Contents of a Complete Submission for Threshold Analyses and Human Factors Submissions to Drug and Biologic Applications

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Contents of a Complete
Submission for Threshold
Analyses and Human
Factors Submissions to Drug
and Biologic Applications
Guidance for Industry and FDA Staff
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to https://www.regulations.gov. Submit written
comments to the Dockets Management Staff (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 Quynh Nhu Nguyen, 301-796- 6273, or
(CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010.
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)
September 2018
Procedural

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Contents of a Complete
Submission for Threshold
Analyses and Human
Factors Submissions to Drug
and Biologic Applications
Guidance for Industry and FDA Staff
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
and/or
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010
Email: ocod@fda.hhs.gov
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
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)
September 2018
Procedural

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TABLE OF CONTENTS
I. INTRODUCTION............................................................................................................. 1
II. BACKGROUND ............................................................................................................... 2
III. SUBMISSION TYPES, COVER LETTER, AND FDA FORMS................................. 3
A. Types of Submissions ..................................................................................................................... 3
B. Cover Letter ................................................................................................................................... 3
C. Form FDA 1571 or Form FDA 356h ............................................................................................ 3
IV. CONTENTS OF THRESHOLD ANALYSES AND HUMAN FACTORS
SUBMISSIONS ............................................................................................................................. 4
A. Use-Related Risk Analysis ............................................................................................................. 4
B. Human Factors Validation Study Protocol ................................................................................. 5
C. Human Factors Validation Study Report .................................................................................... 7
D. Threshold Analyses ........................................................................................................................ 9
E. Comparative Use Human Factors Study Protocol .................................................................... 10
F. Comparative Use Human Factors Study Results Report ......................................................... 11
V. WHERE TO SEND A THRESHOLD ANALYSIS OR HUMAN FACTORS
SUBMISSION ............................................................................................................................. 12
A. Drug Products, Including Biologics, and Combination Products, That Are the Subject of an
IND Paper Submission ......................................................................................................................... 13
B. Drug-Device Combination Products Under Development for Submission Under ANDA .... 13
C. Electronic Submissions ................................................................................................................ 14
VI. REVIEW TIMELINE .................................................................................................... 14
VII. HOW TO OBTAIN ADDITIONAL INFORMATION ............................................... 15
VIII. REFERENCES ................................................................................................................ 16
GLOSSARY................................................................................................................................. 18
APPENDIX A .............................................................................................................................. 21
APPENDIX B .............................................................................................................................. 22
APPENDIX C .............................................................................................................................. 22
APPENDIX D .............................................................................................................................. 23

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Contents of a Complete Submission for Threshold Analyses and	1
Human Factors Submissions to Drug and Biologic Applications	2
Draft Guidance for Industry and FDA Staff1
3
4
5
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	6
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	7
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	8
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	9
for this guidance as listed on the title page.	10
11
12
13
14
I. INTRODUCTION	15
16
This document provides guidance to industry and FDA staff on the contents of and submission	17
procedures for threshold analyses2 and human factors (HF) submissions3 that will support	18
efficient Agency review, and presents timelines for FDA’s review of such submissions.4	
19
20
This guidance applies to the following types of products5:	21
22
• Human prescription drug products, including biologics, that are the subject of an	23
investigational new drug application (IND)6, a new drug application (NDA), a	24
biologics license application (BLA), or an abbreviated new drug application	25
(ANDA),7 and supplements to these applications	26
27
• Human nonprescription drug products that are the subject of an IND, NDA, or ANDA	28
29
1 This guidance has been prepared by the Office of Surveillance and Epidemiology in the Center for Drug Evaluation and
Research (CDER), in cooperation with the Center for Biologics Evaluation and Research (CBER), the Center for Devices and
Radiological Health, and the Office of Combination Products (OCP) at the Food and Drug Administration.
2 All terms presented in bold italic at first use in this guidance are defined in the Glossary.
3 See section III of this guidance for the types of submissions.
4 This document is one of several documents FDA is issuing to fulfill the performance goals under the sixth authorization of the
Prescription Drug User Fee Act (PDUFA VI). This document also provides information on what to include in submissions for
products under other user fee programs.
5 This includes combination products. See definition of combination product in 21 CFR 3.2. For the purposes of this guidance, we
are referring to combination products assigned to CDER or CBER as the lead center.
6 Sponsors can engage FDA on human factors issues as early as the pre-IND phase.
7 The recommendations in this guidance apply to ANDA submissions covering drug-device combination products.

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All such products in this guidance are jointly referred to as products,8 and persons responsible	30
for making submissions are referred to as sponsors.	31
32
This guidance does not describe when threshold analyses or HF submissions are warranted for	33
any particular application pathway, the processes or procedures associated with their review, or	34
the methods used by the Agency for evaluation. Furthermore, this guidance does not describe the	35
methods used to design, conduct, or analyze HF studies. In addition to the information described	36
in this guidance, FDA recommends that sponsors refer to other relevant guidance documents	37
related to product design and human factors (see section VIII).	38
39
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	40
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	41
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	42
the word should in Agency guidances means that something is suggested or recommended, but	43
not required.	44
45
46
II. BACKGROUND	47
48
The Federal Food, Drug, and Cosmetic Act (FD&C Act) requires that drug products submitted	49
for approval under section 505(b) be proven safe and demonstrate substantial evidence of	50
effectiveness for the product's intended use (21 U.S.C. 355(b)). Under section 351 of the Public	51
Health Service Act, FDA licenses a biological product based on a demonstration that it is safe,	52
pure, potent, and it is manufactured in a facility designed to ensure that the product continues to	53
be safe, pure, and potent.	54
55
As part of evaluating drug and biologic products for safety and effectiveness, FDA will evaluate	56
HF data submitted by sponsors in support of the product user interface when submission of such	57
data is warranted. For products that sponsors intend to submit as an ANDA, the sponsor can rely	58
on the Agency’s previous finding that its listed drug is safe and effective so long as the sponsor	59
can demonstrate certain findings.9 Certain products, including drug-device combination products,	60
may warrant threshold analyses and additional data, such as data from comparative HF studies.10	
61
62
8 For purposes of this guidance, unless otherwise specified, references to “products” include drugs submitted for approval or
approved under sections 505(b) or 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(b) or 355(j))
and biological products licensed under section 351 of the PHS Act.
9 See Section 505(j)(2)(A), 505(j)(4) of the FD&C Act (21 U.S.C. 355(j)(2)(a), 355(j)(4)); 21 CFR 314.127.
10 See draft guidance for industry and FDA staff Comparative Analyses and Related Comparative Use Human Factors Studies for
a Drug-Device Combination Product Submitted in an ANDA (Comparative Analyses Draft Guidance), available at
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM536959.pdf. When final,
this guidance will represent the FDA’s current thinking on this topic. For the most recent version of a guidance, check the FDA
Drugs guidance web page at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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III. SUBMISSION TYPES, COVER LETTER, AND FDA FORMS	63
64
A. Types of Submissions	65
66
Listed below are the different threshold analysis and human factors submission types:	67
68
1) Use-Related Risk Analysis	69
70
2) HF Validation Study Protocol	71
72
3) HF Validation Study Results Report	73
74
4) Threshold Analyses	75
76
5) Comparative Use HF Study Protocol	77
78
6) Comparative Use HF Study Results Report	79
80
See section IV for information regarding the content of each submission type listed in this	81
section:	82
83
B. Cover Letter	84
85
Each submission should include a cover letter that includes the statement “REQUEST FOR	86
[Type of Submission] REVIEW” in bolded capital letters.	87
88
For submission amendments, the cover letter should include the statement “AMENDMENT TO	89
REQUEST FOR [Type of Submission] REVIEW” in bolded capital letters.11	
90
91
See Appendix A for examples.	92
93
C. Form FDA 1571 or Form FDA 356h	94
95
All electronic submissions should include only fillable forms and electronic signatures to enable	96
automated processing. A submission that is the subject of an active IND should include Form	97
FDA 1571, “Investigational New Drug Application (IND).” A submission that is the subject of a	98
marketing application should include Form FDA 356h, “Application to Market a New or	99
Abbreviated New Drug or Biologic for Human Use.” Refer to the FDA Forms website for the	100
latest versions of these forms and their corresponding instruction files.12	
101
102
103
11 See section VI for additional considerations for amendments.
12 See the FDA Forms website for latest versions of forms and instruction files at:
http://www.fda.gov/aboutfda/reportsmanualsforms/forms/default.htm.

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IV. CONTENTS OF THRESHOLD ANALYSES AND HUMAN FACTORS	104
SUBMISSIONS	105
106
This section describes the information that a sponsor should include for each respective	107
submission type.	108
109
A. Use-Related Risk Analysis13	110
111
A comprehensive use-related risk analysis may be a separate submission or may be included as	112
part of another submission (e.g. with the HF validation study protocol (see section IV.B) or	113
Human Factors Engineering (HFE) Report (see section IV.C).14 The risk analysis submission	114
should include:	115
116
• A comprehensive and systematic evaluation of all the steps involved in using the	117
proposed product (e.g., based on a task analysis)	118
119
• The errors that intended product users might commit or the tasks they might fail	120
to perform, taking into consideration known problems with similar products	121
122
• The potential negative clinical consequences of use errors and task failures	123
including the severity of the resulting harm	124
125
• User task description and categorization (e.g., critical)	126
127
• The mitigation strategies employed to reduce identified risks or eliminate hazards	128
129
• The proposed methods used to validate these mitigation strategies	130
131
• Description of intended product users, uses, use environments, and training (if	132
applicable)	133
134
• Graphical depiction and written description of product user interface (see	135
Appendix C for example)	136
137
• Summary of known use problems with previous or similar products15	
138
13 ANSI/AAMI/ISO 14971, Medical Devices – Application of risk management to medical devices, defines risk as the
combination of the probability of occurrence of harm and the severity of the potential harm. However, because probability is very
difficult to determine for use errors, and in fact many use errors cannot be anticipated until product use is simulated and
observed, the severity of the potential harm may be more meaningful for determining the need to eliminate (design out) or reduce
resulting harm. Therefore, it may be appropriate when conducting the use-related risk analysis to focus on the resulting harm, and
including estimated occurrence rates may not be needed.
14 See guidance Applying Human Factors and Usability Engineering to Medical Devices available at
https://www.fda.gov/downloads/medicaldevices/.../ucm259760.pdf
15 In certain circumstances, there may be post-marketing experience that is relevant to the product under consideration. Such
information might include known use problems with previous models of the subject product or known use problems with similar
products.

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139
• Summary of preliminary analyses and evaluations, including formative	140
evaluation	141
142
See Appendix B for an example of how to present some of the key information for a use-related	143
risk analysis.	144
145
A sponsor can employ the use-related risk analysis to identify the need for risk mitigation	146
strategies and to design an HF validation study that adequately evaluates the risk mitigation	147
strategies. In circumstances where, based on the use-related risk analysis and other information, a	148
sponsor determines that an HF validation study is not needed, the sponsor may submit the use-	149
related risk analysis and other information, together with the justification for not conducting a	150
HF validation study, for review under the IND.	151
152
B. Human Factors Validation Study Protocol	153
154
Sponsors should include the following elements in the submission:	155
156
1. Background	157
158
• Description of intended product users, uses, use environments, and training	159
(if applicable)	160
161
• Graphical depiction and written description of product user interface (see	162
Appendix C for example), including the intend-to-market labels and labeling	163
that will be evaluated in the HF validation study	164
165
▪ For Instructions for Use (IFUs), in addition to an intended	166
commercial printed layout version, sponsors should provide a Word	167
version to facilitate the exchange of labeling comments and revisions	168
between the sponsor and FDA.16	
169
170
• Summary of known use problems with previous or similar products17	
171
172
• Summary of preliminary analyses and evaluations, including formative	173
evaluations; a discussion of key findings; and any changes made to the user	174
interface (e.g., device constituent part design change, labeling changes), as	175
well as a discussion of how the sponsor used the formative evaluation results	176
and findings to update the product user interface and use-related risk analysis	177
16 Submitting the IFU document in a Word version is consistent with recommendations to submit labeling content to FDA as part
of a marketing application; see draft guidance SPL Standard for Content of Labeling Technical Qs & As. When final, this
guidance will represent the FDA’s current thinking on this topic. For the most recent version of a guidance, check the FDA Drugs
guidance web page at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
17 In certain circumstances, there may be post-marketing experience that is relevant to the product under consideration. Such
information might include known use problems with previous models of the subject product or known use problems with similar
products.

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178
2. Analysis of hazards and risks associated with use of the product in a use-related	179
risk analysis	180
181
3. HF validation testing details	182
183
a. Study objective(s)	184
185
b. Type of testing (simulated-use vs. actual use)18	
186
187
c. Test environment and conditions19	
188
189
d. Training provided to participants and rationale for how it corresponds to	190
real-world training and training decay (if applicable)	191
192
e. Distinct user groups by number and type of test participants20	
193
194
f. User task description and categorization (e.g., critical)21 and a description of	195
use scenarios that include critical tasks	196
197
g. Definition of successful performance or failure of each test task	198
199
h. Description of data (e.g., data collected from observational tasks, knowledge	200
tasks, and subjective interview) to be collected and methods for documenting	201
202
i. Methods for root cause analysis of all use errors, difficulties, and close	203
calls22	204
205
j. Moderator script	206
18 See draft guidance for industry and FDA staff Human Factors Studies and Related Clinical Study Considerations in
Combination Product Design and Development (Combination Products Human Factors Draft Guidance), available at
https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM484345.pdf, for further discussion of simulated vs.
actual use studies. When final, this guidance will represent the FDA’s current thinking on this topic.
19 A rationale for how the testing environment and conditions of testing is representative of real-world use is helpful. In
identifying conditions of testing, sponsors should consider aspects of use that can be reasonably anticipated, such as use with
gloves or wet fingers, in dim lighting, or in noisy situations.
20 When describing study participants and how they represent distinct user populations (groups), it is helpful to describe the
characteristics that distinguish the groups and that can affect user interaction with the product (e.g., limited hand dexterity,
cognitive deficit).
21 The selection of user tasks can be derived from the comprehensive use-related risk analysis. Tasks that could lead to harm
(e.g., underdose or overdose), including those requiring the user to respond to alerts or alarms, should be categorized as critical
and prioritized for testing. A task requiring comprehension of warnings, caution statements, or contraindications in the product
labels or labeling would generally be considered a critical knowledge task. See Combination Products Human Factors Draft
Guidance), available at https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM484345.pdf, for definition of
critical tasks.
22 While close calls and difficulties may not manifest into use errors/task failures, they are good sources of data in terms of
providing potential user interface inadequacies that should be further evaluated.

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207
4. Product samples (5 samples of product that will be tested in the HF validation)23	
208
209
C. Human Factors Validation Study Report24	210
211
Sponsors should include the following elements in their submission:	212
213
1. Summary of findings and conclusions	214
215
a. Conclusions based on HFE process25	
216
217
b. Brief summary of validation study results	218
219
c. Discussion of whether additional risk mitigation measures are necessary	220
221
i. If additional mitigation measures are needed, the study report should	222
include a description of the additional mitigation measures and justify	223
whether additional validation testing is not warranted. However, if	224
additional validation testing is needed, the results should be submitted	225
within the report.	226
227
d. Discussion of residual use-related risks versus benefits of the product	228
229
2. Background26	
230
231
a. Brief summary of Human Factors Engineering processes applied throughout	232
the development of the product	233
234
b. Descriptions of intended product users, uses, use environments, and training	235
(if applicable)	236
237
c. Graphical depiction and written description of user interface (see Appendix	238
C), including the intend-to-market labels and labeling that were evaluated in	239
the HF validation study	240
241
23 FDA recognizes that in some circumstances, the ability to provide the requested quantity of samples may not be feasible. In
this instance, we recommend you contact FDA for further guidance.
24 The contents of the HF validation study report are intended to be equivalent to the contents outlined in Appendix A of the
guidance Applying Human Factors and Usability Engineering to Medical Devices.
25 If the HFE process identifies no use errors or problems that could result in harm, the sponsor should discuss how the validation
study results supports a conclusion of safe and effective use by the end user. Otherwise, the sponsor should include a discussion
of why the existing mitigations are effective and why the Agency should find the residual risks acceptable in the report. The
discussion should incorporate findings from the entire HFE process.
26 If previously submitted, cross-reference the prior submission and include the eCTD sequence number and date of submission.
Sponsors should not resubmit the electronic files when referencing that document.

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d. Summary of known use problems with previous products or similar products	242
243
e. Summary of preliminary analyses and evaluations, including formative	244
evaluations	245
246
i. The summary should include a discussion of key findings and any	247
changes made to the product design and its labeling based on key	248
findings, and should explain how the sponsor used the formative	249
results and findings to update the product user interface and risk	250
analysis.	251
252
f. Reference to previous HF validation study protocol submission, description	253
of changes made to the protocol after prior feedback from the FDA, and	254
description of any protocol deviations that occurred during the study	255
256
3. Analysis of hazards and risks associated with use of the product in a use-related	257
risk analysis27	
258
259
4. HF validation testing details	260
261
a. Study objective(s)	262
263
b. Rationale for test type selected (simulated-use or actual use)28	
264
265
c. Test environment and conditions of use	266
267
d. Training provided to test participants and how it will correspond to real-world	268
training levels and training decay (if applicable)	269
270
e. Distinct user groups broken out by number and type of test participants	271
272
f. User tasks description and categorization and a description of use scenarios	273
that include critical tasks	274
275
g. Definition of successful performance or failure of each test task	276
277
h. Test results and analysis (see example in Appendix D)	278
279
i. Observations of task performance, including occurrences and	280
description of use errors, close calls, and use difficulties	281
27 If previously submitted, cross-reference the prior submission and include the eCTD sequence number and date of submission.
Sponsors should not resubmit the electronic files when referencing that document.
28 See Combination Products Human Factors Draft Guidance for further discussion of simulated vs. actual use studies. When
final, this guidance will represent the FDA’s current thinking on this topic

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ii. Documentation of subjective data from study participants regarding	282
product use, use errors, close calls and use difficulties.	283
iii. Root cause analysis of all use errors, difficulties, and close calls and	284
discussion of risk mitigation strategies	285
286
5. Product samples (5 samples of intend-to-market product) 29	
287
288
D. Threshold Analyses	289
290
Threshold analyses generally are utilized in comparing two drug products. For these analyses,	291
sponsors should include the following elements in their submission:	292
293
1. Labeling comparison (a side-by-side, line-by-line comparison between the	294
proposed product and the product it references that includes the full prescribing	295
information, instructions for use, container labels and carton labeling, and	296
descriptions of the products)	297
298
2. Comparative task analysis30 (a comparative task analysis of the proposed product	299
and the product it references)	300
301
3. Physical comparison of the device constituent part(s) (e.g., examine, through a	302
visual or tactile examination, the physical features of the product that it plans to	303
reference and compare them to those of the proposed product)	304
305
4. Sponsor’s determination of whether design differences exist and, if so, whether	306
they are characterized as minor design differences or other design differences,31	
307
and the rationale for each characterization	308
309
29 FDA recognizes that in some circumstances, the ability to provide the requested quantity of samples may not be feasible. In
this instance, we recommend you contact FDA for further guidance.
30 To conduct a comparative task analysis, sponsors should systematically dissect the use process for each product (i.e., for both
the proposed product and the product it references) and analyze and compare the sequential and simultaneous manual and
cognitive activities for end-users interacting with each product. FDA recommends that sponsors analyze the differences with the
goal of characterizing the potential for use error. See the Association for the Advancement of Medical Instrumentation/American
National Standards Institute HE75: 2009-Human factors engineering—Design of medical devices, available at:
http://my.aami.org/aamiresources/previewfiles/HE75_1311_preview.pdf. Presenting this information in a side-by-side
comparison table can help to facilitate FDA evaluation of this information.
31 For further discussion on identifying design differences and characterizing design difference(s), see Comparative Analyses
Draft Guidance, available at
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM536959.pdf and draft
guidance for industry Considerations in Demonstrating Interchangeability With a Reference Product, available at
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf. When final,
these guidance will represent the FDA’s current thinking on this topic. For the most recent version of a guidance, check the FDA
Drugs guidance web page at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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5. Product samples (5 samples each of the proposed product and the product it	310
references)32	
311
312
E. Comparative Use Human Factors Study Protocol33	313
314
Sponsors should include the following elements in their submission:	315
316
1. Background, including description of the intended product users, uses, and use	317
environments	318
319
2. Threshold analyses (see section IV.D, above)34	
320
321
3. Comparative use HF testing details	322
323
a. Study objective(s)	324
325
b. Type of testing (simulated-use vs. actual use)35	
326
327
c. Statistical analysis plan (SAP) and sample size considerations (including	328
proposed analyses and all assumptions, as well as literature references or other	329
justification supporting the methods or assumptions)	330
331
d. Test environment and conditions of testing	332
333
e. Distinct user groups broken out by number and type of test participants	334
335
f. User task description and categorization (e.g., critical)36 and a description of	336
use scenarios that include critical tasks	337
338
g. Definition of successful performance or failure of each test task	339
340
h. Description of data (e.g., data collected from observational tasks, knowledge	341
tasks, and subjective interview) to be collected and methods for documenting	342
343
32 FDA recognizes that in some circumstances, the ability to provide the requested quantity of samples may not be feasible. In
this instance, we recommend you contact FDA for further guidance.
33 Potential applicants intending to submit a drug-device combination product under an ANDA are strongly encouraged to discuss
the results of the threshold analyses with the Agency via the controlled correspondence or pre-ANDA submission pathways, or
both, prior to conducting comparative use human factors studies.
34 If previously submitted, cross-reference the prior submission and include the eCTD sequence number and date of submission.
Sponsors should not resubmit the electronic files when referencing that document.
35 See Combination Products Human Factors Draft Guidance for further discussion of simulated vs. actual use studies.
36 In some instances, it may be appropriate to focus the selection of user tasks on the critical tasks related to the external critical
design attributes found to be different between the proposed product and the product it references.

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i. Methods for evaluating error rates	344
345
j. Moderator script	346
4. Product samples (5 samples each of the proposed product and the product it	347
references that will be tested in the comparative use HF study) 37	
348
349
F. Comparative Use Human Factors Study Results Report	350
351
Sponsors should include the following elements in the submission:	352
353
1. Summary of study findings and conclusions	354
355
▪ Conclusions38	
356
357
▪ Brief summary of study results	358
359
2. Background39	
360
361
a. Descriptions of intended product users, uses, and use environments	362
363
b. Reference to previous protocol submission, description of changes made to	364
the protocol after prior feedback from the FDA, and description of any	365
protocol deviations that occurred during the study	366
367
3. Threshold analyses (see section IV.D, above)40	
368
369
4. Comparative use HF testing details	370
371
a. Study objective(s)	372
373
b. Rationale for test type selected (simulated-use or actual use) 41	
374
375
37 FDA recognizes that in some circumstances, the ability to provide the requested quantity of samples may not be feasible. In
this instance, we recommend you contact FDA for further guidance.
38 A comparative use human factors study should be designed to provide sufficient data to confirm that the use error rate for the
critical task(s), as impacted by the differing external critical design attribute of the device constituent part(s) for the proposed
generic combination product, is not worse than the corresponding use error rate for the RLD when used by patients and
caregivers in representative use scenarios and use environments consistent with the labeled conditions of use. See Comparative
Analyses Draft Guidance for further discussion.
39 If previously submitted, cross-reference the prior submission and include the eCTD sequence number and date of submission.
Sponsors should not resubmit the electronic files when referencing that document.
40 If previously submitted, cross-reference the prior submission and include the eCTD sequence number and date of submission.
Sponsors should not resubmit the electronic files when referencing that document.
41 See Combination Products Human Factors Draft Guidance for further discussion of simulated vs. actual use studies.

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c. SAP and sample size considerations (including analyses and all assumptions,	376
as well as literature references or other justifications supporting the methods	377
or assumptions)	378
379
d. Test environment and conditions of use	380
381
e. Distinct user groups broken out by number and type of test participants	382
383
f. Critical tasks and use scenarios included in testing	384
385
g. Definition of successful performance or failure of each test task	386
387
h. Test results and analysis	388
389
i. Use error rates and analysis	390
391
ii. Observations of task performance, including occurrences of use errors	392
393
394
V. WHERE TO SEND A THRESHOLD ANALYSIS OR HUMAN FACTORS	395
SUBMISSION	396
397
Generally, FDA expects that sponsors will submit threshold analyses or HF submissions	398
consistent with the respective regulatory pathway. Sponsors should submit an HF validation	399
study protocol and questions regarding the protocol to the IND. For proposed generic products,	400
sponsors should submit threshold analyses, device assessments, and questions via the controlled	401
correspondence or pre-ANDA submission pathways, or both, as appropriate. Comparative use	402
HF study protocols should be submitted within a specific pre-ANDA meeting request.	403
It is recommended that all sponsors plan their development timelines to allow for Agency	404
feedback on protocols prior to initiation and conduct of the appropriate HF study. In addition,	405
sponsors should submit HF validation study results reports or comparative use HF study results	406
reports in their application for FDA review (i.e., NDA, BLA, or ANDA).	407
408
Submissions to a Commercial IND, NDA, BLA, or ANDA must be made in Electronic Common	409
Technical Document (eCTD) format.42 Submissions to a Research IND43 may be in paper or	410
electronic format. For paper submissions, sponsors should submit 3 copies to the appropriate	411
address below.	412
42 See guidance for industry Providing Regulatory Submissions in Electronic Format – Certain Human Pharmaceutical Product
Applications and Related Submissions Using the eCTD Specifications (Using eCTD Specifications Guidance); see also section
745A(a) of the FD&C Act (21 U.S.C. 379k-1(a)).
43 See FDA’s web page on Investigational New Drug (IND) Application at
https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/investigationa
lnewdrugindapplication/default.htm.

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413
A. Drug Products, Including Biologics, and Combination Products, That Are	414
the Subject of an IND Paper Submission	415
416
1. Human Factors Submissions for Prescription or Nonprescription Drugs,	417
Including Biologics, That Are the Subject of an IND Reviewed by CDER	418
419
Food and Drug Administration	420
Center for Drug Evaluation and Research	421
Central Document Room	422
5901-B Ammendale Rd.	423
Beltsville, MD 20705-1266	424
425
2. Human Factors Submissions for Prescription or Nonprescription Biologics That	426
Are the Subject of an IND Reviewed by CBER	427
428
Food and Drug Administration	429
Center for Biologics Evaluation and Research	430
Document Control Center	431
10903 New Hampshire Ave.	432
Bldg. 71, Rm. G112	433
Silver Spring, MD 20993-0002	434
435
B. Drug-Device Combination Products Under Development for Submission	436
Under ANDA	437
438
1. Controlled Correspondence	439
440
Sponsors seeking FDA’s feedback on a specific element in the development of a drug-device	441
combination product (e.g., identification and assessment of identified differences between the	442
user interface of a proposed generic combination product and its reference listed drug) should	443
submit the correspondence through the process outlined in FDA’s draft guidance Controlled	444
Correspondence Related to Generic Drug Development.44 This will facilitate prompt	445
consideration of and response to the controlled correspondence by the appropriate discipline.	446
447
2. Pre-ANDA Meeting	448
449
A request for a product development or pre-submission meeting for complex products that may	450
be submitted in an ANDA should be sent through the process outlined in FDA’s draft guidance	451
for industry Formal Meetings Between FDA and ANDA Applicants of Complex Products Under	452
GDUFA (Generic Drug User Fee Act). The meeting request should clearly identify in the subject	453
line that the prospective applicant is requesting a product development or pre-submission	454
44 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at
https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.

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meeting and should include adequate information for FDA to assess the potential utility of the	455
meeting and identify the appropriate staff that should attend the meeting.	456
457
C. Electronic Submissions	458
459
The sponsor should place the request for HF submission review in Module 1.2 and associated	460
documents (e.g. use-related risk analysis, protocols, reports) in Module 5, section 5.3.5.4 – Other	461
Study Reports and Related Information in eCTD.	462
463
The eCTD leaf title of the document should be clear, concise, and indicative of the content.	464
Examples include:	465
466
• HF - REQUEST FOR HUMAN FACTORS VALIDATION STUDY PROTOCOL	467
REVIEW	468
469
• HF - AMENDMENT TO REQUEST FOR HUMAN FACTORS VALIDATION STUDY	470
PROTOCOL REVIEW	471
472
• HF - REQUEST FOR HUMAN FACTORS VALIDATION STUDY REPORT REVIEW	473
474
• HF - AMENDMENT TO REQUEST FOR HUMAN FACTORS VALIDATION STUDY	475
REPORT REVIEW	476
477
• HF-REQUEST FOR HUMAN FACTORS VALIDATION OTHER REVIEW45	
478
479
• HF-AMENDMENT TO REQUEST FOR HUMAN FACTORS VALIDATION OTHER	480
REVIEW	481
482
The sponsor should also provide the eCTD location of the contents of the HF submission on the	483
cover letter and, if possible, include cross-document links or external bookmarks to the	484
information. This approach will help ensure that the information can be accessed quickly and	485
easily. For further information on providing leaf titles and study results reports (including file-	486
tags) in eCTD, see the eCTD Technical Conformance Guide.46	
487
488
489
VI. REVIEW TIMELINE	490
491
45 For the purposes of the eCTD, there are three options: protocols, reports, or other. “Other” includes use-related risk analyses
and threshold analyses.
46 The eCTD Technical Conformance Guide is available at:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ucm153574.ht
m.

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The Agency intends to review and comment on HF validation study protocol submissions in	492
accordance with PDUFA VI performance goals.47 The review clock for the performance review	493
goals begins when the Agency receives a complete submission. FDA will:	494
495
• By fiscal year (FY) 2019, review 50% of HF protocol submissions and provide the	496
sponsor with written comments within 60 days	497
498
• By FY 2020, review 70% of HF protocol submissions and provide the sponsor with	499
written comments within 60 days	500
501
• By FY 2021, review 90% of HF protocol submissions and provide the sponsor with	502
written comments within 60 days	503
504
If, after submitting an HF validation study protocol, a sponsor submits additional questions,	505
unsolicited revisions to the protocol, or a lengthy or complex response to an FDA question, or	506
amends original submission materials with new information for any reason, FDA ordinarily will	507
not respond to the original questions and will consider the original protocol submission	508
withdrawn. FDA will consider submission of a revised protocol, or revised or additional	509
supporting materials, to be a new submission with a new 60-day timeline for response.	510
511
FDA will review all threshold analyses or comparative use HF submissions consistent with good	512
review management principles and practices, as applicable, and in a timeframe to support any	513
applicable performance goals under FDA’s various user fee programs, taking into consideration	514
the specific circumstances (e.g. breakthrough designation) surrounding the individual	515
application.	516
517
518
VII. HOW TO OBTAIN ADDITIONAL INFORMATION	519
520
FDA encourages industry to meet with the Agency when appropriate48 to obtain Agency advice	521
during product development. Meetings should not be used to obtain Agency review of HF	522
validation study protocols or reports.	523
524
Prior to submitting an ANDA for a generic combination product, sponsors are encouraged to	525
submit a controlled correspondence49 or pre-ANDA meeting package, or both,50 when	526
appropriate.	527
47 PDUFA VI reauthorization performance goals and procedures for fiscal years 2018 through 2022, Section I.1.5.e, available at:
http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM511438.pdf.
48 Please refer to Guidance for Industry Formal Meetings between FDA and Sponsors or Applicants, available at:
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM590547.pdf.
49 Draft guidance for industry, Controlled Correspondence Related to Generic Drug Development, available at:
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm583436.pdf. When final, this
guidance will represent the FDA’s current thinking on this topic. For the most recent version of a guidance, check the FDA Drugs
guidance web page at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
50 Please refer to draft guidance for industry, Formal Meetings Between FDA and ANDA Applicants of Complex Products Under
GDUFA, available at

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528
529
VIII. REFERENCES	530
531
Applicable guidance documents relating to HF, product design, requesting meetings with the	532
Agency, and providing electronic submissions include those listed below:	533
534
A. Guidance documents related to HF	535
536
• Draft Guidance on Human Factors Studies and Related Clinical Study Considerations	537
in Combination Product Design and Development	538
539
• Draft guidance for industry Comparative Analyses and Related Comparative Use	540
Human Factors Studies for a Drug-Device Combination Product Submitted in an	541
ANDA	542
543
• Draft guidance for industry Considerations in Demonstrating Interchangeability With	544
a Reference Product	545
546
• Guidance for industry and FDA staff Applying Human Factors and Usability	547
Engineering to Medical Devices	548
549
B. Guidance documents related to product design	550
551
• Guidance for industry Safety Considerations for Product Design to Minimize	552
Medication Errors	553
554
• Draft guidance for industry Safety Considerations for Container Labels and Carton	555
Labeling Design to Minimize Medication Errors	556
557
C. Guidance on requesting meetings with Agency	558
559
• Draft guidance for industry Formal Meetings Between the FDA and Sponsors or	560
Applicants of PDUFA Products	561
562
• Draft guidance for industry, Controlled Correspondence Related to Generic Drug	563
Development	564
565
• Draft guidance for industry, Formal Meetings Between FDA and ANDA Applicants of	566
Complex Products Under GDUFA	567
568
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm578366.pdf. When final, this
guidance will represent the FDA’s current thinking on this topic. For the most recent version of a guidance, check the FDA Drugs
guidance web page at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

Contains Nonbinding Recommendations
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17
• Guidance for industry and review staff Best Practices for Communication Between	569
IND Sponsors and FDA During Drug Development	570
571
D. Guidance on providing electronic submissions	572
573
• Guidance for industry Providing Regulatory Submissions in Electronic Format –	574
Certain Human Pharmaceutical Product Applications and Related Submissions	575
Using the eCTD Specifications	576
577
578

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GLOSSARY	579
580
Applicant or sponsor: The entity that submits proposed Threshold Analyses or HF submissions	581
for the following types of products:	582
583
• Prescription drug products (including biologics) that are the subject of an NDA (21 CFR	584
314.3(b)), a BLA (21 CFR 601.2), or an ANDA (21 CFR 314.92), or that are currently	585
the subject of an IND (21 CFR 312.3(b)) in anticipation of the submission of a marketing	586
application	587
588
• Nonprescription drug products that are the subject of an IND, NDA, or ANDA	589
590
Close calls: Instances in which a user almost makes a use error that could result in harm, but the	591
user takes an action to “recover” and prevent the use error from occurring.	592
593
Comparative Use Human Factors Study Protocol: A study protocol for a proposed	594
combination product that describes the design and methodology for a comparative use human	595
factors study.	596
597
Comparative Use Human Factors Study Results Report: A study report that provides the	598
results of a comparative use human factors study.	599
600
Complete submission: The information FDA identifies for a sponsor to include to ensure that	601
the Agency can conduct a complete review of a proposed Human Factors Validation Study	602
Protocol.	603
604
Critical task: A user task which, if performed incorrectly or not performed at all, may cause	605
harm to the patient or user, where “harm” includes compromised medical care.	606
607
Formative evaluation: The process of assessing, at one or more stages during the product	608
development process, a user interface or user interactions with the user interface in order to	609
identify the interface’s strengths and weaknesses and to identify potential use errors that would	610
or could result in harm to the patient or user.	611
612
Hazard: A potential source of harm.	613
614
Human Factors Engineering: The application of knowledge about human behavior, abilities,	615
limitations, and other characteristics of medical device users when designing medical devices,	616
including mechanical and software-driven user interfaces, systems, tasks, user documentation,	617
and user training, to demonstrate and enhance safe and effective use. HF engineering and	618
usability engineering can be considered synonymous.	619
620
Human Factors Validation Study Protocol: A study protocol that describes the design and	621
methodology for a human factors validation study.	622
623

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Human Factors Validation Study Results Report: A study report that provides the results of a	624
human factors validation study.	625
626
Human factors validation testing: Testing conducted at the end of the product development	627
process to assess user interactions with a product user interface and to identify use errors that	628
may result in serious harm to the patient or user. Human factors validation testing is also used to	629
assess the effectiveness of risk management measures. Human factors validation testing	630
represents one portion of design validation.	631
632
Label: As defined in section 201(k) of the FD&C Act (21 U.S.C. 321(k)), the term label means	633
“a display of written, printed, or graphic matter upon the immediate container of any article.”	634
635
Labeling: As defined in section 201(m) of the FD&C Act (21 U.S.C. 321(m)), the term labeling	636
means “all labels and other written, printed, or graphic matter (1) upon any article or any of its	637
containers or wrappers, or (2) accompanying such article.” Labeling includes outside containers	638
or wrappers and package liners.	639
640
Medication error: The National Coordinating Council for Medication Error Reporting and	641
Prevention describes medication error as any preventable event that may cause or lead to	642
inappropriate medication use or patient harm while the medication is in the control of the health	643
care professional, patient, or consumer. Such events may be related to professional practice,	644
health care products, procedures, and systems, including prescribing; order communication;	645
product labeling, packaging, and nomenclature; compounding; dispensing; distribution;	646
administration; education; monitoring; and use.51	
647
648
Residual use-related risks: The risks that remain after risk control measures have been taken.	649
650
Simulated-use testing: Testing of a product under conditions of use that mimic real-world use	651
conditions without administering the actual therapy to patients.	652
653
Task: An action or set of actions performed by a user to achieve a specific goal.	654
655
Task Analyses: A systematic breakdown of device use process into discrete sequences of	656
tasks.52	
657
658
Threshold analyses: Conducted to identify differences (if any) that may exist between the	659
proposed combination product’s user interface and the product it references. Consist of labeling	660
comparison, comparative task analysis, and physical comparison of the device constituent	661
part(s).53	
662
663
51 National Coordinating Council for Medication Error Reporting and Prevention web page, available at:
http://www.nccmerp.org/aboutMedErrors.html.
52 See an example of a task analysis in Guidance for Industry and FDA Staff titled “Applying Human Factors and Usability
Engineering to Medical Devices,” available at https://www.fda.gov/downloads/MedicalDevices/.../UCM259760.pdf.
53 See Comparative Analyses Draft Guidance.

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Training decay: The time elapsed between receiving training and first product use.	664
665
Use environment: The environment(s) in which the product will be used. This may include a	666
variety of settings, such as clinical settings or home settings.	667
668
Use error: A user action, or lack of action, that was different from that expected by the	669
manufacturer and that caused an outcome that (1) was different from the result expected by the	670
user, (2) was not caused solely by product failure, and (3) did or could result in harm.	671
672
Use-related risk analysis: An analytical method to identify use errors associated with each use	673
step, and then the hazards/risks and clinical significance of those hazards/risks. The use-related	674
risk analysis includes a comprehensive and systematic evaluation of all the steps involved in	675
using the product (e.g., based on a task analysis), the errors that users might commit or the tasks	676
they might fail to perform (considering known problems for similar products), the potential	677
negative clinical consequences of use errors and task failures, the mitigation strategies, and	678
methods for validating the risk mitigation strategies.	679
680
User: A person who interacts with (i.e., operates or handles) the product.	681
682
User interface: All components of the product with which the user interacts, including the	683
device constituent part(s) of the product and any associated controls and displays, as well as	684
product labels, labeling, and packaging.	685
686

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APPENDIX A	687
688
EXAMPLE OF STATEMENTS TO INCLUDE IN THE COVER LETTER	689
690
1) For use-related risk analysis reviews, include the statement “REQUEST FOR	691
USE-RELATED RISK ANALYSIS REVIEW” in bold capital letters.	692
693
2) For amendments to use-related risk analysis reviews, include the statement	694
“AMENDMENT TO REQUEST FOR USE-RELATED RISK ANALYSIS	695
REVIEW” in bold capital letters.	696
697
3) For HF protocol reviews, include the statement “REQUEST FOR HUMAN	698
FACTORS VALIDATION STUDY PROTOCOL REVIEW” in bold capital	699
letters.	700
701
4) For amendments to HF protocols, include the statement “AMENDMENT TO	702
REQUEST FOR HUMAN FACTORS VALIDATION STUDY PROTOCOL	703
REVIEW” in bold capital letters.	704
705
5) For HF study results reports, include the statement “REQUEST FOR HUMAN	706
FACTORS VALIDATION STUDY REPORT REVIEW” in bold capital	707
letters.	708
709
6) For amendments to HF study results reports, include the statement	710
“AMENDMENT TO REQUEST FOR HUMAN FACTORS VALIDATION	711
STUDY REPORT REVIEW” in bold capital letters.	712
713
7) For comparative use HF threshold analyses reviews, include the statement	714
“REQUEST FOR THRESHOLD ANALYSES REVIEW” in bold capital	715
letters.	716
717
8) For amendments to comparative use HF threshold analyses reviews, include the	718
statement “AMENDMENT TO REQUEST FOR THRESHOLD ANALYSES	719
REVIEW” in bold capital letters.	720
721
9) For comparative use HF protocol reviews, include the statement “REQUEST	722
FOR COMPARATIVE USE HUMAN FACTORS PROTOCOL REVIEW”	723
in bold capital letters.	724
725
10) For amendments to comparative use HF protocol reviews, include the statement	726
“AMENDMENT TO REQUEST FOR COMPARATIVE USE HUMAN	727
FACTORS PROTOCOL REVIEW” in bold capital letters.	728
729
11) For comparative use HF study results report reviews, include the statement	730
“REQUEST FOR COMPARATIVE USE HUMAN FACTORS REPORT	731
REVIEW” in bold capital letters.	732

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22
733
12) For amendments to comparative use HF study results report review, include the	734
statement “AMENDMENT TO REQUEST FOR COMPARATIVE USE	735
HUMAN FACTORS REPORT REVIEW” in bold capital letters.	736
737
738
APPENDIX B	739
740
EXAMPLE OF USE-RELATED RISK ANALYSIS	741
742
Task
No.
Use task
description
Description
of potential
use errors
Potential
hazards/harm
and severity54
Critical
task
(Yes/
No)
Risk
mitigation
measure for
each use
error
Evaluation
method in HF
validation study
4 Press green
button and
hold for 10
seconds
Button is
held for less
than 10
seconds
Full dose is
not injected;
leads to
patient death
Yes Redesign
product to
eliminate
the need to
hold for 10
seconds
Evaluated in HF
validation study
in use scenario 1:
Administration
of Drug, task 4
743
744
APPENDIX C	745
746
EXAMPLE OF DESCRIPTION OF USER INTERFACE	747
748
Interface
Item
Written description of the user interface Graphical depiction of the
user interface
Inspection
Window
The user inspects the window to ensure that
the drug color is clear and drug solution does
not have any particulates
749
750
54 Describe potential hazard/harm and severity for each potential use error.

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APPENDIX D	751
752
HYPOTHETICAL EXAMPLE OF HF VALIDATION DATA	753
754
A hypothetical example of the results of analyzing human factors validation study data are	755
shown in the table below. Analysis of human factors validation study data should focus on any	756
problems found during the testing. The study data should be analyzed to determine which part of the	757
user interface was involved and how the user interaction could have resulted in the use error or	758
problem.	759
760
Description
of Tasks
(denote C
for critical)
Number of
use errors
and
description
of use
errors
Number of
close calls and
use
difficulties55
and
description of
close calls and
use difficulties
Study
participan
t’s
subjective
feedback
56
Sponsor’s Root
cause analysis57
Sponsor’s
Discussion of
Mitigation
strategies58
Task 4:
Press green
button and
hold for 10
seconds
(C)
1 use error.
The user
did not
press the
green
button for
10
seconds,
he only
held it for
5 seconds.
0 close calls or
use difficulties
The user
heard a
second
click and
stopped
pressing
the button
because
he
thought
the
injection
was
complete
based on
the click.
Root cause
analysis
showed that the
user interface
has audible
cues that do not
coincide with
the labeled
hold time and
contribute to
confusion.
Product was
redesigned to align
the audible cues to
the “hold time”
needed to deliver the
drug. This change
impacts a critical
task for drug
delivery. Thus, the
change was
evaluated in another
validation study
conducted to
demonstrate the
effectiveness of this
change to the user
interface.
761
55 While close calls and difficulties may not manifest into actual use errors/failures, they are good source of data in terms of
providing potential user interface inadequacies that should be further evaluated.
56 What the participant(s) say about the use errors/close calls/use difficulties from their perspective.
57 This should incorporate the sponsor’s analysis of the subjective data obtained from study participants clarifying why or how
the use errors and failures occurred from the participant’s perspective. Some questions to consider: What did study participants
say about the errors/failures? Did they say how/why the errors/failures occurred? Did they comment on any aspect of the user
interface that may have influenced their behavior/action while they were performing the task? Did they note any suggested user
interface improvements?
58 This should address whether additional product modifications, risk mitigations, or risk mitigation validation should be
implemented as necessary.