Comparative Analyses and 
Related Comparative Use Human 
Factors Studies for a Drug-Device 
Combination Product Submitted 
in an ANDA: 
Draft Guidance for Industry 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 http://www.regulations.gov.  Submit written 
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 (CDER) Andrew LeBoeuf, 240-402-0503. 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
January 2017 
Generics   
Comparative Analyses and 
Related Comparative Use Human 
Factors Studies for a Drug-Device 
Combination Product Submitted 
in an ANDA: 
Draft Guidance for Industry 
 
 
 
 
 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
January 2017 
Generics 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  SCOPE ............................................................................................................................... 3 
IV.   CONSIDERATIONS FOR THE USER INTERFACE FOR A PROPOSED 
GENERIC COMBINATION PRODUCT ...................................................................... 4 
A.  General Considerations ................................................................................................................. 4 
B.   Analysis of the User Interface of a Generic Combination Product ........................................... 5 
1. Threshold Analyses ......................................................................................................................... 6 
2. Studies to Evaluate Differences That May Not Be Minor as Observed in Threshold Analyses .. 8 
 
APPENDIX A ................................................................................................................................ 9 
i.  Study Design Considerations .......................................................................................................... 9 
ii.   Sample Size Considerations .......................................................................................................... 11 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Comparative Analyses and Related Comparative Use Human 
2  Factors Studies for a Drug-Device Combination Product Submitted 
3  in an ANDA:  
1
4  Guidance for Industry  
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page.   
12   
13   
14   
15  I.  INTRODUCTION  
16   
17  This guidance is intended to assist potential applicants who plan to develop and submit an 
18  abbreviated new drug application (ANDA) to seek approval of a proposed combination product 
19  that includes both a drug constituent part and a delivery device constituent part.2 The 
20  recommendations included in this guidance generally focus on the analysis of the proposed user 
21  interface for the generic3 drug-device combination product (generic combination product) when 
22  compared to the user interface for the reference listed drug (RLD). For the purposes of this 
23  guidance, the term user interface refers to all components of the combination product with which 
24  a user interacts. This includes the delivery device constituent part of the  combination product 
25  and any associated controls and displays, as well as product labeling and packaging.  
26   
27  In the early stages of development, potential applicants should carefully consider the design of 
28  the user interface of a proposed generic combination product and seek to minimize differences 
29  from the user interface for the RLD. To facilitate that process, this guidance provides general 
30  principles, including how to conduct threshold analyses for the identification and the assessment 
31  of differences in the design of the user interface for the proposed generic combination product 
32  when compared to its RLD. 
33   
34  Depending on the results of the threshold analyses discussed in this guidance, submission of 
35  additional data may be warranted, such as data from comparative use human factors studies, to 
36  assess the acceptability of differences identified in the user interface for the proposed generic 
                                                 
1 This guidance has been prepared by the Office of Generic Drugs and the Office of Surveillance and Epidemiology 
in the Center for Drug Evaluation and Research (CDER), with the assistance of the Office of Combination Products 
and the Center for Devices and Radiological Health at the Food and Drug Administration.  
2 Products that include both a drug constituent part and a device constituent part are regulated as combination 
products. See 21 CFR Parts 3 and 4. Combination products within the scope of this guidance are those with a drug 
primary mode of action. Therefore, CDER will have primary jurisdiction for the review of these combination 
products and will coordinate with the Center for Devices and Radiological Health as appropriate.  
3 The term generic in this guidance refers to a product for which approval is sought under an ANDA. 
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37  combination product as compared to the user interface for the RLD. Applicants may consider 
38  modifying the design of the generic combination product to minimize differences from the RLD 
39  to avoid conducting comparative use human factors studies. To the extent an applicant conducts 
40  comparative use human factors studies, this guidance provides recommendations on the design 
41  and conduct of such studies.  
42   
43  FDAs guidance documents do not generally establish legally enforceable responsibilities.  
44  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
45  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
46  the word should in Agency guidances means that something is suggested or recommended, but 
47  not required.  
48   
49  II.  BACKGROUND 
50   
51  The Drug Price Competition and Patent Term Restoration Act of 1984 (Pub. L. 98-417) (the 
52  Hatch-Waxman Amendments) created, among other things, section 505(j) of the Federal Food, 
53  Drug, and Cosmetic Act (FD&C Act).  Under section 505(j), an ANDA applicant can rely on 
54  FDAs previous finding that the RLD is safe and effective so long as the ANDA applicant 
55  demonstrates that the proposed drug product and the RLD are the same with respect to active 
56  ingredient(s), dosage form, route of administration, strength, and, with certain exceptions, 
57  labeling.4  An ANDA must also include sufficient information to demonstrate that the proposed 
58  product is bioequivalent to the RLD, and that the ANDA meets the approval requirements 
59  relating to chemistry, manufacturing, and controls (CMC). An ANDA generally is not required 
60  to be the same as the listed drug it references in certain respects. For example, a generic drug 
61  generally can differ from its RLD in certain respects with regard to the device or with respect to 
62  inactive ingredients.    
63   
64  Drug products that are approved in ANDAs are generally considered by FDA to be 
65  therapeutically equivalent to their RLD.  Products classified as therapeutically equivalent can be 
66  substituted with the full expectation that the generic product will produce the same clinical effect 
67  and safety profile as the RLD under the conditions specified in the labeling.5   
68   
69  These general principles apply to products submitted in ANDAs, including drug-device 
70  combination products.6 A generic combination product classified as therapeutically equivalent to 
71  the RLD can be expected to produce the same clinical effect and safety profile as the RLD under 
72  the conditions specified in labeling.  This does not mean, however, that the proposed generic 
73  combination product and its RLD need to be identical in all respects. FDA recognizes that an 
74  identical design may not always be feasible and, in certain instances, differences in the design of 
75  the user interface for a generic combination product as compared to the RLD may exist without 
                                                 
4 See, e.g., sections 505(j)(2)(A) and 505(j)(4) of the FD&C Act and 21 CFR 314.94 and 21 CFR 314.127.   
5Therapeutic equivalents are approved drug products that are pharmaceutical equivalents 
for which bioequivalence has been demonstrated, and that can be expected to have the same 
clinical effect and safety profile when administered to patients under the conditions specified in 
the labeling. See 21 CFR 314.3; See also FDAs Approved Drug Products with Therapeutic Equivalents (the Orange 
Book), preface to the 36th edition, at page vii. 
6 See, e.g., sections 505(j)(2)(A), 505(j)(4), and 503(g)(1) of the FD&C Act. 
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76  precluding approval of the generic combination product under an ANDA.7 In some instances in 
77  which differences exist, certain additional information and/or data relating to the user interface of 
78  the proposed generic combination product, such as data from comparative use human factors 
79  studies, may be appropriate to support approval of the proposed generic combination product in 
80  an ANDA.8 The extent to which differences between the proposed product and the RLD affect 
81  the approvability of the proposed ANDA product will be evaluated on a case-by-case basis. 
82   
83  FDA does not consider the comparative use human factors studies described in this guidance to 
84  be clinical investigations intended to demonstrate the safety or effectiveness of the proposed 
85  generic combination product.  Rather, the comparative use human factors studies described in 
86  this guidance are intended to confirm that the differences in device and labeling between the 
87  generic combination product and RLD are acceptable and that the proposed generic combination 
88  product can be substituted with the full expectation that the generic combination product will 
89  produce the same clinical effect and safety profile as the RLD under the conditions specified in 
90  the labeling.  FDA intends to consider whether the generic combination product can be 
91  substituted for the RLD without the intervention of a health care provider and/or without 
92  additional training prior to use of the generic combination product.  
93    
94  III.  SCOPE     
95   
96  This guidance addresses generic combination products that include a drug and a delivery device 
97  intended to administer a drug product.  Such products include, for example, products where the 
98  delivery device constituent part and the drug constituent part of the product are a single entity 
99  (e.g., pre-filled syringe, auto-injector),9 and products where the two constituent parts are co-
100  packaged (e.g., drug in a vial packaged in the same box with a syringe).10  
101   
102  The recommendations in this guidance generally focus on the analysis of the proposed user 
103  interface for the generic combination product when compared to the user interface for the RLD 
104  and are not intended to address all of the information necessary to support approval of a generic 
105  combination product, including the delivery device constituent part. For example, as applicable, 
106  a general description of the entire delivery device constituent part should be provided in the 
107  CMC section of the ANDA.  There should be complete CMC information for the product, 
108  including the design of the delivery device constituent part and development information.  The 
109  delivery device constituent part should be shown to be compatible for use with the final 
110  formulation of the drug constituent part through appropriate studies, including, for example, 
111  extractable/leachable studies, performance testing, and stability studies.  In addition, comparative 
112  in vitro performance testing data may be needed to support the delivery device constituent part of 
113  the proposed generic combination product. Potential applicants should refer to relevant FDA 
                                                 
7 FDA has previously discussed the assessment of differences between a proposed generic combination product and 
its RLD in two citizen petition responses.  See FDA Response to King Pharmaceuticals (Jul. 29, 2009) (Docket No. 
FDA-2009-P-0040) and FDA Response to Dey Pharma L.P. (May 27, 2010) (Docket No. FDA-2009-P-0578). This 
guidance clarifies certain aspects of those responses and represents the Agencys current thinking regarding the 
topics addressed herein. 
8 See, e.g., sections 505(j)(2)(A), 505(j)(4), and 503(g)(1) of the FD&C Act. 
9 21 CFR 3.2(e)(1). 
10 21 CFR 3.2(e)(2). 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
114  guidance documents and other resources that provide information on what data and information 
115  should be included to support the delivery device constituent part(s) of a proposed generic 
116  combination product.11   
117   
118  IV.   CONSIDERATIONS FOR THE USER INTERFACE FOR A PROPOSED 
119  GENERIC COMBINATION PRODUCT 
120   
121  This section discusses certain data and information that may be needed to support the design of 
122  the user interface of the proposed generic combination product to support approval of the product 
123  in an ANDA. Such data and information should support that the generic combination product 
124  may be substituted with the full expectation that the generic combination product will produce 
125  the same clinical effect and safety profile as the RLD under the conditions specified in the 
126  labeling.12  FDA intends to consider whether the generic combination product can be substituted 
127  for the RLD without the intervention of a health care provider and/or without additional training 
128  prior to use of the generic combination product. FDA expects that data and information 
129  comparing the user interface of the proposed generic combination product to the RLDs user 
130  interface will be submitted to support an ANDA application.  
131   
132  A.  General Considerations 
133   
134  When developing a generic combination product for submission in an ANDA, it is important that 
135  applicants carefully consider the overall design of the user interface and should generally seek 
136  approval of a presentation approved for the RLD.13   
137   
138  FDA recognizes that a potential applicant of a proposed generic combination product may 
139  develop a user interface that has certain differences from the user interface approved for the 
                                                 
11 Additional guidances that provide the Agencys current thinking on this topic or otherwise set forth relevant 
principles include, but are not limited to: 
  Draft Guidance for Industry: MDI and DPI Drug Products; CMC Documentation (when finalized, this 
guidance will reflect FDAs current thinking on this topic) 
  Guidance for Industry: Nasal Spray and Inhalation Solution, Suspension and Spray Drug Products; CMC 
Documentation 
  Guidance for Industry and FDA Staff: Technical Considerations for Pen, Jet, and Related Injectors 
Intended for Use with Drugs and Biological Products  
  Draft Guidance to Industry and FDA Staff: Glass Syringes for Delivering Drug and Biological Products: 
Technical Information to Supplement International Organization for Standardization (ISO) Standard 
11040-4; (when finalized, this guidance will reflect FDAs current thinking on this topic) 
12 There has been some confusion regarding whether FDA expects for ANDA approval that a generic combination 
product be used in accordance with the labeling for the RLD.  FDA does not necessarily expect for approval that a 
generic combination product can be used according to the RLD labeling per se, but rather it is critical that the 
generic combination product can be substituted for the RLD without additional physician intervention and/or 
retraining prior to use.  To this end, a comparative use human factors study as described in this guidance could be 
designed to account for how a particular proposed generic combination product might be used when substituted for 
the RLD. See also footnote 7. 
13 If a sponsor is proposing a presentation for which the RLD is not approved (e.g., seeking approval of a generic 
combination product as a pre-filled syringe in instances when the RLD was approved in a vial), FDA strongly 
encourages the sponsor to discuss the proposed presentation with FDA via controlled correspondence and/or pre-
ANDA meeting package prior to product development or submission of an ANDA. 
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Draft  Not for Implementation 
140  RLD.  FDA may accept such design differences if they are adequately analyzed, scientifically 
141  justified, and do not preclude approval in an ANDA.  In general, FDA expects that end-users of 
142  generic combination products, including but not limited to lay-persons, such as patients, and/or 
143  caregivers, can use the generic combination product when it is substituted for the RLD without 
144  the intervention of the health care provider and/or without additional training prior to use of the 
145  generic combination product.     
146   
147  FDA intends to consider any differences in the design of the user interface of a proposed generic 
148  combination product and the RLD, and assess the need for additional data, such as data from 
149  comparative use human factors studies, on a case-by-case basis.  The following sections describe 
150  our current thinking and recommendations for identifying and evaluating design differences 
151  between a proposed generic combination product and its RLD.   
152   
153  B.   Analysis of the User Interface of a Generic Combination Product 
154   
155  For purposes of this guidance, FDA recommends that potential applicants analyze the overall 
156  user interface of a proposed generic combination product to identify differences in design when 
157  compared to the RLD.  Potential applicants are strongly encouraged to utilize the threshold 
158  analyses described below throughout product development and seek to minimize differences 
159  from the RLD. These threshold analyses may also assist potential applicants in identifying 
160  differences in the user interface of a proposed generic combination product and determine 
161  whether certain data, including data from comparative use human factors studies (as described 
162  further in this section), should be submitted to support approval of a proposed combination 
163  product submitted in an ANDA. 
164   
165  To conduct a comparative analysis of the user interface of a proposed generic combination 
166  product and its RLD, potential applicants should examine, among other things, the external 
167  critical design attributes of the proposed delivery device constituent part in comparison to the 
168  external critical design attributes of the RLD.  External critical design attributes are those 
169  features that directly affect how users perform a critical task14 that is necessary in order to use or 
170  administer the drug product. To identify the external critical design attributes, a potential 
171  applicant should examine the overall external operating principles of the delivery device 
172  constituent part by evaluating all the tasks that an end-user needs to perform to prepare and 
173  administer the product.  Among those tasks, certain ones will be identified as critical to the use 
174  of the product, and the external critical design attributes of the product would be those features 
175  that end-users rely on to safely and effectively perform those identified critical tasks.  FDA 
176  recommends that potential applicants consider the external critical design attributes of the RLD 
177  beginning in the early stages of their development program.   
178   
179   
180    
                                                 
14 For additional information on critical tasks, see FDA draft guidance for industry Human Factors Studies and 
Related Clinical Study Considerations in Combination Product Design and Development, Section III.B.1: Critical 
Tasks.  When final, this guidance will reflect FDAs current thinking on this topic. 
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181  1.  Threshold Analyses 
182   
183  Three types of threshold analyses can be used throughout the development program for the 
184  purposes of identifying, evaluating, and minimizing differences in design.  These analyses 
185  should also be conducted after the design for the user interface of a proposed generic 
186  combination product has been finalized by the potential applicant and is representative of the 
187  commercial product. 
188   
189  FDA recommends that potential applicants carefully evaluate the risks associated with any 
190  differences identified in the user interface that may affect the ability of the patient, caregiver, or 
191  other user15 to use the product.  In particular, patient and caregiver end-user groups may lack the 
192  expertise that a health care provider user group is expected to possess.  Patient and caregiver user 
193  groups may be less accustomed to navigating differences in the user interface of a generic 
194  combination product than health care providers.  As a result, there is concern that patients or 
195  caregivers who encounter different user interfaces, such as differences in external critical design 
196  attributes, may be at increased risk for a use-related error that may impact their ability to use a 
197  generic combination product when substituted for the RLD. 
198   
199  a.  Types of Threshold Analyses 
200   
201  The following three types of analyses are recommended as part of the threshold analyses to 
202  compare the user interface of the proposed generic combination product to the user interface of 
203  its RLD: 
204   
205  i.  Labeling comparison:  FDA recommends a side-by-side, line-by-line comparison of the 
206  full prescribing information, instructions for use, and descriptions of the delivery device 
207  constituent parts of the generic combination product and its RLD.16  
208   
209  ii.  Comparative task analysis:  FDA recommends that potential applicants conduct a 
210  comparative task analysis between the RLD and the proposed generic combination product.17 
                                                 
15 For additional information about end user group considerations, see FDA draft guidance for industry Human 
Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development, 
Section III.B.2. Intended Users and Use Environment.  When final, this guidance will reflect FDAs current thinking 
on this topic. 
16 ANDAs are required to include information to show that the labeling proposed for the generic drug is the same 
as the RLD, with certain limited exceptions, such as for changes required because of differences approved under a 
suitability petition (see section 505(j)(2)(C) of the FD&C Act and 21 CFR 314.93), or because the generic drug and 
the RLD are produced or distributed by different manufacturers (see section 505(j)(2)(A)(v) of the FD&C Act). 
Labeling differences that stem from permissible differences in design between the user interface for the proposed 
generic combination product and its RLD may fall within the scope of permissible differences in labeling for a 
product approved under an ANDA. 
17 To conduct a comparative task analysis, sponsors should systematically dissect the use process for each product, 
i.e., both the proposed generic product and the RLD, and analyze and compare the sequential and simultaneous 
manual and intellectual activities for end-users interacting with both the products.  FDA recommends that sponsors 
analyze the differences with the goal to characterize the potential for use error.  Also see the Association for the 
Advancement of Medical Instrumentation/American National Standards Institute HE75: 2009-Human factors 
 
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211   
212  iii.  Physical comparison of the delivery device constituent part:  FDA recommends that the 
213  potential applicant of the proposed generic combination product acquire the RLD to examine 
214  (e.g., visual and tactile examination) the physical features of the RLD and compare them to those 
215  of the delivery device constituent part for the proposed generic combination product. 
216   
217  b.  Outcomes of Threshold Analyses 
218   
219  After completing the threshold analyses, the following outcomes are possible18: 
220   
221  i.   No design differences:  When no differences are identified between the user interface of 
222  the proposed generic combination product and the user interface for the RLD, it is likely that 
223  certain information and/or data, such as data from comparative use human factors studies, will 
224  not be necessary to support approval of the ANDA.   
225   
226  ii.  Differences in design:  If differences are identified between the design of the user 
227  interface of a proposed generic combination product and the user interface of its RLD, the 
228  sponsor should focus on whether the difference(s) involves an external critical design attribute 
229  that may potentially impact whether the proposed generic combination product can be substituted 
230  for the RLD19  and seek to establish and categorize the differences as follows: 
231   
232    Minor design difference:  FDA views a design difference as minor if the 
233  differences in the user interface of the proposed generic combination 
234  product, in comparison to the user interface of the RLD, do not affect an 
235  external critical design attribute.  Minor differences in design are likely to 
236  be viewed by FDA as acceptable provided that the data and information 
237  submitted by the applicant demonstrate that the differences are in fact 
238  minor.  For example, such data and information may be collected through 
239  threshold analyses described in section IV.B.1.a of this guidance, that 
240  demonstrate that the differences in design do not involve an external 
241  critical design attribute that can impact whether the proposed generic 
242  combination product can be substituted for the RLD.  Similarly, for those 
243  products that would be expected to be administered only by a health care 
244  provider, the risks associated with substitution may be adequately 
245  addressed through threshold analyses rather than a comparative use human 
246  factors study.  As mentioned previously, patient and caregiver end-user 
247  groups may be less accustomed to navigating differences in user interfaces 
248  among drug products than health care providers.   
                                                                                                                                                             
engineeringDesign of medical devices.  The standard can be accessed at 
http://my.aami.org/aamiresources/previewfiles/HE75_1311_preview.pdf. 
18 Prior to submitting an ANDA for a generic combination product, potential applicants are strongly encouraged to 
contact FDA via controlled correspondence and/or pre-ANDA meeting package to discuss the applicants proposed 
product. This communication should include a prototype of their proposed generic combination  product, a sample 
RLD, and the results of threshold analyses described in this guidance. 
19 In assessing the significance of differences of design, potential applicants should consider the impact of the 
identified difference(s) in the context of the overall risk profile for the product. 
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249   
250    Other design differences:  FDA may not view a design difference as minor 
251  if any aspect of the threshold analyses suggests that differences in the 
252  design of the user interface of a proposed generic combination product as 
253  compared to the RLD may impact an external critical design attribute that 
254  involves administration of the product.  In such cases, the potential 
255  applicant should first strongly consider modifying the design of the user 
256  interface (e.g., delivery device constituent part) to minimize differences 
257  from the RLD. Alternatively, if such differences are present in the final 
258  design of the user interface of the proposed generic combination product, 
259  FDA may request that applicants provide additional information and/or 
260  data, such as data from a comparative use human factors study, to address 
261  whether the differences identified in the user interface introduce a risk that 
262  might impact the clinical effect or safety profile of the generic 
263  combination product as compared to the RLD when the generic 
264  combination product is substituted for the RLD.  Based on the results of 
265  additional studies, FDA may or may not determine that the design 
266  difference(s) between the user interface of the proposed generic 
267  combination product and the RLD is acceptable for a proposed generic 
268  combination product. 
269   
270  2.  Studies to Evaluate Differences That May Not Be Minor as Observed in Threshold 
271  Analyses 
272   
273  If the threshold analyses determine that a design difference may not be minor, as described in 
274  section IV.B.1 of this guidance, potential applicants should first consider modifying the design of 
275  the user interface (e.g., delivery device constituent part) for the proposed generic combination 
276  product to minimize differences from the RLD.  Alternatively, FDA may request data to support 
277  that the user interface design difference(s) will not preclude approval of the generic combination 
278  product in an ANDA. Such data may be gathered in a comparative use human factors study that 
279  evaluates user performance of the critical tasks related to the external critical design attributes 
280  that are found to be different. In addition, there may be instances in which a comparative use 
281  human factors study is limited to the patient, caregiver and/or health care provider end-user 
282  group(s) that are most likely to be impacted by the differences in the design of the presentation 
283  of the proposed generic combination product compared to its RLD.  
284   
285  Comparative Use Human Factors Studies 
286   
287  Comparative use human factors studies may be warranted to provide the data to assess whether 
288  differences that may not be minor in the design of the user interface of a proposed generic 
289  combination product would preclude its approval under an ANDA. The objective of the 
290  comparative use human factors studies described in this guidance is to demonstrate that the use 
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291  error rate, associated with a change in an external critical design attribute for the proposed user 
292  interface, does not preclude approval of the proposed product in an ANDA.20  
293   
294  See Appendix A of this guidance for considerations on the design and conduct of comparative 
295  use human factors studies, when appropriate, to evaluate differences that may not be minor, as 
296  observed in threshold analyses. 
297   
298  APPENDIX A 
299   
300  Considerations for comparative use human factors studies to evaluate differences that may not be 
301  minor as observed in threshold analyses, where appropriate: 21 
302   
303  i.  Study Design Considerations 
304   
305  A comparative use human factors study, as discussed in this guidance, should be designed to 
306  provide sufficient data to confirm that the use error rate, for the critical task(s) as impacted by the 
307  differing external critical design attribute of the delivery device constituent part for the proposed 
308  generic combination product, is not worse than the corresponding use error rate for the RLD 
309  when used by patients and caregivers in representative use scenarios and use environments 
310  consistent with the labeled conditions of use. The comparative use human factors studies 
311  described in this guidance would generally be simulated-use studies22 where the participants, 
312  who are representative of the patients and caregivers, are asked to simulate the use of the 
313  proposed generic combination product without actually administering the product.  
314   
315  For the purpose of the comparative use human factors studies described here, the risks associated 
316  with the user interface are derived from errors that occur in using the delivery device constituent 
317  part of the proposed generic combination product.  FDA would generally accept a proposed 
318  generic combination product that had the same rates of error as the RLD, as demonstrated by an 
319  adequately designed comparative use human factors study or studies.  However, we also 
320  recognize that lower error rates for a proposed generic combination product compared to error 
321  rates for the RLD would not necessarily preclude a finding of therapeutic equivalence.  
322  Therefore, lower bounds on error rates are generally not necessary in comparative use human 
                                                 
20 Potential applicants should note that the objective of a comparative use human factors study differs from the 
objective of human factors validation studies. Specifically, human factors validation studies are not designed to 
assess differences in use error rates for specific external critical design attributes between two products. Therefore, 
the human factors validation report and studies, as described in FDAs guidance entitled, Applying Human Factors 
and Usability Engineering to Medical Devices, are separate and distinct from the comparative use human factors 
study described in Appendix A.   
21 Potential applicants are strongly encouraged to discuss their proposed design of a comparative use human factor 
study, including determining the value of d for the specific proposed test product, prior to conducting a comparative 
use human factors study. This can be done through pre-ANDA meeting request or controlled correspondence 
submitted to FDA. 
22 For more information on simulation techniques, see FDA draft guidance for industry Human Factors Studies and 
Related Clinical Study Considerations in Combination Product Design and Development, Section D.1. Human 
Factors Simulated Use Validation Studies.  When final, this guidance will reflect FDAs current thinking on this 
topic. 
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323  factors studies described here.  For this reason, instead of using equivalence designs, 
324  noninferiority (NI) study designs are generally appropriate in such situations.  NI tests comparing 
325  use error rates with the delivery device constituent part of a proposed generic combination 
326  product to those of the RLD are similar to usual statistical tests for a difference, but translated to 
327  account for allowable differences in error rates between the proposed generic combination 
328  product and its RLD. 
329   
330  In comparing pharmaceutical products, NI tests are often conducted to indirectly demonstrate 
331  that a proposed product is more efficacious than a placebo.23  In contrast, a comparative use 
332  human factors study with an NI design as described in this guidance is intended to help confirm 
333  one aspect of the substitutability of a proposed generic combination product for its RLD, and not 
334  for determining differences relative to a placebo. 
335   
336  Careful consideration should be given to the design of the NI study. Using the result of the 
337  threshold analyses described earlier as a guide, a risk assessment should be done to identify the 
338  external critical design attributes and their impact to critical task performance for each end-user 
339  group, use scenario, and use environment consistent with the approved conditions of use for the 
340  RLD. FDA recommends that patient and caregiver (if applicable) end-users of the RLD be 
341  considered for inclusion in the comparative use human factors study.  The risk assessment should 
342  explore risks for the various subgroups of the current patient and caregiver end-user groups and 
343  may identify an appropriate subpopulation on which to focus the comparative use human factors 
344  study.  For example, in some cases, the risk assessment may determine that only a certain patient 
345  subpopulation (or subpopulations) is likely to experience difficulty administering the product, 
346  and thus the comparative use human factors study may be most appropriately focused on the 
347  identified patient subpopulation(s). If substitution is demonstrated in a higher-risk subgroup, an 
348  applicant would generally not be expected to conduct comparative use human factors studies in 
349  lower-risk subgroups. 
350   
351  The primary endpoint for a comparative use human factors study in the context of a generic 
352  combination product will be the rates of errors observed when using the proposed generic 
353  combination product when compared to the use rates when using the RLD. In this guidance, we 
354  use the notation ER  and ER  to represent the error rates observed when using the presentation 
T R
355  associated with the proposed generic combination product (T) and that of the RLD (R), 
356  respectively. 
357   
358  The goal of a comparative use human factors study with an NI design intended to support the 
359  approval of a generic combination product is to demonstrate that for each critical task impacted 
360  by a change in critical external design attribute, ER  is no greater than ER  + d, where d is some 
T R
361  acceptable deviance above ER . In determining the margin d, the variability in ER , which is an 
R R
362  expected observation when conducting an experiment on any product, should be considered as 
363  well as the risk any difference in outcomes will pose to patients.  That is, the value of d will 
                                                 
23 For additional insight, see the draft guidance for industry Non Inferiority Clinical Trials. When final, this 
guidance will reflect FDAs current thinking on this topic. 
 
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Draft  Not for Implementation 
364  differ between products, depending on the indication(s) and the clinical consequences associated 
365  with failing to perform the critical tasks appropriately.24  
366   
367  The results of the risk assessment should be considered when determining the NI margin (d) 
368  between ER  and ER . The best choice of d enables creating a statistical test through which one 
R T
369  can demonstrate that the error rate using the proposed generic combination product will not be 
370  unacceptably greater than that of the RLD while acknowledging and allowing for the inherent 
371  variability in use error rates.25   
372   
373  An example of a simple and direct approach to an NI test comparing ER  and ER  can be 
T R
374  summarized as follows: 
375   
376    Determine the allowable margin (d) by which ER  could exceed ER . 
T R
377    Calculate the study sample size considering assumed error rates and d. 
378    Observe error rates for the critical task(s) during the experiment. 
379    Perform the statistical hypothesis test: 
380   
381    H :     ER  - ER  >d 
o 0 T R
382    H :     ER  - ER  d 
o A T R
383   
384  Rejecting the null hypothesis (H ) in favor of the alternative hypothesis (H ) supports the claim 
0 A
385  of NI as defined by d. Typically, the acceptable Type I error probability () will be set at 5%. 
386   
387  The NI test may be performed by comparing the upper bound of the appropriate level confidence 
388  interval for the difference in event rates to d.  This would be 95% if the type 1 error as stated 
389  above is set at 5%. If the upper bound is less than d, NI is demonstrated. 
390   
391  Paired designs and parallel designs are appropriate approaches to the NI studies discussed here.  
392  A paired design in which each end-user uses both presentations and acts as his or her own 
393  control will generally be applicable and more efficient with respect to resources than a parallel 
394  design.  When using a paired design, subjects should be randomly assigned to the sequence of 
395  use, such as AB or BA in order to control for the effects associated with order, such as user 
396  learning. Parallel group designs in which end-users are randomized to groups using one or the 
397  other presentation are also viable in situations where paired designs are not possible.  Sponsors 
398  are advised to propose and discuss study designs with FDA before initiating studies. 
399   
400  ii. Sample Size Considerations 
401   
402  The sample size of a comparative use human factors study should be adequate to support a 
403  demonstration that design differences of a generic combination product do not impact the 
404  products clinical effect or safety profile compared to the RLD. The sample size required to 
405  support a showing that the difference between ER  and ER is negligible depends on conditions 
R T 
                                                 
24 The acceptable margin should be decided in consultation with the FDA before the study is conducted.      
25 Note that if we were to set d=0, the condition would be tantamount to requiring that the proposed product 
presentation be superior to that of the RLD, which is not the goal for this testing. 
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Draft  Not for Implementation 
406  under which the experiment is run. The sample size of a paired design, as mentioned above, will 
407  depend on the margin (d), within-subject correlation, the underlying use error rates, desired 
408  statistical power and allowable Type I error probability.   
409   
410  Within-subject correlation can be thought of as the closeness of individuals outcomes using 
411  both devices. For example, a high level of this correlation can be interpreted to mean that a given 
412  person being able to properly use one device tends to imply that same person will have a high 
413  likelihood of being able to operate the other. This correlation is one reason paired designs often 
414  require fewer subjects than parallel designs.  
415   
416  The table below shows some examples of power simulations under assumed experimental 
417  conditions for a paired comparison of error rates. These numbers are provided as examples only, 
418  and sample sizes for specific product studies will depend on the settings under which they are 
419  conducted.  The desired sample size for each user group population or set of circumstances will 
420  be a function of the assumed use error probability, the within subject correlation, and statistical 
421  power to rule out the chosen d. In general, these sample sizes can range from 50 to 100 or more 
422  when the d =.10 and  desired statistical power ranges from 75% to 90% and use error 
423  probabilities range from 15% to 30%. Sample sizes generally will be smallest as the within 
424  subject correlation approaches one.   
425   
426  Power of Paired Design to Compare Use Error Rates under Various Assumptions. 
Power (%)  Within-subject Correlation    Use Error         Probability  Sample Size 
(%) 
85  0.90  10  45 
83  0.90  20  50 
80  0.90  30  55 
80  0.90  40  60 
80  0.70  10  55 
81  0.70  20  75 
81  0.70  30  90 
81  0.70  40  100 
80  0.50  10  70 
80  0.50  20  110 
80  0.50  30  135 
81  0.50  40  155 
427  Simulated power given selected sample sizes, assuming equal success probabilities,  a= 0:05 and d = 0:10 and 
428  using the method of  Tango [Statist. Med. 17, pp. 891-908 (1998)]. 2500 simulated clinical trials were used for 
429  each table line. 
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