Regulatory Considerations 
for Prescription Drug Use-
Related Software  
 
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  DRAFT GUIDANCE   
 
  This guidance document is being distributed for comment purposes only.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 90 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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 (CDER) Office of Medical Policy, 
CDEROMP@fda.hhs.gov, 301-796-2500 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) 
Center for Devices and Radiological Health (CDRH) 
Office of Combination Products (OCP) 
Oncology Center of Excellence (OCE) 
 
September 2023 
Labeling 
48697696dft   
Regulatory Considerations for 
Prescription Drug Use-Related 
Software 
Guidance for Industry 
 
Additional copies are available from: 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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and/or 
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Center for Biologics Evaluation and Research 
 Food and Drug Administration 
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https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-
guidances    
and/or  
Office of Policy 
Center for Devices and Radiological Health 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 66, Room 5431 
Silver Spring, MD 20993-0002 
Email: CDRH-Guidance@fda.hhs.gov 
https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/guidance-documents-
medical-devices-and-radiation-emitting-products  
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Devices and Radiological Health (CDRH) 
Office of Combination Products (OCP) 
Oncology Center of Excellence (OCE) 
 
September 2023 
Labeling 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 4 
III.  PRESCRIPTION DRUG USE-RELATED SOFTWARE FUNCTIONS AND END-
USER OUTPUT ................................................................................................................ 5 
IV.   DESCRIBING PRESCRIPTION DRUG USE-RELATED SOFTWARE 
FUNCTIONS AND END-USER OUTPUT IN THE PRESCRIBING 
INFORMATION ............................................................................................................... 6 
A.  When the Drug Sponsor Submits Evidence Demonstrating That the Use of Prescription 
Drug Use-Related Software Leads to a Clinically Meaningful Benefit ..................................... 7 
B.  When the Drug Sponsor Does Not Submit Evidence of a Clinically Meaningful Benefit 
Associated With the Use of the Prescription Drug Use-Related Software ................................ 8 
C.  Additional Considerations Relating to Review of End-User Output ........................................ 9 
APPENDIX A:  EXAMPLES OF PRESCRIPTION DRUG USE-RELATED SOFTWARE 
FUNCTIONS AND END-USER OUTPUT .............................................................................. 11 
APPENDIX B:  EXAMPLES OF DEVICE SOFTWARE FUNCTIONS THAT ARE 
REGULATED BY FDA UNDER AN APPROPRIATE CDRH MARKETING 
SUBMISSION AND WHERE THE END-USER OUTPUT IS CONSIDERED 
PROMOTIONAL LABELING ................................................................................................. 14 
GLOSSARY................................................................................................................................. 16 
 
   
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Regulatory Considerations for Prescription Drug Use-Related 
2  Software 
3  Guidance for Industry1 
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page.   
11   
12   
13   
14   
15  I.  INTRODUCTION  
16   
17  This guidance describes how FDA intends to apply its drug labeling authorities to certain 
18  software outputs that are disseminated by or on behalf of a drug sponsor2 for use with a 
19  prescription drug or a prescription drug-led, drug-device combination product (hereafter referred 
20  to as a combination product)3,4 that is assigned to the Center for Drug Evaluation and Research 
21  (CDER) or the Center for Biologics Evaluation and Research (CBER) as the lead center.  This 
22  guidance expands on and was developed in response to comments submitted in response to the 
23  Federal Register notice Prescription Drug-Use-Related Software; Establishment of a Public 
24  Docket; Request for Comments.5  
25   
 
1 This guidance has been prepared by the Office of Medical Policy 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 (CDRH), and the Office of Combination Products (OCP) at the Food and Drug Administration.  
 
2 As defined in 21 CFR 3.2(c) and (p), a sponsor is any person who submits or plans to submit an application to the 
FDA for premarket review.  Hereafter, in this guidance, the term sponsor refers to both sponsors and applicants. 
 
3  In this guidance, all references to drugs or drug products include human drug products, including biological 
products, regulated by CDER or CBER, unless otherwise specified. 
 
4 In this guidance, all references to combination products (21 CFR 3.2(e)) include products containing both a drug 
constituent part and a device constituent part.  Combination products within the scope of this guidance are those 
with a drug primary mode of action (i.e., the drug provides the greater contribution to the intended therapeutic 
effects; see 21 U.S.C. 353(g)(1)(C) and 21 CFR 3.2(k) and (m)).  Therefore, CDER or CBER will have primary 
jurisdiction for the review of these combination products and will consult with CDRH, as appropriate (see 21 U.S.C. 
353(g)(1)(C), 21 CFR 3.2(k) and (m), and staff manual guide 4101 (Combination Products, Inter-Center Consult 
Request Process)). 
 
5 See 83 FR 58574 (November 20, 2018), available at https://www.federalregister.gov/d/2018-25206.  
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
26  In this guidance, prescription drug use-related software6 generally includes software that (1) is 
27  disseminated by or on behalf of a drug sponsor and (2) produces an end-user output that 
28  supplements, explains, or is otherwise textually related to one or more of the sponsors drug 
29  products.  A software function is any distinct purpose of the software, and end-user output is any 
30  material (content) that the prescription drug use-related software presents to the end user (a 
31  patient, caregiver, or health care practitioner).  As discussed in this guidance, FDA considers 
32  end-user output a type of prescription drug labeling.7  Prescription drug labeling includes a 
33  variety of communications by sponsors about their drugs; FDA generally recognizes two broad 
34  categories of prescription drug labeling:  (1) FDA-required labeling or (2) promotional labeling.  
35  As used in this guidance, the term FDA-required labeling includes the labeling reviewed and 
36  approved by FDA as part of a new drug application (NDA), an abbreviated new drug application 
37  (ANDA), or a biologics license application (BLA), as well as supplemental applications (21 CFR 
38  314.50(c)(2) and 314.94(a)(8); 21 CFR 601.2(a)).8  The term promotional labeling is generally 
39  used to describe any labeling other than FDA-required labeling.  
40   
41  The guidance clarifies:  
42   
43    How FDA intends to apply its drug labeling authorities to end-user output of prescription 
44  drug use-related software 
45   
46    How the FDA-required labeling, in particular the Prescribing Information (PI), should 
47  describe prescription drug use-related software that: 
48   
49    Is determined to be essential for the safe and effective use of the drug product, or  
-
50   
51    Relies on data directly transferred from the device constituent part of a 
-
52  combination product (see 21 CFR 3.2(e) (defining combination product) and 21 
53  CFR 4.2 (defining constituent part))  
54   
55    When and how sponsors should submit end-user output to FDA 
56   
57  This guidance does not apply to software developers (e.g., companies or individuals) who are 
58  unaffiliated with the drug sponsor even if the developers intention is for the software to be used 
59  with one or more drugs or combination products. 
60   
 
6 Words and phrases in bold italics are defined in the Glossary. 
 
7 Section 201(m) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 321(m)) defines labeling as 
all labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers, or 
(2) accompanying such article.  The U.S. Supreme Court has explained that the language accompanying such 
article in the labeling definition is interpreted broadly to include materials that supplement, explain, or are 
otherwise textually related to the article.  No physical attachment between the materials and the article is necessary; 
rather, it is the textual relationship between the items that is significant Kordel v. United States, 355 U.S. 345, 350 
(1948).  In evaluating whether materials accompany a product, the Court also considered whether the drug product 
and the materials related to the drug product were part of an integrated distribution program (Ibid., 348).   
 
8 See also 21 CFR 314.70 and 21 CFR 601.12. 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
61  Generally, the recommendations provided in this guidance are intended to align with ongoing 
62  Agency initiatives across all product centers, including digital health initiatives at the Center for 
63  Devices and Radiological Health (CDRH).9  This guidance considers existing Agency policies 
64  for the regulation of software to ensure appropriately consistent regulation of such software and 
65  efficient, coordinated review in instances when prescription drug use-related software is 
66  reviewed by the Agency as a device.  This guidance does not alter the regulatory framework for 
67  devices or the applicability of such framework to prescription drug use-related software.  Rather, 
68  it focuses on the application of drug labeling authorities to the end-user output of prescription 
69  drug use-related software, regardless of whether such software is regulated as a device under the 
70  Federal Food, Drug, and Cosmetic Act (FD&C Act).  Consistent with FDAs policies for the 
71  regulation of device software functions, at this time, FDA intends to focus its device regulatory 
72  oversight on only those software functions that are devices and whose functionality could pose a 
73  risk to a patients safety if the device were not to function as intended.10 
74   
75  FDA anticipates that a significant proportion of prescription drug use-related software functions 
76  will be intended to provide information directly to a patient about the use of a prescription drug 
77  (e.g., helping a patient keep track of their own prescription drug use).  While the end-user output 
78  of a software function is subject to FDA drug labeling authorities, some of these software 
79  functions may meet the definition of a device11 as defined in the FD&C Act and would be 
80  subject to device requirements.  When device software functions are subject to premarket review 
81  by CDRH, review of the end-user output for potential drug labeling-related issues will be part of 
82  the CDRH review in consultation with CDER or CBER.  Under these circumstances, FDA would 
83  not expect separate submission of a Form FDA 2253.12  Examples provided throughout this 
84  guidance should not be interpreted as determinations on whether the software would be regulated 
85  as a device or FDAs intent to enforce applicable device requirements under the FD&C Act at 
86  this time.    
87   
88  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
89  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
90  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
 
9 The CDRH Digital Health Center of Excellence, which was established to empower stakeholders to advance health 
care by fostering responsible and high-quality digital health innovation, can also serve as a resource.  For further 
information and examples of such initiatives, see https://www.fda.gov/medical-devices/digital-health-center-
excellence. 
 
10 To see examples, see the guidance for industry and FDA staff Policy for Device Software Functions and Mobile 
Medical Applications (September 2013, updated September 2019 and September 2022).  We update guidances 
periodically.  For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  See also the FDA web page 
Guidances with Digital Health Content at https://www.fda.gov/medical-devices/digital-health-center-
excellence/guidances-digital-health-content.   
 
11 See section 201(h) of the FD&C Act.  The term device does not include software functions excluded pursuant to 
section 520(o) of the FD&C Act (21 U.S.C. 360(o)). 
 
12 Form FDA 2253 Transmittal of Advertisements and Promotional Labeling for Drugs and Biologics for Human 
Use. 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
91  the word should in Agency guidances means that something is suggested or recommended, but 
92  not required.  
93   
94   
95  II.  BACKGROUND 
96   
97  FDA recognizes that the use of digital health technologies13 with prescription drugs has the 
98  potential to offer new opportunities for patient care, and the Agency is working to promote 
99  responsible, risk-based oversight of digital health.  Various software functions, including those 
100  associated with mobile applications (apps), are currently available to consumers for a variety of 
101  health-related uses, such as assisting patients with tracking their own drug ingestion, allowing 
102  health care practitioners to monitor patients taking a prescription drug, or providing information 
103  on how to use a drug.  To the extent that sponsors of drug products or combination products 
104  disseminate digital health technologies for use with one or more of their drugs, FDA intends to 
105  implement its policies and exercise its authorities, including drug labeling authorities, according 
106  to an evidence-driven, risk-based framework.   
107   
108  Section 201(m) of the FD&C Act defines labeling as all labels and other written, printed, or 
109  graphic matter upon any article or any of its containers or wrappers or accompanying such 
110  article.  FDA generally recognizes two broad categories of prescription drug labeling:  (1) FDA-
111  required labeling and (2) promotional labeling.  
112   
113  For prescription drugs and prescription drug-led, drug-device combination products, FDA-
114  required labeling is the labeling that is reviewed and approved by FDA as part of an NDA, 
115  ANDA, or BLA, as well as supplemental applications (21 CFR 314.50(c)(2) and 314.94(a)(8); 
116  21 CFR 601.2(a)).  The PI is part of the FDA-required labeling for drugs described in 21 CFR 
117  201.56(b) and summarizes the essential scientific information needed for the safe and effective 
118  use of the drug.14  Sponsors must update their PI as needed to ensure that the labeling is accurate 
119  and is not false or misleading.15 
120   
121  Promotional labeling is generally any labeling other than the FDA-required labeling.  
122  Promotional labeling can include printed, audio, or visual matter descriptive of a drug that is 
123  disseminated by or on behalf of a drugs manufacturer, packer, or distributor (21 CFR 
124  202.1(l)(2)).16  Promotional labeling must be truthful and non-misleading, convey balanced 
125  information about a drugs efficacy and its risks, and reveal material facts about the drug, 
 
13 In this guidance, digital health technologies are systems that use computing platforms, connectivity, software, 
and/or sensors for health care and related uses. 
 
14 See 21 CFR 201.56(a)(1). 
 
15 See, for example, sections 301(a), 301(b), and 502(a) of the FD&C Act (21 U.S.C. 331(a), 331(b), and 352(a)) 
and 21 CFR 201.56(a)(2). 
 
16 Applicants, sponsors, and firms that choose to disseminate promotional communications, including promotional 
labeling, are subject to the postmarketing reporting requirements for submitting promotional materials to FDA 
(Form FDA 2253 submissions for prescription drugs and biologics).  See 745A(a) of the FD&C Act (21 U.S.C. 
379k-1), 21 CFR 314.81(b)(3)(i), and 21 CFR 601.12(f)(4). 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
126  including facts about the consequences that can result from use of the drug as suggested in a 
127  promotional piece.17 
128   
129   
130  III.  PRESCRIPTION DRUG USE-RELATED SOFTWARE FUNCTIONS AND END-
131  USER OUTPUT 
132   
133  As mentioned in the Introduction, prescription drug use-related software generally includes 
134  software that (1) is disseminated by or on behalf of a drug sponsor and (2) produces an end-user 
135  output that supplements, explains, or is otherwise textually related to one or more of the 
136  sponsors drug products, regardless of whether the software is a device.  When a sponsor 
137  proposes to disseminate prescription drug use-related software for use with a drug or 
138  combination product, FDA intends to analyze several factors to determine whether the end-user 
139  output should be treated as FDA-required labeling or promotional labeling and how, or if, the 
140  corresponding software function should be described in the PI.  These factors include (1) 
141  whether the prescription drug use-related software provides a function that is essential to the safe 
142  and effective use of the product, (2) whether evidence is provided to support a clinical benefit 
143  when the prescription drug use-related software is used, and (3) whether the prescription drug 
144  use-related software relies on data directly transferred from the device constituent part of a 
145  combination product. 
146   
147  To help identify the labeling regulatory considerations for prescription drug use-related software, 
148  it is important to appropriately describe the software.  As demonstrated by examples in Appendix 
149  A, prescription drug use-related software can be characterized using the following terminology 
150  that relates to the softwares design and intended use: 
151   
152    Software function:  A software function18 is any distinct purpose of the softwarein 
153  this case, prescription drug use-related software.  Prescription drug use-related software 
154  can have one or more software functions.  
155   
156    Device-connected prescription drug use-related software functions (hereafter 
-
157  referred to as device-connected software functions) rely on data directly19 
158  transferred from the device constituent part of a combination product.  
159   
160    All remaining prescription drug use-related software functions (e.g., those functions 
-
161  that rely on user-inputted data) would not be considered device-connected software 
162  functions.  
163   
 
17 See sections 502(a) and 201(n) of the FD&C Act. 
   
18 A function is any distinct purpose of the software, which could be the intended use or a subset of the intended use 
of the product, as described in the guidance for industry and FDA staff Multiple Function Device Products:  Policy 
and Considerations (July 2020).  
 
19 Directly refers to the electronic transfer of data. 
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
164    End-user output:  Any material or content presented to a patient, caregiver, or health 
165  care practitioner (end user) by the prescription drug use-related software constitutes the 
166  end-user output, and such end-user output constitutes drug labeling.  End-user output 
167  includes, for example, screen displays created by the software, whether static or dynamic, 
168  as well as sounds or audio messages created by the software. 
169   
170  When a prescription drug use-related software function receives input data from the device 
171  constituent part of a combination product (i.e., device-connected software function), FDA 
172  intends to assess whether the combination product used with the software can accurately and 
173  reliably provide the data, perform analyses, and display the end-user output (regardless of 
174  whether the end-user output is FDA-required or promotional labeling).20  Sponsors should 
175  provide information to support how the combination product used with the software will not lead 
176  to medication errors, such as inappropriate administration of extra doses.   
177   
178   
179  IV.   DESCRIBING PRESCRIPTION DRUG USE-RELATED SOFTWARE 
180  FUNCTIONS AND END-USER OUTPUT IN THE PRESCRIBING 
181  INFORMATION 
182   
183  Sponsors may propose to include information about prescription drug use-related software and 
184  its functions in the PI.21,22  One of the purposes of the PI is to allow the health care practitioner to 
185  make an informed decision about the benefits and risks of prescribing the drug.  This prescribing 
186  decision could be informed by knowledge about a products prescription drug use-related 
187  software. 
188   
189  The PI must contain a summary of the essential scientific information needed for the safe and 
190  effective use of the drug product;23 for a combination product, this includes information on the 
191  drug and the device constituent part.  Device-connected software functions are likely to require 
192  additional device features that a prescriber should be aware of when choosing the product.  
193  However, to date, the Agencys experience with software functions not considered to be device-
194  connected is that these software functions are more akin to an optional tool that is used with drug 
 
20 21 CFR 820.30(g). 
 
21 If an applicant for an ANDA proposes a generic product with prescription drug use-related software 
considerations (e.g., prescription drug use-related software accompanies the proposed generic product and/or the 
reference listed drug (RLD)), FDA will consider, among other things, the proposed labeling.  Labeling differences 
that stem from permissible differences in design between the user interface for a proposed generic product and its 
RLD may fall within the scope of permissible differences in labeling for a product approved under an ANDA.  See 
section 505(j)(2)(A)(v) of the FD&C Act (21 U.S.C. 355(j)(2)(A)(v)) and 21 CFR 314.94(a)(8)(iv).  A generic drug 
that is therapeutically equivalent to its RLD can be expected to have the same clinical effect and safety profile as the 
RLD when administered to patients under the conditions specified in the labeling.  See 21 CFR 314.3(b). 
 
22 FDA intends to evaluate a BLA proposing a biosimilar or interchangeable biological product with prescription 
drug use-related software considerations (e.g., prescription drug use-related software accompanies the proposed 
biosimilar or interchangeable biological product and/or the reference product) consistent with the requirements for 
licensure in section 351(k) of the Public Health Service Act (42 U.S.C. 262(k)). 
 
23 See 21 CFR 201.56(a)(1).  
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
195  products (e.g., a patient diary that is an app or paper journal) where patients record taking their 
196  medication on certain days of the week and might record other information, such as severity of 
197  symptoms.  Functions such as these that are not directly transferring information from a device 
198  constituent part to software, including mobile apps, should not be described in the PI unless there 
199  is an additional factor (e.g., the function is necessary for safe and effective use of the drug) that 
200  warrants including this information in the PI.  
201   
202  Typically, the PI should describe device-connected software functions and the end-user output of 
203  the device-connected software functions (e.g., in the HOW SUPPLIED/STORAGE AND 
204  HANDLING section).  However, which section(s) of the PI include this information should be 
205  determined on a case-by-case basis, depending on the function and output of the software.  For 
206  example, if a sponsor provided evidence from adequate and well-controlled studies that 
207  demonstrate that use of the prescription drug use-related software results in a meaningful 
208  improvement in a clinical outcome (e.g., compared to drug product use without the prescription 
209  drug use-related software), it might be appropriate to include such information in the CLINICAL 
210  STUDIES section of the PI.  
211   
212  FDAs assessment of the prescription drug use-related software-related information included in 
213  the PI should be consistent with the general approach used for evaluation of PI content.  FDA 
214  intends to base decisions about the placement and extent of such information in the PI on the 
215  data provided by the sponsor, the labeling requirements, and the principles outlined in this 
216  guidance.  The following sections discuss the placement and extent of information describing 
217  software functions in the PI depending on the evidence submitted by the sponsor and whether the 
218  software functions are device-connected. 
219   
220  A.  When the Drug Sponsor Submits Evidence Demonstrating That the Use of 
221  Prescription Drug Use-Related Software Leads to a Clinically Meaningful 
222  Benefit 
223   
224  For prescription drug use-related software, sponsors may propose including information 
225  specifying that use of the prescription drug use-related software with the product results in a 
226  meaningful improvement in a clinical outcome as compared to use of the product without the 
227  prescription drug use-related software (demonstrated by one or more adequate and well-
228  controlled studies).24  For example, the evidence may demonstrate that a combination product 
229  with device-connected prescription drug use-related software (e.g., a dose-tracking app that relies 
230  on data on drug use directly transferred from a device constituent part within the product) leads 
231  to a meaningful change in a clinical outcome or validated surrogate endpoint compared to using 
232  the combination product without the device-connected prescription drug use-related software.  
233  FDA generally intends to recommend including such information in the CLINICAL STUDIES 
234  section of the PI.   
235   
236  If FDA determines the evidence demonstrates a clinically meaningful benefit, the end-user 
237  output associated with the software function generally would constitute FDA-required labeling, 
238  and certain post-approval changes to such output (e.g., end-user output from a mobile app 
239  specific to the software function) should be reviewed and approved by FDA as is required for 
 
24 See 21 CFR 314.126(b). 
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240  other changes25 to FDA-required labeling.  When a sponsor is considering developing clinical 
241  evidence to support the use of prescription drug use-related software and the sponsor would like 
242  to include this information in FDA-required labeling, the sponsor should work with the 
243  appropriate FDA review division early in the development process to discuss the types of data 
244  and information that would support inclusion of the prescription drug use-related software-
245  related information in the PI. 
246   
247  B.  When the Drug Sponsor Does Not Submit Evidence of a Clinically 
248  Meaningful Benefit Associated With the Use of the Prescription Drug Use-
249  Related Software  
250   
251  In many cases, a sponsor may develop prescription drug use-related software that relies on data 
252  directly transferred from the device constituent part of a drug sponsors combination product 
253  without generating evidence showing that use of the prescription drug use-related software 
254  confers additional clinical benefit beyond that of the combination product alone.  The following 
255  examples describe software with such device-connected software functions: 
256   
257    Software disseminated by a sponsor that allows connectivity between an inhaler and an 
258  app to provide general information about inhaler use.  For example, a sponsor may 
259  develop (1) an inhaler that captures data about an inhaler event and (2) software that 
260  displays such data in a mobile app.  The sponsor should propose including a brief 
261  description in the PI about the inhalers ability to track inhaler events with a compatible 
262  mobile app (e.g., in the HOW SUPPLIED/STORAGE AND HANDLING section).26   
263   
264    Software disseminated on behalf of a sponsor that allows connectivity between an 
265  autoinjector and a mobile app to provide information to a patient.  For example, a sponsor 
266  may develop an autoinjector that captures when the autoinjector is used and transfers that 
267  information to a mobile app.  The sponsor should propose including a brief description in 
268  the PI about the autoinjectors ability to track injections with a compatible mobile app 
269  (e.g., in the HOW SUPPLIED/STORAGE AND HANDLING section). 
270   
271  Notably, in these examples, the prescription drug use-related software relies on data directly 
272  transferred from the device constituent part of the combination product.  The prescriber should 
273  be made aware of this to inform the prescribing decision and so that the prescriber can also 
274  inform the patient that such information is directly transferred during their use of the product.  
275  The presence of this information in the PI also may help to differentiate between a combination 
276  product with and without device-connected software functions.  In this situation, the PI (e.g., in 
277  the HOW SUPPLIED/STORAGE and HANDLING section) should provide a brief description 
278  of the device constituent part and the associated software function(s).  Information beyond 
279  describing the device constituent part and associated software function(s) or statements 
280  suggesting a clinical benefit should not be included in the PI.  The end-user output would be 
 
25 Applicants must notify FDA about changes to an existing NDA consistent with 21 CFR 314.70.  Certain 
prescription drug use-related software function information may be submitted in an annual report if the information 
is consistent with 21 CFR 314.70(d)(2). 
 
26 Ibid.   
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281  considered promotional labeling and should not be described in the PI (e.g., from the example 
282  above regarding tracking inhaler events, the output could be the display of how frequently the 
283  inhaler is used).   
284   
285  The end-user output from prescription drug use-related software with no device-connected 
286  software functions generally would be considered promotional labeling and would not be 
287  described in the PI, unless the prescription drug use-related software is considered essential to 
288  the safe and effective use of a product or the drug sponsor submits evidence demonstrating that 
289  the use of prescription drug use-related software leads to a clinically meaningful benefit.27 
290   
291  C.  Additional Considerations Relating to Review of End-User Output  
292   
293  End-user output and updates to end-user output from prescription drug use-related software that 
294  constitutes promotional labeling must be submitted to FDA by the applicant at the time of initial 
295  dissemination using Form FDA 2253 (Transmittal of Advertisements and Promotional Labeling 
296  for Drugs and Biologics for Human Use).28,29  Software updates that do not alter the end-user 
297  output, such as security patches, would not need to be submitted using Form FDA 2253.  
298  Furthermore, 21 CFR 202.1(j)(4) provides sponsors with a voluntary opportunity to submit 
299  promotional communications to FDA for comment before the dissemination or publication of 
300  their promotional communications.  
301   
302  In some cases, prescription drug use-related software can be submitted under a device marketing 
303  submission.  For prescription drug use-related software that is regulated by FDA under an 
304  appropriate CDRH marketing submission, any considerations raised during CDRHs premarket 
305  review related to representations about the drug within the prescription drug use-related software 
306  will be addressed within CDRHs review, and CDRH will consult with CDER or CBER.30  Any 
307  subsequent postmarket revisions made to end-user output of such software that constitutes 
308  promotional labeling and does not require a CDRH marketing submission must be submitted on 
309  Form FDA 2253 at the time of initial dissemination (see Appendix B).31  Form FDA 2253 is not 
310  a replacement for device marketing submission requirements for a device modification.32  
 
27 See 21 CFR 201.56(a)(1) and (2). 
 
28 Under FDAs regulations implementing postmarketing reporting requirements, applicants must submit specimens 
of mailing pieces and any other labeling or advertising devised for promotion of the drug product at the time of 
initial dissemination of the labeling and at the time of initial publication of the advertisement for a prescription drug 
product (21 CFR 314.81(b)(3)(i) and 21 CFR 601.12(f)(4)). 
 
29 See the guidance for industry Providing Regulatory Submissions in Electronic and Non-Electronic Format  
Promotional Labeling and Advertising Materials for Human Prescription Drugs (April 2022). 
 
30 Please note that some changes to device software functions regulated by FDA under an appropriate CDRH 
marketing submission could require a marketing submission to CDRH.  For example, changes that include new 
clinical claims or are inconsistent with the approved drug label affect the safety or effectiveness of the device (in the 
case of approved devices) (see 21 CFR 814.39(a)) or could significantly affect the safety or effectiveness of the 
device (in the case of cleared devices) (see 21 CFR 807.81(a)(3)), would require a marketing submission to CDRH. 
 
31 See footnote 28. 
 
32 See 21 CFR 814.39(a) or 21 CFR 807.81(a)(3).  
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311   
312  FDA recommends that sponsors engage with the appropriate CDER or CBER review division if 
313  they are considering developing new or significantly modified device-connected software that 
314  requires a new or modified device constituent part or component of a combination product.   
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315  APPENDIX A:  EXAMPLES OF PRESCRIPTION DRUG USE-RELATED SOFTWARE 
316  FUNCTIONS AND END-USER OUTPUT 
317   
318  Example A 
319   
320  Example A is a mobile app intended to connect1 to and receive data directly transferred from a 
321  combination product and to analyze and display data about the patients use of the combination 
322  product with their health care practitioner.  Specifically, Example As network-connected mobile 
323  app collects data (e.g., detection of tablet ingestion) from an oral tablet with an embedded sensor 
324  device system ingested by the patient, performs analysis of the ingestion data, displays the data 
325  on a screen via the mobile app, and wirelessly transfers data to a health care practitioners cloud-
326  based web-application.  The data showing ingestion over time are displayed on a mobile 
327  platforms screen using the mobile app and are available for a health care practitioners review 
328  via access to their web-application.  The end-user output relies on data that were received by the 
329  app from a sensor embedded in an oral tablet that records an ingestion event.  
330   
331  Example A can be characterized using the following terminology: 
332   
333    Software functions:  The five distinct software functions include (1) the transfer of data 
334  from an embedded sensor device to a mobile app, (2) the analysis of ingestion data by the 
335  mobile app, (3) the transfer of data from the mobile app to a cloud-based web-
336  application, (4) the display of ingestion data on the web-application, and (5) the display 
337  of ingestion data on the mobile app. 
338   
339    All five software functions are considered device-connected software functions 
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340  because they rely on data that are directly transferred from the device constituent part 
341  of a sponsors combination product. 
342   
343    End-user output:  The two end-user outputs are the mobile apps display of ingestion 
344  data and the display of ingestion data on the web-application. 
345   
346  Example B 
347   
348  Example B is a mobile app intended to prompt patients to answer specific questions pertaining to 
349  their use of a prescription drug and provides a web-application for health care practitioners to 
350  review the patients self-reported data stored on a cloud-based application.  More specifically, 
351  the Example B mobile app facilitates a patients ability to document in a standardized manner the 
352  incidence or severity of symptoms of their condition over time while taking their prescription 
353  drug and then transfers the self-reported information to a cloud-based application for their health 
354  care practitioner to review on a web-application.   
355   
 
1 In this instance, the term connect describes a wireless connection; however, a connection can be wired or wireless. 
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356  Example B can be characterized using the following terminology: 
357   
358    Software functions:  The four distinct software functions include (1) the capture of self-
359  reported patient entry of information into the mobile app, (2) the display of symptom 
360  incidence and severity data via the mobile app display screen, (3) the transfer of self-
361  reported data to a cloud-based application, and (4) the display of data on the health care 
362  practitioner web-application. 
363   
364    All four software functions are not considered device-connected software functions 
-
365  because they do not rely on data directly transferred from the device constituent part 
366  of a sponsors combination product. 
367   
368    End-user output:  The two end-user outputs are the mobile apps display of symptom 
369  incidence and severity and the web-applications display of self-reported information. 
370   
371  Example C 
372   
373  Example C is composed of a cloud-based analysis program, patient mobile app, and health care 
374  practitioner web-application.  Example C is intended to be used with a combination product that 
375  includes a prescription drug and a device constituent part with a network-connected electronic 
376  interface that automatically uploads data (e.g., information about the dose of drug delivered, time 
377  of dosing) to a cloud-based analysis program.  The cloud-based analysis program then processes 
378  and assesses the data to identify signals relating to the safe and effective use of the combination 
379  product and pushes notifications and alerts to the health care practitioner web-application.  The 
380  patient mobile app facilitates self-reporting of symptoms relating to the use of the prescription 
381  drug, displays the information via the mobile app display screen, and transfers the self-reported 
382  data to the health care practitioner web-application independently of the data collected from the 
383  device constituent part of the combination product.  The web-application aggregates the self-
384  reported symptoms data and the data collected from the device constituent part of the 
385  combination product for the health care practitioners review to manage a patients use of a 
386  prescription drug.  
387   
388  Example C can be characterized using the following terminology: 
389   
390    Software functions:  The nine distinct software functions include (1) the automatic 
391  transfer of data from the device constituent part to the cloud-based analysis program; (2) 
392  the cloud-based analysis of the data collected from the device constituent part of the 
393  combination product; (3) the transfer of notifications and alerts to a health care 
394  practitioner web-application; (4) the display of combination product data, notifications, 
395  and alerts on the web-application; (5) the display of the data collected from the device 
396  constituent part of the combination product via the patient mobile app screen display, (6) 
397  the collection of patient self-reported data on the mobile app; (7) the transfer of patient-
398  self reported data to the health care practitioner web-application; (8) the display of 
399  patient-self reported data on the health care practitioner web-application; and (9) the 
400  display of the self-reported symptom data via the patient mobile app screen display. 
401   
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402    Software functions (1), (2), (3), (4), and (5) are considered device-connected software 
-
403  functions because they rely on data that are directly transferred from the device 
404  constituent part of a sponsors combination product. 
405   
406    Software functions (6), (7), (8), and (9) are not considered device-connected software 
-
407  functions because they do not rely on data that are transferred directly from the device 
408  constituent part of a sponsors combination product. 
409   
410    End-user output:  The four end-user outputs are the web-applications display of data 
411  collected from the device constituent part of the combination product, notifications, and 
412  alerts; the web-applications display of patient self-reporting data; the patient mobile 
413  apps display of data collected from the device constituent part of the combination 
414  product; and the patient mobile apps display of self-reported symptom data.    
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415  APPENDIX B:  EXAMPLES OF DEVICE SOFTWARE FUNCTIONS THAT ARE 
416  REGULATED BY FDA UNDER AN APPROPRIATE CDRH MARKETING 
417  SUBMISSION AND WHERE THE END-USER OUTPUT IS CONSIDERED 
418  PROMOTIONAL LABELING 
419   
420  Example A:  A manufacturer of insulin develops a mobile app intended for use with their insulin 
421  product.  The software includes a dose calculator function to aid patients with mealtime insulin 
422  dose calculations.  This is a device software function that is subject to the relevant device 
423  requirements, including the submission of a new premarket notification (510(k)) to CDRH.  In 
424  addition to the dose calculator, the software output mentions the insulin product.  This output is 
425  determined to be promotional labeling for the prescription drug.  
426   
427  Any considerations raised during CDRHs premarket review related to representations about the 
428  drug will be addressed within CDRHs review in consultation with CDER (including 
429  promotional review).  The manufacturer receives clearance of the 510(k) from CDRH and 
430  disseminates the mobile app as cleared by CDRH.  The manufacturer does not need to submit a 
431  Form FDA 2253 at that time.   
432   
433  Example B:  The manufacturer of the cleared mobile app in Example 1 makes changes to the 
434  output of a device software function that is subject to the relevant device requirements, which do 
435  not affect the clinical use of the device, such as updating a logo after the device has received 
436  clearance.  Referring to the guidance for industry and FDA staff Deciding When to Submit a 
437  510(k) for a Software Change to an Existing Device (October 2017),1 the sponsor appropriately 
438  determines a 510(k) is not needed because the intended changes are not changes that could 
439  significantly affect the devices safety or effectiveness or that constitute a major change or 
440  modification in the devices intended use.  The mobile apps output must be submitted on Form 
441  FDA 2253 because it mentions the sponsors drug name (e.g., the insulin product), is drug 
442  promotional labeling, and no 510(k) is required for these changes.2  
443   
444  Example C:  After the device (the mobile app) has received clearance, the manufacturer of the 
445  cleared mobile app in Example 1 makes modifications to add a new function to the device:  a 
446  welcome video.  The welcome video includes information on the safety and effectiveness of the 
447  insulin product but does not provide information on the dose calculator.  The software displaying 
448  the welcome video function would not be an FDA-regulated device.3  In addition, the output of 
449  this software function does not impact the device that is the subject of the cleared 510(k).  As 
 
1 We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
2 Under FDAs regulations implementing postmarketing reporting requirements, applicants must submit specimens 
of mailing pieces and any other labeling or advertising devised for promotion of the drug product at the time of 
initial dissemination of the labeling and at the time of initial publication of the advertisement for a prescription drug 
product (21 CFR 314.81(b)(3)(i) and 21 CFR 601.12(f)(4)). 
 
3 The manufacturer should also assess the impact of the new non-device software function on the safety and 
effectiveness of the device functions.  See the guidance for industry and FDA staff Multiple Function Device 
Products: Policy and Considerations (July 2020).  Although this analysis might lead to submission of an additional 
510(k) for the device function, the new non-device software function would not itself be subject to review.  
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450  such, no CDRH marketing submission is needed for the addition of this welcome video to the 
451  mobile app.  However, the revised output must be submitted on Form FDA 2253 at the time of 
452  initial dissemination.4    
 
4 See footnote 2. 
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453  GLOSSARY 
454   
455  Constituent Part:  A drug, device, or biological product that is part of a combination product 
456  (21 CFR 4.2).  
457   
458  End-User Output:  Any material (content) that the prescription drug use-related software 
459  presents to the end user (a patient, caregiver, or health care practitioner). 
460   
461  Prescription Drug Use-Related Software:  Software that (1) is disseminated by or on behalf of 
462  a drug sponsor and (2) produces an end-user output that supplements, explains, or is otherwise 
463  textually related to one or more of the sponsors drug products. 
464   
465  Software Function:  Any distinct purpose of the prescription drug use-related software. 
466   
467  Device-Connected Prescription Drug Use-Related Software Functions:  Software functions 
468  that rely on data directly transferred from the device constituent part of a sponsors combination 
469  product. 
16