Guidance for Industry

Computerized Systems Used 

in Clinical Trials 

DRAFT GUIDANCE — ERRATUM

On line 563 of this draft guidance, reference is made to Compliance Policy Guide 

(CPG) # 7130.13. This is incorrect. The CPG number should be 7150.13.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

Center for Devices and Radiological Health (CDRH)

Center for Food Safety and Nutrition (CFSAN)

Center for Veterinary Medicine (CVM)

Office of Regulatory Affairs (ORA)

 September 2004

Compliance

Revision 1
Guidance for Industry 

Computerized Systems Used 

in Clinical Trials 

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only. 

Comments and suggestions regarding this draft document should be submitted within 90 days of 

publication in the Federal Register of the notice announcing the availability of the draft 

guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and 

Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments 

should be identified with the docket number listed in the notice of availability that publishes in 

the Federal Register. 

For questions regarding this draft document contact Patricia M. Beers Block 301-827-3340. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

Center for Biologics Evaluation and Research (CBER) 

Center for Devices and Radiological Health (CDRH) 

Center for Food Safety and Nutrition (CFSAN) 

Center for Veterinary Medicine (CVM) 

Office of Regulatory Affairs (ORA) 

 September 2004 

Compliance 

Revision 1 
Contains Nonbinding Recommendations 

Draft — Not for Implementation

 

Guidance for Industry 

Computerized Systems Used 

in Clinical Trials

Additional copies are available at: 

http://www.fda.gov/cder/guidance/index.htm

or 

http://www.fda.gov/cber/guidelines.htm 

or 

http://www.fda.gov/cvm/guidance/guidance.html

or 

http://www.fda.gov/cdrh/ggpmain.html 

or 

http://www.cfsan.fda.gov/~dms/guidance.html 

or 

http://www.fda.gov/ora/compliance_ref/bimo 

or 

http://www.fda.gov/oc/gcp 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

Center for Biologics Evaluation and Research (CBER) 

Center for Devices and Radiological Health (CDRH) 

Center for Food Safety and Nutrition (CFSAN) 

Center for Veterinary Medicine (CVM) 

Office of Regulatory Affairs (ORA) 

September 2004 

Compliance 

Revision 1 
Contains Nonbinding Recommendations 

Draft — Not for Implementation

 1

TABLE OF CONTENTS 

I. INTRODUCTION............................................................................................................. 2

II. BACKGROUND ............................................................................................................... 3

III. GENERAL PRINCIPLES ............................................................................................... 3

IV. OVERALL APPROACH TO MEETING PART 11 REQUIREMENTS ................... 5

V. STANDARD OPERATING PROCEDURES................................................................. 5

VI. DATA ENTRY .................................................................................................................. 5

A. Computer Access Controls............................................................................................................5

B. Audit Trails or other Security Measures .....................................................................................6

C. Date/Time Stamps..........................................................................................................................7

VII. SYSTEM FEATURES...................................................................................................... 8

A. Systems Used for Direct Entry of Data ........................................................................................8

B. Retrieval of Data and Record Retention......................................................................................8

VIII. SYSTEM SECURITY ...................................................................................................... 8

IX. SYSTEM DEPENDABILITY.......................................................................................... 9

A. Legacy Systems ............................................................................................................................10

B. Off-the-Shelf Software.................................................................................................................10

C. Change Control ............................................................................................................................11

X. SYSTEM CONTROLS................................................................................................... 11

XI. TRAINING OF PERSONNEL ...................................................................................... 12

XII. COPIES OF RECORDS AND RECORD INSPECTION........................................... 12

XIII. CERTIFICATION OF ELECTRONIC SIGNATURES ............................................ 13

DEFINITIONS ............................................................................................................................ 14

REFERENCES............................................................................................................................ 16
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Guidance for Industry1 1 

2 Computerized Systems Used in Clinical Trials 

3 

4 

5 

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

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

8 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 

9 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 

10 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 

11 the appropriate number listed on the title page of this guidance. 

12 

13 

14 

15 

16 I. INTRODUCTION 

17 

18 This document provides guidance about computerized systems that are used to create, modify, 

19 maintain, archive, retrieve, or transmit clinical data required to be maintained and/or submitted to 

20 the Food and Drug Administration (FDA) These data form the basis for the Agency's decisions 

21 regarding the safety and effectiveness of new human and animal drugs, biological products, 

22 medical devices, and certain food and color additives. Because the data have broad public health 

23 significance, they are expected to be of the highest quality and integrity. This guidance 

24 document addresses long-standing FDA regulations concerning clinical trial records. It also 

addresses requirements of the Electronic Records/Electronic Signatures rule (21 CFR part 11).2 25 

26 

27 Once finalized, this document will supersede the guidance of the same name issued in April 

28 1999. Revisions will make it consistent with Agency policy as reflected in the guidance for 

29 industry on Part 11, Electronic Records; Electronic Signatures — Scope and Application, which 

issued in August 2003, and the Agency's international harmonization efforts.3 30 

31 

32 FDA's guidance documents, including this guidance, do not establish legally enforceable 

33 responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 

 

1

 This guidance has been prepared by an Agency working group representing the Bioresearch Monitoring Program 

Managers for each Center within the Food and Drug Administration, the Office of Regulatory Affairs, and the 

Office of the Commissioner. 

2

 Part 11 applies to records in electronic form that are created, modified, maintained, archived, retrieved, or 

transmitted under any records requirements set forth in Agency regulations. Part 11 also applies to electronic 

records submitted to the Agency under the requirements of Federal Food, Drug, and Cosmetic Act and the Public 

Health Service Act, even if such records are not specifically identified in Agency regulations. 

3

 In August 2003, FDA issued the guidance for industry entitled Part 11, Electronic Records; Electronic SignaturesScope and Application clarifying that the Agency intended to interpret the scope of part 11 narrowly and to exercise 

enforcement discretion with regard to part 11 requirements for validation, audit trails, record retention, and record 

copying. In 1996, the International Conference on Harmonisation of Technical Requirements for Registration of 

Pharmaceuticals for Human Use (ICH) issued E6 Good Clinical Practice: Consolidated Guidance. 
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34 be viewed only as recommendations, unless specific regulatory or statutory requirements are 

35 cited. The use of the word should in Agency guidances means that something is suggested or 

36 recommended, but not required. 

37 

38 

39 II. BACKGROUND 

40 

41 FDA has the authority to inspect all records relating to clinical investigations conducted under 21 

42 CFR 312, 511.1(b), and 812 , regardless of how they were created or maintained (e.g., §§ 312.58, 

43 312.68, and 812.145). FDA established the Bioresearch Monitoring (BIMO) Program of 

44 inspections and audits to monitor the conduct and reporting of clinical trials to ensure that 

45 supporting data from these trials meet the highest standards of quality and integrity, and conform 

46 to FDA's regulations. FDA's acceptance of data from clinical trials for decision-making 

47 purposes depends on FDA's ability to verify the quality and integrity of the data during FDA on48 site inspections and audits. To be acceptable, the data should meet certain fundamental elements 

49 of quality whether collected or recorded electronically or on paper. For example, data should be 

attributable, legible, contemporaneous, original4 50 and accurate. 

51 

52 This guidance addresses how Agency expectations and regulatory requirements regarding data 

53 quality might be satisfied where computerized systems are being used to create, modify, 

54 maintain, archive, retrieve, or transmit clinical data. Although the primary focus of this guidance 

55 is on computerized systems used at clinical sites to collect data, the principles set forth may also 

56 be appropriate for computerized systems belonging to contract research organizations, data 

57 management centers, and sponsors. Persons using the data from computerized systems should 

58 have confidence that the data are no less reliable than data in paper form. 

59 

60 Computerized medical devices, diagnostic laboratory instruments, and instruments in analytical 

61 laboratories that are used in clinical trials are not the subject of this guidance. This guidance 

62 does not address electronic submissions or methods of their transmission to the Agency, except 

63 to the degree to which these records comply with Part 11. 

64 

The principles in this guidance may be applied where supporting data or source documents5 65 are 

66 created (1) in hardcopy and later entered into a computerized system, (2) by direct entry by a 

67 human into a computerized system, and (3) automatically by a computerized system. 

68 

69 

70 III. GENERAL PRINCIPLES 

71 

 

4

 FDA is allowing original documents to be replaced by certified copies provided the copies are identical and have 

been verified as such. (see FDA Compliance Policy Guide # 7130.13). See “Definitions” section for a definition of 

original data. 

 

5

 Under 21 CFR 312.62 (b) reference is made to records that are part of case histories as “supporting data;” the 

ICH E6 Good Clinical Practice consolidated guidance uses the term "source documents." These terms describe the 

same information and have been used interchangeably in this guidance. 
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72 The Agency recommends the following general principles with regard to computerized systems 

73 that are used to create, modify, maintain, archive, retrieve, or transmit clinical data required to be 

74 maintained and/or submitted to FDA. 

75 

76 1. We recommend that each study protocol identify at which steps a computerized system 

77 will be used to create, modify, maintain, archive, retrieve, or transmit data. 

78 2. For each study, we recommend that documentation identify what software and hardware 

79 are to be used in computerized systems that create, modify, maintain, archive, retrieve, or 

80 transmit data. We also recommend that this documentation be retained as part of the 

81 study records. 

82 3. We recommend that computerized systems be designed (1) so that all requirements 

83 assigned to these systems in a study protocol are satisfied (e.g., data are recorded in 

84 metric units, the study blinded) and (2) to preclude errors in data creation, modification, 

85 maintenance, archiving, retrieval, or transmission. 

86 4. It is important to design a computerized system in such a manner so that all applicable 

87 regulatory requirements for record keeping and record retention in clinical trials are met 

88 with the same degree of confidence as is provided with paper systems. 

89 5. Under 21 CFR 312.62 , 511.1(b)(7)(ii) and 812.140, the clinical investigator must retain 

90 records required to be maintained under part 312, § 511.1(b) and § 812, respectively, for 

91 a period of time specified in these regulations. Retaining the original source document or 

92 a certified copy of the source document at the site where the investigation was conducted 

93 can assist in meeting these regulatory requirements. It can also assist in the 

94 reconstruction and evaluation of the trial throughout and after the completion of the trial. 

95 6. When original observations are entered directly into a computerized system, the 

96 electronic record is the source document. 

97 7. Records relating to an investigation must be adequate and accurate in the case of 

98 investigational new drug applications (INDs) (see § 312.57 and § 312.62), complete in 

99 the case of new animal drugs for investigational use (INADs) (see §511.1(b)(7)(ii)), and 

100 accurate, complete and current in the case of investigational device exemptions (IDEs) 

101 (see § 812.140(a) and § 812.140(b)). An audit trail that is electronic or consists of other 

102 physical, logical, or procedural security measures to ensure that only authorized 

103 additions, deletions, or alterations of information in the electronic record have occurred 

104 may be needed to facilitate compliance with applicable records regulations. Firms should 

105 determine and document the need for audit trails based on a risk assessment that takes 

106 into consideration circumstances surrounding system use, the likelihood that information 

107 might be compromised, and any system vulnerabilities. We recommend that audit trials 

108 or other security methods used to capture electronic record activities document who made 

109 the changes, when, and why changes were made to the electronic record. 

110 8. We recommend that data be retrievable in such a fashion that all information regarding 

111 each individual subject in a study is attributable to that subject. 

112 9. To ensure the authenticity and integrity of electronic records, it is important that security 

113 measures be in place to prevent unauthorized access to the data in the electronic record 

114 and to the computerized system. 
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115 

116 IV. OVERALL APPROACH TO MEETING PART 11 REQUIREMENTS 

117 

118 As described in the FDA guidance entitled Part 11, Electronic Records; Electronic Signatures119 Scope and Application (August 2003), while the re-examination of part 11 is underway, FDA 

120 intends to exercise enforcement discretion with respect to part 11 requirements for validation, 

121 audit trail, record retention, and record copying. That is, FDA does not intend to take 

122 enforcement action to enforce compliance with these requirements of part 11 while the agency 

123 re-examines part 11. Note that part 11 remains in effect and that the exercise of enforcement 

124 discretion applies only to the extent identified in the FDA guidance on part 11. Also, records 

125 must still be maintained or submitted in accordance with the underlying requirements set forth in 

126 the Federal Food, Drug, and Cosmetic Act (Act), the Public Health Service Act (PHS Act), and 

127 FDA regulations (other than part 11), which are referred to in this guidance document as 

128 predicate rules, and FDA can take regulatory action for noncompliance with such predicate 

rules.6 129 

130 

131 Specific details about the Agency’s approach to enforcing part 11 can be found in the Part 11 

132 Scope and Application guidance. 

133 

134 

135 V. STANDARD OPERATING PROCEDURES 

136 

137 We recommend that standard operating procedures (SOPs) pertinent to the use of the 

138 computerized system be available on site. We recommend that SOPs be established for the 

139 following: 

140 • System Setup/Installation 

141 • Data Collection and Handling 

142 • System Maintenance 

143 • Data Backup, Recovery, and Contingency Plans 

144 • Security 

145 • Change Control 

146 • Alternative Recording Methods (in the case of system unavailability) 

147 

148 

149 VI. DATA ENTRY 

150 

151 A. Computer Access Controls 

152 

153 To ensure that individuals have the authority to proceed with data entry, data entry systems must 

154 be designed to limit access so that only authorized individuals are able to input data 

 

6

 This term refers to underlying requirements set forth in the Federal Food, Drug, and Cosmetic Act, the PHS Act, 

and FDA regulations (other than 21 CFR Part 11). Regulations governing good clinical practice and human subject 

protection can be found at 21 CFR parts 50, 56, 312, 511, and 812. See Definitions section at the end of this 

document listing definitions of this and other terms used in this guidance. 
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(§ 11.10(d)).7 155 Examples of methods for controlling access include using combined identification 

156 codes/passwords or biometric-based identification at the start of a data entry session. Controls 

157 and procedures must be in place that are designed to ensure the authenticity and integrity of 

158 electronic records created, modified, maintained, or transmitted using the data entry system 

159 (§ 11.10). Therefore, we recommend that each user of the system have an individual account 

160 into which the user logs-in at the beginning of a data entry session, inputs information (including 

161 changes) on the electronic record, and logs out at the completion of data entry session. 

162 

163 We recommend that individuals work only under their own password or other access key and not 

164 share these with others. We recommend that individuals not be allowed to log onto the system to 

165 provide another person access to the system. We also recommend that passwords or other access 

166 keys be changed at established intervals. 

167 

168 When someone leaves a workstation, we recommend that the SOP require that person to log off 

169 the system. Alternatively, an automatic log off may be appropriate for long idle periods. For 

170 short periods of inactivity, we recommend that some kind of automatic protection be installed 

171 against unauthorized data entry. An example could be an automatic screen saver that prevents 

172 data entry until a password is entered. 

173 

174 B. Audit Trails or other Security Measures 

175 

176 Section 11.10(e) requires persons who use electronic record systems to maintain an audit trail as 

177 one of the procedures to protect the authenticity, integrity, and, when appropriate, the 

178 confidentiality of electronic records. As clarified in the Part 11 Scope and Application guidance, 

179 however, the Agency intends to exercise enforcement discretion regarding specific part 11 

180 requirements related to computer-generated, time-stamped audit trails (§ 11.10(e), (k)(2) and any 

181 corresponding requirement in § 11.30). Persons must still comply with all applicable predicate 

182 rule requirements for clinical trials, including, for example, that records related to the conduct of 

183 the study must be adequate and accurate (§§ 312.57, 312.62, and 812.140). It is therefore 

184 important to keep track of all changes made to information in the electronic records that 

185 document activities related to the conduct of the trial. Computer-generated, time-stamped audit 

186 trails or information related to the creation, modification, or deletion of electronic records may 

187 be useful to ensure compliance with the appropriate predicate rule. 

188 

189 In addition, clinical investigators must, upon request by FDA, at reasonable times, permit agency 

190 employees to have access to, and copy and verify any required records or reports made by the 

191 investigator (§§ 312.68, 511.1(b)(7)(ii) and 812.145). In order for the Agency to review and 

192 copy this information, FDA personnel should be able to review audit trails or other documents 

193 that track electronic record activities both at the study site and at any other location where 

194 associated electronic study records are maintained. To enable FDA's review, information about 

195 the creation, modification, or deletion of electronic records should be created incrementally, and 

196 in chronological order. To facilitate FDA’s inspection of this information, we recommend that 

197 clinical investigators retain either the original or a certified copy of any documentation created to 

198 track electronic records activities. 

199 

 

7

 As FDA announced in the Part 11 Scope and Application guidance, we intend to enforce certain controls for 

closed systems in § 11.10, including §11.10(d). 
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200 Even if there are no applicable predicate rule requirements, it may be important to have 

201 computer-generated, time-stamped audit trails or other physical, logical, or procedural security 

202 measures to ensure the trustworthiness and reliability of electronic records. We recommend that 

203 any decision on whether to apply computer-generated audit trails or other appropriate security 

204 measures be based on the need to comply with predicate rule requirements, a justified and 

205 documented risk assessment, and a determination of the potential effect on data quality and 

206 record integrity. Firms should determine and document the need for audit trails based on a risk 

207 assessment that takes into consideration circumstances surrounding system use, the likelihood 

208 that information might be compromised, and any system vulnerabilities. 

209 

210 If you determine that audit trails or other appropriate security measures are needed to ensure 

211 electronic record integrity, we recommend that personnel who create, modify, or delete 

212 electronic records not be able to modify the documents or security measures used to track 

213 electronic record changes. We recommend that audit trials or other security methods used to 

214 capture electronic record activities document who made the changes, when, and why changes 

215 were made to the electronic record. 

216 

217 Some examples of methods for tracking changes to electronic records include: 

218 

219 • Computer-generated, time-stamped electronic audit trails. 

220 • Signed and dated printed versions of electronic records that identify what, when, and by 

221 whom changes were made to the electronic record. When using this method, it is important 

222 that appropriate controls be utilized that ensure the accuracy of these records (e.g., sight 

223 verification that the printed version accurately captures all of the changes made to the 

224 electronic record). 

225 • Signed and dated printed standard electronic file formatted versions (e.g., pdf, xml or sgml) 

226 of electronic records that identify what, when, and by whom changes were made to the 

227 electronic record. 

228 • Procedural controls that preclude unauthorized personnel from creating, modifying, or 

229 deleting electronic records or the data contained therein. 

230 

231 C. Date/Time Stamps 

232 

233 We recommend that controls be put in place to ensure that the system's date and time are correct. 

234 The ability to change the date or time should be limited to authorized personnel and such 

235 personnel should be notified if a system date or time discrepancy is detected. We recommend 

236 that someone always document changes to date or time. We do not expect documentation of 

237 time changes that systems make automatically to adjust to daylight savings time conventions. 

238 We also recommend that dates and times include the year, month, day, hour, and minute. The 

239 Agency encourages establishments to synchronize systems to the date and time provided by 

240 trusted third parties. 

241 Clinical study computerized systems are likely be used in multi-center trials and may be located 

242 in different time zones. For systems that span different time zones, it is better to implement time 

243 stamps with a clear understanding of the time zone reference used. We recommend that system 
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244 documentation explain time zone references as well as zone acronyms or other naming 

245 conventions. 

246 

247 

248 VII. SYSTEM FEATURES 

249 

250 The Agency recommends that a number of computerized system features be available to 

251 facilitate the collection, inspection, review, and retrieval of quality clinical data. Key features 

252 are described here. 

253 

254 A. Systems Used for Direct Entry of Data 

255 

256 We recommend that prompts, flags, or other help features be incorporated into the computerized 

257 system to encourage consistent use of clinical terminology and to alert the user to data that are 

258 out of acceptable range. We recommend against the use of features that automatically enter data 

259 into a field when the field is bypassed. 

260 

261 B. Retrieval of Data and Record Retention 

262 

263 FDA expects to be able to reconstruct a clinical study submitted to the agency. This means that 

264 documentation, such as that described in the General Principles, Sections III.1, III.2 and III.5, 

265 should fully describe and explain how data were obtained and managed and how electronic 

266 records were used to capture data. We suggest that your decision on how to maintain records be 

267 based on predicate rule requirements and that this documented decision be based on a justified 

268 risk assessment and a determination of the value of the records over time. As explained in the 

269 Part 11 Scope and Application guidance, FDA does not intend to object to required records that 

270 are archived in electronic format; nonelectronic media such as microfilm, microfiche, and paper; 

271 or to a standard electronic file format (such as PDF, XML, or SGML). Persons must still comply 

272 with all predicate rule requirements, and the records themselves and any copies of required 

273 records should preserve their original content and meaning. Paper and electronic record and 

274 signature components can co-exist (i.e., as a hybrid system) as long as the predicate requirements 

275 (21 CFR parts 50, 56, 312, 511, and 812) are met, and the content and meaning of those records 

276 are preserved. 

277 

278 It is not necessary to reprocess data from a study that can be fully reconstructed from available 

279 documentation. Therefore, actual application software, operation systems, and software 

280 development tools involved in processing of data or records do not need to be retained. 

281 

282 

283 VIII. SYSTEM SECURITY 

284 

285 In addition to internal safeguards built into the computerized system, external safeguards should 

286 be put in place to ensure that access to the computerized system and to the data is restricted to 

287 authorized personnel as required by 21 CFR 11.10(d). We recommend that staff be kept 

288 thoroughly aware of system security measures and the importance of limiting access to 

289 authorized personnel. 

290 
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291 SOPs should be developed and implemented for handling and storing the system to prevent 

292 unauthorized access. Controlling system access can be accomplished through the following 

293 provisions of part 11 that, as discussed in the part 11 guidance, FDA intends to continue to 

294 enforce: 

295 • Operational system checks (§ 11.10(f)); 

296 • Authority checks (§ 11.10(g)); 

297 • Device (e.g., terminal) checks (§ 11.10(h)); and 

298 • The establishment of and adherence to written policies that hold individuals 

299 accountable for actions initiated under their electronic signatures (§ 11.10(j)). 

300 

301 The Agency recommends that access to data be restricted and monitored through the system's 

302 software with its required log-on, security procedures, and audit trail (or other selected security 

303 measures to track electronic record activities). We recommend that procedures and controls be 

304 implemented to prevent the data from being altered, browsed, queried, or reported via external 

305 software applications that do not enter through the protective system software. 

306 

307 We recommend that a cumulative record be available that indicates, for any point in time, the 

308 names of authorized personnel, their titles, and a description of their access privileges. We 

309 recommend that the record be kept in the study documentation, accessible at the site. 

310 

311 If a sponsor supplies computerized systems exclusively for clinical trials, we recommend that the 

312 systems remain dedicated to the purpose for which they were intended and validated. If a 

313 computerized system being used for a clinical study is part of a system normally used for other 

314 purposes, we recommend that efforts be made to ensure that the study software be logically and 

315 physically isolated as necessary to preclude unintended interaction with nonstudy software. If 

316 any of the software programs are changed, we recommend that the system be evaluated to 

317 determine the effect of the changes on logical security. 

318 

319 We recommend that controls be implemented to prevent, detect, and mitigate effects of computer 

320 viruses, worms, or other potentially harmful software code on study data and software. 

321 

322 

323 IX. SYSTEM DEPENDABILITY 

324 

325 The Agency recommends that sponsors ensure and document that all computerized systems 

326 conform to their own established requirements for completeness, accuracy, reliability, and 

327 consistent intended performance. 

328 

329 We recommend that systems documentation be readily available at the site where clinical trials 

330 are conducted and provide an overall description of the computerized systems and the 

331 relationships among hardware, software, and physical environment. 

332 

333 As noted in the Part 11 Scope and Application guidance, the Agency intends to exercise 

334 enforcement discretion regarding specific part 11 requirements for validation of computerized 

335 systems. We suggest that your decision to validate computerized systems and the extent of the 

336 validation take into account the impact the systems have on your ability to meet predicate rule 

337 requirements. You should also consider the impact those systems might have on the accuracy, 
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338 reliability, integrity, availability, and authenticity of required records and signatures. Even if 

339 there is no predicate rule requirement to validate a system, it may still be important to validate 

340 the system, based on criticality and risk, to ensure the accuracy, reliability, integrity, availability 

341 and authenticity of required records and signatures. 

342 

343 We recommend that you base your approach on a justified and documented risk assessment and 

344 determination of the potential of the system to affect data quality and record integrity. For 

345 example, in the case where data are directly entered into electronic records and the business 

346 practice is to rely on the electronic record, validation of the computerized system is important. 

347 However when a word processor is used to generate SOPs for use at the clinical site, validation 

348 would not be important. 

349 

350 If validation is required, FDA may ask to see the regulated company's documentation that 

351 demonstrates software validation. The study sponsor is responsible for making any such 

352 documentation available if requested at the time of inspection at the site where software is used. 

353 Clinical investigators are not generally responsible for validation unless they originated or 

354 modified software. 

355 

356 A. Legacy Systems 

357 

358 As noted in the Part 11 Scope and Application guidance, the Agency intends to exercise 

359 enforcement discretion with respect to all part 11 requirements for systems that otherwise were 

360 fully operational prior to August 20, 1997, the effective date of part 11, under the circumstances 

361 described below. These systems are also known as legacy systems. The Agency does not intend 

362 to take enforcement action to enforce compliance with any part 11 requirements if all the 

363 following criteria are met for a specific system: 

364 

365 • The system was in operation before the part 11 effective date. 

366 • The system met all applicable predicate rule requirements prior to the part 11 effective date. 

367 • The system currently meets all applicable predicate rule requirements. 

368 • There is documented evidence and justification that the system is fit for its intended use. 

369 

370 If a system has changed since August 20, 1997, and if the changes would prevent the system 

371 from meeting predicate rule requirements, part 11 controls should be applied to part 11 records 

372 and signatures pursuant to the enforcement policy expressed in the part 11 guidance. Please refer 

373 to the Part 11 Scope and Application guidance for further information. 

374 

375 B. Off-the-Shelf Software 

376 

377 While the Agency has announced that it intends to exercise enforcement discretion regarding 

378 specific part 11 requirements for validation of computerized systems, persons must still comply 

379 with all predicate rule requirements for validation. We suggested in the guidance for industry on 

380 part 11 that the impact of computerized systems on the accuracy, reliability, integrity, 

381 availability, and authenticity of required records and signatures be considered when you decide 

382 whether to validate, and noted that even absent a predicate rule requirement to validate a system, 

383 it might still be important to validate in some instances. 

384 
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385 For most off-the-shelf software, the design level validation will have already been done by the 

386 company that wrote the software. Given the importance of ensuring valid clinical trial data, 

387 FDA suggests that the sponsor or contract research organization (CRO) have documentation 

388 (either original validation documents or on-site vendor audit documents) of this design level 

389 validation by the vendor and would itself have performed functional testing (e.g., by use of test 

390 data sets) and researched known software limitations, problems, and defect corrections. Detailed 

391 documentation of any additional validation efforts performed by the sponsor or CRO will 

392 preserve the findings of these efforts. 

393 

394 In the special case of database and spreadsheet software that is: (1) purchased off-the-shelf, (2) 

395 designed for and widely used for general purposes, (3) unmodified, and (4) not being used for 

396 direct entry of data, the sponsor or contract research organization may not have documentation of 

397 design level validation. FDA suggests that the sponsor or contract research organization perform 

398 functional testing (e.g., by use of test data sets) and research known software limitations, 

399 problems, and defect corrections. 

400 

401 In the case of off-the-shelf software, we recommend that the following be available to the 

402 Agency on request: 

403 

404 • A written design specification that describes what the software is intended to do and how 

405 it is intended to do it; 

406 • A written test plan based on the design specification, including both structural and 

407 functional analysis; and 

408 • Test results and an evaluation of how these results demonstrate that the predetermined 

409 design specification has been met. 

410 Additional guidance on general software validation principles can be found in FDA’s guidance 

411 entitled General Principles of Software Validation; Final Guidance for Industry and FDA Staff. 

412 

413 C. Change Control 

414 

415 FDA recommends that written procedures be put in place to ensure that changes to the 

416 computerized system, such as software upgrades, including security and performance patches, 

417 equipment, or component replacement, or new instrumentation, will maintain the integrity of the 

418 data and the integrity of protocols. We recommend that the effects of any changes to the system 

419 be evaluated and a decision made regarding whether, and if so, what level of validation activities 

420 related to those changes would be appropriate. We recommend that validation be performed for 

421 those types of changes that exceed previously established operational limits or design 

422 specifications. Finally, we recommend that all changes to the system be documented. 

423 

424 

425 X. SYSTEM CONTROLS 

426 

427 The Agency recommends that appropriate system control measures be developed and 

428 implemented. 

429 
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430 • Software Version Control 

431 

432 We recommend that measures be put in place to ensure that versions of software used to 

433 generate, collect, maintain, and transmit data are the versions that are stated in the systems 

434 documentation. 

435 

436 • Contingency Plans 

437 

438 We recommend that written procedures describe contingency plans for continuing the study 

439 by alternate means in the event of failure of the computerized system. 

440 

441 • Backup and Recovery of Electronic Records 

442 

443 When electronic formats are the only ones used to create and preserve electronic records, the 

444 Agency recommends that backup and recovery procedures be outlined clearly in SOPs and 

445 be sufficient to protect against data loss. We also recommend that records be backed up 

446 regularly in a way that would prevent a catastrophic loss and ensure the quality and integrity 

447 of the data. We recommend that records be stored at a secure location specified in the SOPs. 

448 Storage is typically offsite or in a building separate from the original records. 

449 

450 We recommend that backup and recovery logs be maintained to facilitate an assessment of 

451 the nature and scope of data loss resulting from a system failure. 

452 

453 Firms that rely on electronic and paper systems should determine the extent to which backup 

454 and recovery procedures are needed based on the need to meet predicate rule requirements, a 

455 justified and documented risk assessment, and a determination of the potential effect on data 

456 quality and record integrity. 

457 

458 

459 XI. TRAINING OF PERSONNEL 

460 

461 Under 21 CFR 11.10(i), firms using computerized systems must determine that persons who 

462 develop, maintain, or use electronic systems have the education, training, and experience to 

463 perform their assigned tasks. 

464 

465 The Agency recommends that training be provided to individuals in the specific operations with 

466 regard to computerized systems that they are to perform. We recommend that training be 

467 conducted by qualified individuals on a continuing basis, as needed, to ensure familiarity with 

468 the computerized system and with any changes to the system during the course of the study. 

469 

470 We recommend that employee education, training, and experience be documented. 

471 

472 

473 XII. COPIES OF RECORDS AND RECORD INSPECTION 

474 

475 FDA has the authority to inspect all records relating to clinical investigations conducted under 21 

476 CFR Parts 312 and 812, regardless of how the records were created or maintained (21 CFR 
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477 312.58, 312.68, and 812.145). Therefore, you should provide the FDA investigator with 

478 reasonable and useful access to records during an FDA inspection. As noted in the Part 11, 

479 Electronic Records; Electronic Signatures- Scope and Application guidance, the Agency intends 

480 to exercise enforcement discretion with regard to specific part 11 requirements for generating 

481 copies of records (§ 11.10(b) and any corresponding requirement in § 11.30). We recommend 

482 that you supply copies of electronic records by: 

483 

484 • Producing copies of records held in common portable formats when records are 

485 maintained in these formats 

486 • Using established automated conversion or export methods, where available, to make 

487 copies available in a more common format (e.g., pdf, xml, or sgml formats) 

488 

489 Regardless of the method used to produce copies of electronic records, it is important that the 

490 copying process used produces copies that preserve the content and meaning of the record. For 

491 example, if you have the ability to search, sort, or trend records, copies given to FDA should 

492 provide the same capability if it is reasonable and technically feasible. FDA expects to inspect, 

493 review, and copy records in a human readable form at your site, using your hardware and 

494 following your established procedures and techniques for accessing records. 

495 

496 We recommend you contact the Agency if there is any doubt about what file formats and media 

497 the Agency can read and copy. 

498 

499 

500 XIII. CERTIFICATION OF ELECTRONIC SIGNATURES 

501 

502 As required by 21 CFR 11.100(c), persons using electronic signatures to meet an FDA signature 

503 requirement must, prior to or at the time of such use, certify to the Agency that the electronic 

504 signatures in their system, used on or after August 20, 1997, are intended to be the legally 

505 binding equivalent of traditional handwritten signatures. 

506 

507 As set forth in § 11.100(c)(1), the certification must be submitted in paper, signed with a 

508 traditional handwritten signature, to the Office of Regional Operations (HFC-100), 5600 Fishers 

509 Lane, Rockville, Maryland 20857. The certification is to be submitted prior to or at the time 

510 electronic signatures are used. However, a single certification can be used to cover all electronic 

511 signatures used by persons in a given organization. This certification is created by persons to 

512 acknowledge that their electronic signatures have the same legal significance as their traditional 

513 handwritten signatures. See the following example of a certification statement: 

514 

515 Pursuant to Section 11.100 of Title 21 of the Code of Federal Regulations, 

516 this is to certify that ___[name of organization]__ intends that all electronic 

517 signatures executed by our employees, agents, or representatives, located 

518 anywhere in the world, are the legally binding equivalent of traditional 

519 handwritten signatures. 

520 

521 

522 
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522 

523 DEFINITIONS

524 

525 

526 The following is a list of definitions for terms as they are used in, and for the purposes of, this 

527 guidance document. 

528 

529 Attributable Data: Attributable data are those that can be traced to individuals responsible for 

530 observing and recording the data. In an automated system, attributability could be achieved by a 

531 computer system designed to identify individuals responsible for any input. 

532 

533 Audit Trail: An audit trail is a secure, computer generated, time-stamped electronic record that 

534 allows reconstruction of the course of events relating to the creation, modification, and deletion 

535 of an electronic record. 

536 

537 Certified Copy: A copy of original information that has been verified, as indicated by dated 

538 signature, as an exact copy having all of the same attributes and information as the original 

539 

540 Computerized System: A computerized system includes computer hardware, software, and 

541 associated documents (e.g., user manual) that create, modify, maintain, archive, retrieve, or 

542 transmit in digital form information related to the conduct of a clinical trial. 

543 

544 Direct Entry: Recording data where an electronic record is the original capture of the data. 

545 Examples are the keying by an individual of original observations into the system, or automatic 

546 recording by the system of the output of a balance that measures subject’s body weight. 

547 

548 Electronic Record: Any combination of text, graphics, data, audio, pictorial, or other 

549 information representation in digital form that is created, modified, maintained, archived, 

550 retrieved, or distributed by a computer system. 

551 

552 Electronic Signature: A computer data compilation of any symbol or series of symbols 

553 executed, adopted, or authorized by an individual to be the legally binding equivalent of the 

554 individual's handwritten signature. 

555 

556 Original data: Original data are those values that represent the first recording of study data. 

557 FDA is allowing original documents and the original data recorded on those documents to be 

558 replaced by certified copies provided the copies are identical and have been verified as such. (see 

559 FDA Compliance Policy Guide # 7130.13

560 

561 Predicate rule: This term refers to underlying requirements set forth in the Federal Food, Drug, 

562 and Cosmetic Act, the PHS Act, and FDA regulations (other than 21 CFR part 11). Regulations 

563 governing good clinical practice and human subject protection can be found at 21 CFR parts 50, 

564 56, 312, 511, and 812. 

565 

566 Software Validation: Confirmation by examination and provision of objective evidence that 

567 software specifications conform to user needs and intended uses and that the particular 

568 requirements implemented through the software can be consistently fulfilled. Design level 
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569 validation is that portion of the software validation that takes place in parts of the software life 

570 cycle before the software is delivered to the end user. 

571 

572 Source Documents: Original documents and records including, but not limited to, hospital 

573 records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation 

574 checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 

575 transcriptions certified after verification as being accurate and complete, microfiches, 

576 photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at 

577 the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical 

578 trial. 

579 

580 Transmit: Transmit is to transfer data within or among clinical study sites, contract research 

581 organizations, data management centers, or sponsors. Other Agency guidance covers 

582 transmission from sponsors to the Agency.

583 
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584 

585 REFERENCES 

586 

587 

588 FDA, 21 CFR Part 11, "Electronic Records; Electronic Signatures; Final Rule." Federal 

589 Register Vol. 62, No. 54, 13429, March 20, 1997. 

590 FDA, Compliance Program Guidance Manual, "Compliance Program 7348.810 - Sponsors, 

591 Contract Research Organizations and Monitors," October 30, 1998. 

592 FDA, Compliance Program Guidance Manual, "Compliance Program 7348.811 - Bioresearch 

593 Monitoring - Clinical Investigators," September 2, 1998. 

594 FDA, Glossary of Computerized System and Software Development Terminology, 1995. 

595 FDA, Good Clinical Practice VICH GL9, 2001. 

596 FDA, Guideline for the Monitoring of Clinical Investigations, 1988. 

597 FDA, Information Sheets for Institutional Review Boards and Clinical Investigators, 1998. 

598 FDA, Software Development Activities, 1987. 

599 International Conference on Harmonisation, "E6 Good Clinical Practice: Consolidated 

600 Guideline," Federal Register, Vol. 62, No. 90, 25711, May 9, 1997. 

601 FDA, Part 11, Electronic Records; Electronic Signatures — Scope and Application, 2003. 

602 FDA, General Principles of Software Validation; Guidance for Industry and FDA Staff, 2002. 

603