of an investigational drug; and 

110 • comparability trials conducted to support changes in the manufacturing process 

111 of medicinal products. 

112 

 

4 For classification of clinical trials see ICH E8 General considerations for clinical trials. 
8413dft.doc Page6 of 34 

113 The DSUR should focus primarily on the investigational drug, providing information 

114 on comparators only where relevant to the safety of trial subjects. A DSUR should be 

115 concise and provide information to assure regulators that sponsors are adequately 

116 monitoring and evaluating the safety profile of the investigational drug. It should not 

117 contain initial notification of any significant new safety issues, as these should have 

118 been communicated to regulatory authorities via expedited reporting. 

119 2 GUIDANCE 

120 2.1 When Should a DSUR be Prepared? 

121 A sponsor overseeing more than one clinical trial of a single investigational drug 

122 should prepare one DSUR for that drug with a single data lock point (DLP) wherever 

123 possible. If this is not possible, an explanation should be provided in the covering 

124 letter.

125 2.2 Periodicity and DSUR Data Lock Point 

126 The DSUR is intended to be an annual report that should be submitted to regulatory 

127 authorities, as appropriate, for as long as the sponsor conducts clinical trials with the 

128 investigational drug, or for as long as appropriate to satisfy local requirements. 

129 Where local authorities ask for periodic submission of safety information on an 

130 investigational drug to ethics committees, institutional review boards, or investigators, 

131 the DSUR Executive Summary should suffice, supplemented with line listings of 

132 serious adverse reactions as warranted. 

133 

134 The DSUR should be submitted no later than 60 calendar days from the DSUR data 

135 lock point. The data lock point of the DSUR should be based on the date of the 

136 sponsor’s first authorisation to conduct a clinical trial in any country. This date is 

termed the “Development International Birth Date” (DIBD). 5 137 For administrative 

138 convenience, if desired by the sponsor, the DIBD can be designated as the last day 

139 of the month of authorisation. 

140 

 

5 This is analogous to the International Birth Date (IBD) for a PSUR, defined as the date of first 

marketing approval worldwide.
8413dft.doc Page7 of 34 

141 Where clinical trials are ongoing in one country and are later initiated in another 

142 country(ies), one DSUR based on the same DIBD should be used for all countries. 

143 2.3 Change of DSUR Data Lock Point 

Once a drug has received a marketing approval6 144 in any country or region, and clinical 

145 trials continue or are initiated, both a PSUR and a DSUR should be prepared in 

146 accordance with directions from local authorities. The sponsor should change the 

147 DSUR data lock point to coincide with the International Birth Date (IBD) so that the 

148 DSUR and the PSUR can be synchronised. In synchronising the data lock points for 

149 the DSUR and PSUR, the period covered by the next DSUR should be no longer 

150 than one year. 

151 2.4 Interruption or Discontinuation of Clinical Trials 

152 A DSUR should be prepared and submitted as indicated by local authorities, even 

153 when the clinical trials are interrupted or discontinued. If the sponsor has not 

154 collected any further data pertinent to the clinical development programme in the 

155 period of the DSUR, a letter stating this can replace the DSUR. 

156 2.5 Final DSUR 

157 When an annual report of clinical trials is no longer required in an individual country 

158 or region, the DSUR should be accompanied by a cover letter indicating that the 

159 report serves as the final DSUR for the investigational drug in that country or region. 

160 The letter should also indicate whether or not clinical trials are continuing elsewhere. 

161 

162 2.6 Responsibilities for Preparing and Submitting a DSUR 

163 2.6.1 Sponsor’s responsibilities 

164 The sponsor of a clinical trial, whether commercial or non-commercial, should be 

165 responsible for the preparation, content and submission of a DSUR. 

166 2.6.2 Shared responsibilities 

167 Where individual clinical trials or a drug development programme involve 

168 collaboration with public or private institutions, business partners or other parties, a 

 

6

 For the purposes of this document, we use the term “authorisation/ authorised” to refer to approvals 

of clinical trials, and “approved/ marketing approval” to refer to marketing authorisations
8413dft.doc Page8 of 34 

169 written agreement should be in place clearly detailing the responsibilities for 

170 preparation and submission of the DSUR. The same principle applies in situations 

171 where the sponsor delegates the preparation of the DSUR to a third party, e.g., a 

172 contract research organisation. 

173 2.6.3 Non-commercial sponsor responsibilities

174 Non-commercial sponsors should be responsible for the preparation of the DSURs 

175 for the clinical trials they conduct, in accordance with local requirements. Sections of 

176 the DSUR that are not applicable to non-commercial sponsors (e.g., manufacturing 

177 issues, non-clinical data, and marketing status) should be identified as such. 

178 

179 2.6.4 Responsibilities of multiple sponsors in formal agreements 

180 When there is more than one sponsor, e.g., when a sponsor is in a formal co181 development or licensing relationship with one or more partners, or more than one 

182 partner is a sponsor of a clinical trial(s) of the investigational drug, the parties should 

183 arrange to prepare a single DSUR whenever possible. Written agreements should be 

184 in place specifying how safety data will be exchanged so that a single DSUR can be 

185 produced by one sponsor on behalf of all parties. 

186 

187 When unavoidable, multiple sponsors can agree in writing to prepare separate 

188 DSURs for the same investigational drug. This can include situations where different 

189 indications, routes of administration, or formulations are being investigated. The 

190 rationale for separate DSURs should be provided in each report. 

191 

192 2.7 DSURs for Combination Products 

193 Given the potential complexities of clinical development involving combination 

194 therapies, it is not possible to provide guidance that addresses all such situations. 

195 The sponsor should select the most appropriate option based on judgement, taking 

196 into account patient population, indication, formulation etc., as well as the 

197 circumstances in which the clinical trials are being conducted and local regulatory 

198 requirements. The rationale for this decision should be provided in the report. 
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199 

200 In general, a single DSUR should be prepared for clinical trials involving a fixed 

201 combination product. 

202 

203 For trials involving drug combinations that are not fixed, it can be appropriate to 

204 prepare a stand-alone DSUR. Alternatively, information on the multidrug regimen 

205 trials can be included in the DSUR of one or all of the components. 

206 

207 Although medical devices are outside the scope of the DSUR, specific local 

208 regulations can require a DSUR for certain drug-device combinations, depending 

209 upon whether the principal therapeutic effect is achieved by the drug or the device. 

210 2.8 Reference Safety Information 

211 A single document containing the reference safety information should be used to 

212 assess whether the safety information received during the reporting period remains 

213 consistent with previous knowledge of the safety profile of the investigational drug. 

214 

215 The Investigator’s Brochure (IB) in effect at the start of the reporting period should 

216 serve as the reference safety information for the DSUR for an investigational drug 

217 whether or not the drug has a marketing approval. The report should clearly indicate 

218 the version number and date of the IB used for this purpose. If the IB has been 

219 revised during the reporting period and not previously submitted to the relevant 

220 regulatory authority, the sponsor should provide a copy of the revised version of the 

221 IB as an attachment to the DSUR. When an IB is not required for the trial by local 

222 regulations (e.g., non-commercial sponsors conducting a clinical trial with a marketed 

product) the applicable local product label7 223 or another suitable document should be 

224 used as the reference safety information. 

 

7 In the EU this would be the Summary of Product Characteristics (SmPC); in Japan this would be the 

Japanese Package Insert; and in the US this would be the US Package Insert.
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225 2.9 Format and Presentation of DSUR 

226 2.9.1 Format 

227 The format and content of the DSUR should follow the table of contents below. For 

228 each heading where information is available, the information should be presented 

229 concisely; when no information is available, this should be stated. Guidance on the 

230 content of each section is provided below. Note that the section numbers below 

231 reflect the numbering in the DSUR. 

232 2.9.2 Table of Contents 

233 Title page 

234 Executive Summary 

235 Table of Contents 

236 1. Introduction 

237 2. Worldwide Marketing Authorisation Status 

238 3. Update on Actions Taken in the Reporting Period for Safety Reasons 

239 4. Changes to Reference Safety Information 

240 5. Status of Clinical Trials Ongoing and Completed During the Reporting 

241 Period 

242 6. Estimated Exposure 

243 6.1 Cumulative subject exposure in clinical trials (Phase I-IV) 

244 6.2 Patient exposure from marketed setting 

245 7. Presentation of Safety Data from Clinical Trials 

246 7.1 General considerations 

247 7.2 Interval line listings of Serious Adverse Reactions (SARs) 

248 7.3 Cumulative summary tabulations 

249 7.4 Deaths in the reporting period 

250 7.5 Subjects who dropped out in association with any adverse event in the 

251 reporting period 

252 8. Significant Findings from Clinical Trials During the Reporting Period 

253 8.1 Completed trials and any interim analyses 

254 8.2 Ongoing clinical trials 

255 8.3 Other therapeutic use of investigational drug 
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256 8.4 New safety data related to combination therapies 

257 9. Relevant Findings from Non-Interventional Studies 

258 10 Relevant Findings from Other Studies 

259 11. Safety findings from marketing experience 

260 12. Other Information 

261 12.1 Non-clinical data 

262 12.2 Long-term follow-up 

263 12.3 Literature 

264 12.4. Other DSURs 

265 12.5 Significant manufacturing changes 

266 12.6 Lack of efficacy 

267 12.7 Phase I protocol modifications 

268 13. Late-Breaking Information 

269 14. Overall Safety Assessment 

270 14.1. Evaluation of the risks 

271 14.2 Benefit-risk considerations 

272 14.3 Conclusions 

273 15. Summary of important risks 

274 Appendices to the DSUR

275 

276 2.10 Guidance on Contents of DSUR 

277 Title page 

278 The title page of the DSUR should include the following information: 

279 • DSUR number (reports should be numbered sequentially); 

280 • Investigational drug(s); 

281 • Reporting period; 

282 • Date of the report; 

283 • Sponsor name and address; 

284 • Confidentiality statement; and 

285 • Note regarding the inclusion of unblinded information in the DSUR. 
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286 Executive Summary 

287 This section should provide a concise summary of the important information 

288 contained in the report. Together with the title page, it should serve as a “stand289 alone” document suitable for submission to ethics committees and other 

290 stakeholders, if required by local regulations. Information on the following should be 

291 included in the Executive Summary: 

292 • Introduction – report version and reporting period; 

293 • Investigational drug – mode of action, class, indications, dose, route of 

294 administration; 

295 • Estimated cumulative clinical trial exposure; 

296 • Marketing authorisation(s)? (yes/no) – If yes, number of countries; 

297 • Summary of overall safety assessment; 

298 • Summary of important risks (based on section 15 of the DSUR); 

299 • Actions taken for safety reasons including significant changes to IB; 

300 • Conclusion. 

301 All sections should be completed; when no information is available, this should be 

302 stated. 

303 Table of Contents 

304 1. Introduction

305 This section should include: 

306 • Reporting period and sequential number of the report; 

307 • Brief description of the drug, e.g., therapeutic class, mode of action, route 

308 of administration, formulation; 

309 • Whether the report covers a development programme or a single clinical 

310 trial. This section should also note the scope of the trials covered by the 

311 report (e.g., all trials with the investigational drug, or indication-specific 

312 trials); 

313 • A brief description of the indications and populations being studied; 
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314 • A brief description and explanation of any information that has been 

315 excluded (e.g., when written agreements with a partner company do not 

316 provide for exchange of all safety data). 

317 

318 2. Worldwide marketing authorisation status 

319 This section should be completed only if a marketing application for the 

320 product has been submitted in one or more countries/regions. Cumulative 

321 information should be provided where available, usually in the form of a table 

322 that provides the status of each application. The content and format for this 

323 table is the same as that recommended for PSURs, as outlined in ICH E2C, 

324 Table 1. 

325 

326 3. Update on Actions Taken in the Reporting Period for Safety Reasons

327 This section should include a description of significant actions related to safety 

328 that have been taken by the sponsor, regulators, Data and Safety Monitoring 

329 Boards or independent ethics committees that could have an impact on the 

330 conduct of a specific trial or the whole clinical development programme. Any 

331 relevant updates to previous actions should also be summarised in this 

332 section. Changes to the Investigator’s Brochure should be discussed 

333 separately in the “Changes to Reference Safety Information”, see section 4. 

334 Examples of significant actions relating to safety issues include: 

335 • Refusal of authorisation of a clinical trial for ethical or safety reasons; 

• Partial 8 336 or complete clinical trial suspension or early termination of a 

337 clinical trial due to lack of efficacy or safety issues; 

338 • Resumption of a clinical trial after suspension; 

339 • Failure to obtain marketing approval for a tested indication; 

340 • Risk management activities, including: 

 

8

 “Partial suspension” may include several actions – e.g., suspension of repeat dose studies, but 

continuation of single dose studies; suspension of trials in one indication, but continuation in another 

and/or suspension of a particular dosing regimen in a trial but continuation of other doses.
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341 o Protocol modifications due to safety or efficacy concerns (e.g., dosage 

342 changes, changes in study inclusion criteria, intensification of 

343 monitoring); 

344 o Restrictions in study population or indications; 

345 o Changes to the informed consent document relating to safety issues; 

346 o Formulation changes for safety reasons; 

347 o Addition of a special reporting requirement; 

348 o Issuance of a communication to investigators or healthcare 

349 professionals; 

350 o Plans for new safety trials. 

351 • Important specific advice for safety reasons from a regulatory authority that 

352 involves a constraint on development (e.g., requirement to conduct long353 term animal studies before initiating a long-term clinical trial; need for 

354 thorough QT/QTc study prior to Phase III clinical trials). In addition a 

355 cumulative listing of advice from regulatory authorities should be provided 

356 as a table in an appendix. 

357 

358 In addition to the above, for drugs with a marketing approval, examples of 

359 significant actions due to safety reasons include: 

360 • Failure to obtain a marketing approval renewal; 

361 • Marketing approval withdrawal or suspension for safety reasons; 

362 • Risk management activities including: 

363 o Significant restrictions on distribution or introduction of risk minimisation 

364 measures; 

365 o Significant changes in labelling documents that could affect the 

366 development programme, e.g., restrictions to indication or population or 

367 a new warning; 

368 o Communications to health care professionals as a result of the above 

369 actions; and 

370 o New postmarketing study requirement(s) imposed by regional 

371 authorities. 
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372 4. Changes to Reference Safety Information

373 This section should list any significant safety-related changes to the IB within 

374 the reporting period. This includes information relating to contraindications, 

375 warnings, precautions, serious adverse drug reactions, adverse reactions of 

376 special interest, interactions, and any important findings from non-clinical 

377 studies (e.g. carcinogenicity studies). Specific information relevant to these 

378 changes should be provided in the appropriate sections of the DSUR. 

379 5. Status of clinical trials ongoing and completed during the reporting period 

380 This section should refer to an appendix that presents a listing of each clinical 

381 trial in progress and each clinical trial completed during the reporting period. 

382 Separate tables can be provided by indication, formulation, and study 

383 population if appropriate. In addition, where required by local authorities, 

384 similar information should be provided for other therapeutic use of an 

385 investigational drug in the reporting period e.g., compassionate use or 

386 expanded access. 

387 The table(s) should include the following information for each trial: 

388 • Protocol number or other trial identifier; 

389 • Clinical trial phase (I, II, III, or IV); 

390 • Status: 

391 o Ongoing (study has begun; study has begun but is currently on hold; 

392 study is completed, but final clinical study report is not yet available); 

393 o Completed (final clinical study report is available); 

394 • Countries/regions where there is at least one investigational site for the 

395 protocol; 

396 • Abbreviated study title ; 

397 • Study design (uncontrolled, controlled, open, single blind, double blind, 

398 parallel, cross-over, etc., including treatment arms); 

399 • Dose and regimen of study drug and any comparators; 

400 • Subject population as appropriate (age; sex; indication(s); specific patient 

401 groups, e.g., trial subjects with impaired renal function or trial subjects 

402 resistant to treatment); 

403 • Date of first visit for first patient; 

404 • Planned enrolment for study as a whole; 
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405 • Estimates of cumulative numbers of exposed subjects where available for 

406 each treatment arm. The actual enrolment numbers for open or completed 

407 trials, and/or an estimate based on the randomisation scheme for blinded 

408 trials should also be provided. 

409 An example of the column headings for this listing is provided in table 1. 

410 6. Estimated exposure 

411 The sponsor should clearly explain in the DSUR the method used to estimate 

412 subject/patient exposure. 

413 6.1 Cumulative subject exposure in development programme

414 Data on subject exposure to the investigational drug and placebo/active 

415 comparators should be included in the DSUR. The DSUR should provide 

416 summary tables including estimates of the overall numbers of subjects 

417 exposed as of the DSUR data lock point, using either number of trial subjects 

418 or patient-time, as appropriate. 

419 

420 When the data are available, the DSUR should provide cumulative exposure 

421 data giving the number of trial subjects by age group, gender, and ethnic 

origin9 422 for the development programme. Tabulation of demographic 

423 characteristics for a single trial can be useful if the trial is of particular 

424 importance, e.g., a pivotal phase III trial. 

425 

426 See table 2 for examples of these tables. 

427 

428 These exposure tables provide context for the cumulative summary tabulations 

429 of serious adverse events (SAEs). Therefore, if the summary tabulations are 

430 presented by indication, the exposure data should also be presented by 

431 indication where available. 

 

9

 Ethnic factors are defined as those factors relating to the genetic and physiologic (intrinsic) and the 

cultural and environmental (extrinsic) characteristics of a population as described in ICH E5(R1): 

Ethnic Factors in the Acceptability of Foreign Clinical Data. 
8413dft.doc Page17 of 34 

432 6.2 Patient exposure from marketing experience

433 If the investigational product is marketed, the commercial sponsor should 

434 provide the estimated patient exposure in the marketed setting based on the 

435 information provided in the PSUR for that product or other suitable data 

436 source. 

437 7 Presentation of Safety Data from Clinical Trials 

438 The DSUR should contain both cumulative and interval (periodic) safety 

439 information relating to the investigational drug. This section of the report 

440 should present important clinical safety information through interval line listings 

441 of the serious adverse reactions that arose during the period covered by the 

442 DSUR, and cumulative tabulations of serious adverse events that have been 

443 reported to the sponsor since the DIBD. If MedDRA is used for coding the 

444 adverse event/reaction terms, the Preferred Term level should be presented in 

445 the line listings and summary tabulations. 

446 In general, the tabulation(s) of serious adverse events should include only 

447 those terms that were used in defining the case as serious. Non-serious and 

448 incidental findings should not be included. 

449 

450 If important and appropriate, the report should also include adverse reactions 

451 of special interest within the line listings and adverse events of special interest 

452 in summary tabulations. The basis for selection of such events/reactions 

453 should be explained. 

454 

455 Certain adverse events can be excluded from the summary tabulations and 

456 line listings, but such exclusions should be explained in the report. For 

457 example, adverse events that have been defined in the protocol as “exempt” 

458 from special collection and entry into the safety database, and those that are 

459 integral to efficacy endpoints, can be excluded (e.g., deaths reported in a trial 

460 of a drug for congestive heart failure where all-cause mortality is the primary 

461 efficacy endpoint or disease progression in cancer trials). 
8413dft.doc Page18 of 34 

462 7.1 General considerations

463 This section of the DSUR should include the version of the coding dictionary 

464 used, and the document and version used as Reference Safety Information for 

465 determining expectedness for the tabulations, where required by regional 

466 authorities. 

467 7.2 Interval Line Listings of Serious Adverse Reactions (SARs) 

468 This section of the DSUR should include general information about the content 

469 of the line listings, the criteria for inclusion, and reference to appropriate 

470 appendices. 

471 The line listings should provide key information on all blinded and unblinded 

472 SARs reported during the reporting period, organised by System Organ Class 

473 (SOC). They can integrate data from all the trials being conducted with an 

474 investigational drug. Alternatively, when useful and feasible, SARs can be 

475 listed by protocol, indication, or other variables. 

476 Where possible the line listing(s) should include each subject only once 

477 regardless of how many SAR terms are reported for the case. If there is more 

478 than one reaction, they should all be mentioned but the case should be listed 

479 under the most serious adverse reaction (sign, symptom or diagnosis), as 

480 judged by the sponsor. It is possible that the same subject could experience 

481 different SARs on different occasions (e.g., weeks apart during a clinical trial). 

482 Such experiences can be treated as separate reports. Under such 

483 circumstances, the same subject can be included in a line listing more than 

484 once, and the line listings should be cross-referenced when possible. 

485 The format and content of the line listings described in ICH E2C can be used 

486 with appropriate modifications (e.g., addition of the clinical trial identification 

487 number). An example of the headings for a line listing is provided in Table 3. 

488 7.3 Cumulative Summary tabulations 

489 This section of the DSUR should include general information about the content 

490 of the tabulations, the criteria for inclusion, and reference to appropriate 

491 appendices. 
8413dft.doc Page19 of 34 

492 Summary tabulations should present cumulative safety data from the DIBD to 

493 the data lock point of the current DSUR. The summary tabulations in a DSUR 

should include the number of serious adverse events,10 494 organised by SOC, for 

495 the investigational drug, as well as for the comparator arm(s) (active 

496 comparators, placebo, and treatment unknown due to blinding) used in the 

497 programme. Data can be integrated across the programme. Alternatively, 

498 when useful and feasible, tabulations of SAEs can be presented by protocol, 

499 indication, or other variables. 

500 An example is provided in Table 4. 

501 7.4 Deaths in the Reporting Period 

502 A list of subjects who died during participation in the investigation should be 

503 provided as an appendix to the DSUR if required by regional authorities. The 

504 list should include the following information at a minimum: case number, 

505 assigned treatment (could still be blinded), and cause of death. 

506 7.5 Subjects who dropped out in association with any adverse event in the 

507 reporting period 

508 Tabulations and listings of information on drop-outs should be provided as an 

509 appendix to the DSUR, if required by regional authorities. Any safety issues 

510 identified from a review of these withdrawals should be briefly described. 

511 8 Significant findings from clinical trials during the reporting period 

512 The information in this section can be provided by indication, when 

513 appropriate, and should address the following topics, when applicable: 

514 8.1 Completed trials and any interim analyses 

515 The DSUR should provide a brief summary of the clinically important safety 

516 findings included in the final study reports from all clinical trials completed and 

517 any interim analyses conducted during the reporting period. This information 

 

10 For DSURs to be submitted to an EU Member State, a regional appendix should be provided. It 

should contain a summary tabulation of all SARs, specifying the number of SARs by: a) SOC, b) 

reaction term and c) treatment arm, if applicable. Unexpected adverse reaction terms should be 

identified. 
8413dft.doc Page20 of 34 

518 can be in narrative format, or in the study synopsis format provided as 

519 Appendix 5 of the Report of CIOMS Working Group VII. 

520 8.2 Ongoing clinical trials 

521 The DSUR should provide a concise summary of any preliminary safety 

522 findings from ongoing trials, including safety issues that are the same or similar 

523 to those previously identified, as well as evidence of new clinically significant 

524 safety signals. 

525 8.3 Other Therapeutic use of Investigational Drug 

526 The DSUR should include safety information from expanded access 

527 programmes, compassionate use programmes and treatment INDs, because 

528 they each follow a specific protocol. 

529 8.4 New Safety Data Related to Combination Therapies 

530 If the sponsor has prepared a separate DSUR for a multidrug regimen or fixed 

531 combination product containing the single investigational drug that is the 

532 subject of this DSUR, relevant findings from that DSUR should be summarised 

533 in this section. 

534 

535 Conversely, if this DSUR is for a multidrug regimen or fixed combination 

536 product, important safety information arising from trials on the individual 

537 components should be briefly summarised here. 

538 

539 Alternatively, the information specific to the combination can be incorporated 

540 into a separate section(s) of the DSUR for one or all of the individual 

541 components of the combination. 

542 

543 9 Relevant findings from non-interventional studies 

544 This section of the DSUR should summarise relevant safety information that 

545 became available in the reporting period from non-interventional studies, e.g., 

546 observational studies, registries, active surveillance programmes or 

547 epidemiological studies. 
8413dft.doc Page21 of 34 

548 10 Relevant findings from other sources 

549 The DSUR should also discuss relevant safety findings from any other 

550 available sources (e.g., results from pooled or meta-analyses of randomised 

551 clinical trials, lack of efficacy from trials in high morbidity/mortality disease 

552 states and trials with vaccines). 

553 11 Safety findings from marketing experience 

554 If the investigational drug has been approved for marketing in any country, this 

555 section should include a concise summary of key safety findings that have 

556 arisen from marketing experience during the reporting period, particularly if the 

557 findings resulted in changes to the labelling or amendments to the product’s 

558 risk management plan. 

559 12 Other Information 

560 

561 12.1 Non-Clinical data 

562 Major safety findings from non-clinical in vivo and in vitro studies (e.g. 

563 carcinogenicity, reproduction, or immunotoxicity studies) initiated or completed 

564 during the reporting period should be summarised, and any impact on the 

565 clinical safety of the investigational drug should be discussed. 

566 12.2 Long-term follow-up 

567 This section of the DSUR should provide information from long-term follow-up 

568 of subjects from clinical trials of investigational drugs, particularly advanced 

569 therapy products (e.g., gene therapy, cell therapy products and tissue 

570 engineered products). This section could be the only information presented in 

571 the DSUR when the clinical trials are completed and long-term follow-up is the 

572 only ongoing activity generating data for the DSUR. 

573 12.3 Literature 

574 The commercial sponsor is expected to review the scientific literature 

575 periodically for new safety information. This section should summarise new 

576 and significant safety findings from non-clinical studies and clinical trials that 

577 have been published during the reporting period. When available, this section 
8413dft.doc Page22 of 34 

578 should also include relevant new information on drugs of the same class. 

579 Significant new safety information published as an abstract for a scientific 

580 meeting should be summarised and a copy provided if possible. 

581 12.4 Other DSURs 

582 When available, a commercial sponsor should summarise significant findings 

583 from the DSUR provided by another sponsor conducting clinical trials with the 

584 investigational drug during the reporting period. 

585 12.5 Significant manufacturing changes 

586 When required by regional authorities, this section should include a summary 

587 of significant changes to the manufacturing process and/or formulation of an 

588 investigational drug during the reporting period and discuss potential safety 

589 issues arising from these changes, if applicable. 

590 12.6 Lack of efficacy 

591 For investigational drugs intended to treat serious or life-threatening illnesses, 

592 lack of efficacy could constitute a significant risk to clinical trial subjects. In this 

593 setting, data received during the reporting period that indicates lack of efficacy 

594 relative to alternative therapies should be summarised. 

595 12.7 Phase I protocol modifications 

596 This section should describe significant Phase I protocol modifications not 

597 previously reported, as required by regional authorities. 

598 

599 13 Late-Breaking Information 

600 Information on potentially important safety findings that present while the 

601 DSUR is in preparation after the data lock point should be included in this 

602 section. Examples include clinically significant new case reports, important 

603 follow-up data, and clinically relevant toxicological findings. Any action that the 

604 sponsor, a Data and Safety Monitoring Board, or regulatory authority has 

605 taken for safety reasons should also be included. 
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606 14 Overall Safety Assessment 

607 The overall safety assessment should be a concise, integrated assessment of 

608 all new relevant clinical, non-clinical, and epidemiologic information obtained 

609 during the reporting period relative to previous knowledge of the 

610 investigational drug. It should not summarise or repeat information presented 

611 in previous sections of the DSUR, but should provide an interpretation of the 

612 information, and its implications for the clinical trial population. If appropriate, 

613 separate assessments can be provided by therapeutic area and/or indication. 

614 14.1 Evaluation of the risks 

615 When relevant, the following points should be considered: 

616 • meaningful changes in previously identified reactions (e.g., increased 

617 frequency or severity, outcome, specific at-risk populations); 

618 • newly identified safety issues (detailed description of adverse reaction; 

619 associated laboratory values; risk factors; relationship to dose, duration, 

620 time course of the treatment; reversibility; factors that could be useful in 

621 predicting or preventing reactions); 

622 • particular emphasis should be placed on symptoms, signs, and laboratory 

623 evidence of newly and previously identified, clinically significant: 

624 o hepatotoxicity; 

625 o cardiovascular effects, including QT interval prolongation and results 

626 from thorough QT/QTc studies; 

627 o bone marrow toxicity; 

628 o renal toxicity; 

629 o central nervous system toxicity; 

630 o immunogenicity and hypersensitivity; 

631 o reactive metabolites; 

632 • deaths that are an outcome of an adverse reaction; 

633 • withdrawals due to safety reasons; 

634 • any specific safety issues related to special populations, such as the 

635 elderly, children, patients with hepatic or renal impairment, or any other at 

636 risk groups (e.g., slow or fast metabolisers); 
8413dft.doc Page24 of 34 

637 • positive and negative experiences during pregnancy or lactation; 

638 • overdose and its treatment; 

639 • drug misuse and abuse; 

640 • experience with long-term treatment; 

641 • risks associated with protocol procedures, including administration of the 

642 investigational drug and diagnostic procedures; 

643 • evidence of clinically significant medication errors; 

644 • potential impact of significant new safety issues identified with another 

645 drug in the same class; and 

646 • drug–drug and other interactions. 

647 The overall safety assessment should also discuss other relevant findings 

648 such as: non-clinical research, manufacturing issues, lack of efficacy and lack 

649 of patient compliance, when available. 

650 14.2 Benefit-risk considerations 

651 This section is not meant to be a full benefit-risk assessment but should be a 

652 succinct statement on the balance between the theoretical benefits and the 

653 identified risks, focusing particularly on whether there have been any changes 

654 in this balance since the previous DSUR. If there has been a change, the 

655 sponsor should provide an assessment of the impact on the clinical 

656 development programme. 

657 14.3 Conclusions 

658 The section should present a brief conclusion, addressing any changes to the 

659 previous knowledge of safety and risks resulting from information gained since 

660 the last DSUR. Finally, the conclusion should describe how risks have been 

661 managed in the trials and any additional actions that should be taken to 

662 address emerging safety issues. 

663 15 Summary of important risks 

664 This section should provide a concise cumulative list of important identified 

665 and potential risks (e.g., those that might lead to warnings, precautions, or 

666 contraindications in labelling). The information in this section could provide the 
8413dft.doc Page25 of 34 

667 basis for the Safety Specification of a risk management plan (ICH E2E). The 

668 list should be continuously evaluated and updated from DSUR to DSUR and 

669 include risks that require further evaluation, as well as safety concerns that 

670 have been fully addressed or resolved. 

671 

672 Appendices to the DSUR 

673 The following are appendices that might accompany the DSUR: 

674 1 Investigator’s Brochure (if required); 

675 2 Cumulative Table of Important Regulatory Advice; 

676 3 Status of Ongoing and Completed Clinical Trials; 

677 4 Cumulative Summary Tabulations of Demographic Data; 

678 5 Line Listings of Serious Adverse Reactions (SARs); 

679 6 Cumulative Summary Tabulation of Serious Adverse Events (SAEs); 

680 7 Scientific Abstracts (if relevant). 

681 Regional Appendices (as required by regional regulatory authority): 

682 1 Drop-outs in Association with Adverse Events; 

683 2 Deaths; 

684 3 Summary Tabulations of SARs. 

685 

686 

687 3 APPENDICES TO THE GUIDELINE 

688 

689 Appendix A. Glossary 

690 

691 Appendix B Tables 1-4 

692 
8413dft.doc Page26 of 34 

693 APPENDIX A 694 Glossary 695 Throughout this guideline the Working Group has used terms previously defined by ICH and other gro696 that were previously defined in ICH documents are not repeated in this glossary. However, the glossa697 CIOMS and other groups. 698 699 

Item Glossary Term Source of 

Definition 

Definition/Commentary 

1. Adverse event of 

special interest

Based on CIOMS VII An adverse event of special interest (serious or non-serious) is one 

specific to the sponsor’s product or programme, for which ongoing mby the investigator to the sponsor could be appropriate. Such an ev

investigation in order to characterise and understand it. Depending communication by the trial sponsor to other parties (e.g., regulators) 

2. Clinical Trial 

Authorisation 

Based on EU Clinical Trials Directive 2001/20/EC 

The authorisation in writing by the relevant regulatory authority of a 

application. Commentary: In this guideline the term “authorisation” is 

conduct a clinical trial and the term “approval” is used to refer to permarket. 

3. Other therapeutic use 

of an investigational drug Synonym:

Expanded Access Compassionate Use ‘Treatment IND’ 

Therapeutic use of an investigational drug under a protocol. This caExpanded Access Programmes, Compassionate Use, and TreatmeExpanded Access Programme: IND-based programme in the US th

investigational drug to patients with an indication for which benefit h

Compassionate Use Programme: A programme in the EU to supply 

patients with an indication for which benefit has been demonstrated
8413dft.doc Page27 of 34 

Item Glossary Term Source of 

Definition 

Definition/Commentary 

 Treatment IND: Allows the supply of an investigational drug to treat 

life-threatening disease for whom no satisfactory alternative is availaCommentary: This term does not include “particular patient”, “name

require a protocol. 

4. Data lock point CIOMS VII The date (month and day) designated as the cut-off for data to be in

is based on the Development International Birth Date (DIBD) and shincrements. 

5. Development 

International Birth Date 

CIOMS VII Glossary Date of first approval (or authorisation) for conducting an interventio

6. Identified risk Volume 9A Rules 

Governing Medicinal Products in the EU 

An untoward occurrence for which there is adequate evidence of an product of interest. Examples of identified risks include: 

-an adverse reaction adequately demonstrated in non-clinical stud

-an adverse reaction observed in well designed clinical trials or ep

magnitude of the difference compared with the comparator grouunexposed group) on a parameter of interest suggests a causal 

-an adverse reaction suggested by a number of well documented 

causality is strongly supported by temporal relationship and bioloanaphylactic reactions or application site reactions. 

7. Important identified 

risk; Important potential risk. 

Volume 9A Rules Governing Medicinal Products in the EU 

An identified risk or potential risk that could impact on the risk-benefimplications for public health. 
8413dft.doc Page28 of 34 

Item Glossary Term Source of 

Definition 

Definition/Commentary 

8. Investigational drug The term investigational drug is used in this guideline to indicate on

study or development. 

9. Non-commercial 

sponsor 

 For the purposes of this guideline, examples of non-commercial spo

university, (b) healthcare centre, (c) a public scientific organisation, 

patient organisation, and (f) an individual researcher who is respons

conduct, recording and publishing of the clinical trial. 

10. Non-interventional 

clinical study

Based on EU Directive 2001/20/EC on Clinical Trials

A study where the medicinal product(s) is (are) prescribed in the us

terms of the marketing authorisation. The assignment of the patient 

is not decided in advance by a trial protocol but falls within current p

medicine is clearly separated from the decision to include the patiendiagnostic or monitoring procedures are applied to the patients and for the analysis of collected data. 

11. Potential risk Volume 9A Rules 

Governing Medicinal Products in the EU 

An untoward occurrence for which there is some basis for suspicion medicinal product of interest but where this association has not beeExamples of potential risks include: • Non-clinical safety concerns that have not been observed or resolv• Adverse events observed in clinical trials or epidemiological studie

difference, compared with the comparator group (placebo or active 

the parameter of interest raises a suspicion of, but is not large enou• A signal arising from a spontaneous adverse reaction reporting sys• An event which is known to be associated with other products of thexpected to occur based on the properties of the medicinal product. 

12. Registry ICH E2E A registry is a list of patients presenting with the same characteristic

disease (disease registry) or a specific exposure (drug registry). Bo

differ by the type of patient data of interest, can collect a battery of iquestionnaires in a prospective fashion. 
8413dft.doc Page29 of 34 

700 APPENDIX B 701 TABLE 1 - EXAMPLES OF TABLE HEADINGS FOR CLINICAL TRIAL STATUS LISTINGS 702 703 STATUS OF ONGOING AND COMPLETED CLINICAL TRIALS 704 OVERVIEW OF ONGOING [study drug] STUDIES 

Study ID Phase Country Study Title Study design Dosing regimen Study population FVFP* Planned 

enrollm

705 

706 * FVFP = first visit first patient 707 ** based upon total number of patients recruited as of [date] and applied randomisation schemes 708 709 OVERVIEW OF [study drug] STUDIES COMPLETED DURING THE DSUR PERIOD 

Study ID Phase Country Study Title Study design Dosing regimen Subject 

population 

Subject/treatme
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710 APPENDIX B 711 TABLE 2 - EXAMPLES OF DEMOGRAPHIC DATA TABLES 712 CUMULATIVE SUMMARY TABULATIONS OF DEMOGRAPHIC DATA 713 Estimated cumulative subject exposure to [study drug] clinical studies by age and gender* 

 Number of subjects 

Age (yr) Male Female Total 

<16 16 - 25 26 - 35 36 – 45 46 – 55 56 – 65 66 – 75 >75 Total 

714 * data from completed studies as of [date]
8413dft.doc Page31 of 34 

715 

716 Estimated cumulative subject exposure to [study drug] in all clinical studies by ethnic origin* 

Ethnic origin Number of subjects 

Caucasian 

Black Oriental Other Total 

717 * data from completed studies as of [date] 718 
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719 APPENDIX B 720 TABLE 3 - EXAMPLES OF HEADINGS FOR INTERVAL LINE LISTINGS OF SERIOUS ADVERSE 721 722 723 INTERVAL LINE LISTINGS OF SERIOUS ADVERSE REACTIONS (SARs) 724 725 726 * Study/centre/patient 727 ** ‘Primary’ SADR only 

Study ID EudraCT number 

Case ID/ Subject number* 

Country Gender Age 

Serious ADR(s) Outcome Date of Onset** 

Time to Onset** 

Suspect Drug 

Daily dose Route Formulation 

Dates of treatment Treatment duration 

 -------- -------- ------- -------- -------- -------- -------- -------- 
8413dft.doc Page33 of 34 

728 729 APPENDIX B 730 TABLE 4 - EXAMPLES OF CUMULATIVE TABULATIONS OF SERIOUS ADVERSE EVENTS 731 732 CUMULATIVE SUMMARY TABULATION OF SERIOUS ADVERSE EVENTS (SAEs) 733 

734 735 736 

System Organ Class Total up to 31-Dec-07 

Preferred Term [study drug] Blinded Active 

comparator 

Placebo 

Investigations 18 4 7 2 

Alanine aminotransferase increased 9 2 4 1 

 Aspartate aminotransferase increased 9 2 3 1 

Nervous System Disorder 2 2 4 7 

 Syncope 2 2 4 7