OCTOBER 2023

GUIDANCE
DOCUMENT
COMMUNICATIONS FROM FIRMS
TO HEALTH CARE PROVIDERS
REGARDING SCIENTIFIC
INFORMATION ON UNAPPROVED
USES OF APPROVED/CLEARED
MEDICAL PRODUCTS
QUESTIONS AND ANSWERS
 Communications From Firms to
Health Care Providers Regarding
Scientific Information on
Unapproved Uses of
Approved/Cleared Medical
Products
Questions and Answers
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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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 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) Kathleen David 301-796-1200;
(CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010;
(CDRH) Ana Loloei 301-796-8774; (CVM) Office of Surveillance and Compliance, 240-402-
7082; or (OC) Julie Finegan, 301-827-4830.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Devices and Radiological Health (CDRH)
Center for Veterinary Medicine (CVM)
Office of the Commissioner (OC)
October 2023
Procedural
Revision 2

54578796dftrev2.docs
10-19-2023
 Communications From Firms to Health Care Providers Regarding Scientific Information on
Unapproved Uses of Approved/Cleared Medical Products
Questions and Answers
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
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
and/or
Office of Communication, Outreach, and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, rm. 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances
and/or
Office of Communication and Education
CDRH-Division of Industry and Consumer Education
Center for Devices and Radiological Health
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 66, rm. 4621
Silver Spring, MD 20993-0002
Phone: 800-638-2041 or 301-796-7100
Fax: 301-847-8149, Email: DICE@fda.hhs.gov
https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/guidance-documents-medical-devices-
and-radiation-emitting-products
and/or
Policy and Regulations Staff, HFV-6
Center for Veterinary Medicine
Food and Drug Administration
7500 Standish Place, Rockville, MD 20855
Phone: 240-276-9300
https://www.fda.gov/animal-veterinary/guidance-regulations/guidance-industry
and/or
Office of Policy
Office of the Commissioner
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 32, Room 4252
Silver Spring, MD 20993-0002
Phone: 301-827-4830

U.S. Department of Health and Human Services

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Devices and Radiological Health (CDRH)
Center for Veterinary Medicine (CVM)
Office of the Commissioner (OC)

October 2023
Procedural
Revision 2
 Contains Nonbinding Recommendations
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TABLE OF CONTENTS

I. INTRODUCTION............................................................................................................. 1
II. SCOPE ............................................................................................................................... 4
III. BACKGROUND ............................................................................................................... 7
IV. QUESTIONS AND ANSWERS ..................................................................................... 10
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1 Communications From Firms to Health Care Providers Regarding

2 Scientific Information on Unapproved Uses of Approved/Cleared
3 Medical Products
4 Questions and Answers
5 Guidance for Industry 1
6
7
8 This draft guidance, when finalized, will represent the current thinking of the Food and Drug
9 Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not
10 binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the
11 applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible
12 for this guidance as listed on the title page.
13
14
15
16 I. INTRODUCTION
17
18 This revised draft guidance, when finalized, will provide FDA’s current thinking on common
19 questions regarding certain communications by firms to health care providers (HCPs) of
20 scientific information on unapproved use(s) (SIUU) of approved/cleared medical products. 2
21 Specifically, this guidance relates to firms sharing the following types of communications with
22 HCPs:
23
24 • Published scientific or medical journal articles (reprints)
25
26 • Published clinical reference resources, as follows:
27
28 - Clinical practice guidelines (CPGs)
29
30 - Scientific or medical reference texts (reference texts)
31
32 - Materials from independent clinical practice resources
33
34 • Firm-generated presentations of scientific information from an accompanying published
35 reprint

1
This guidance has been prepared by the Office of Prescription Drug Promotion in the Office of Medical Policy in
the Center for Drug Evaluation and Research in cooperation with the Center for Biologics Evaluation and Research,
the Center for Devices and Radiological Health, the Center for Veterinary Medicine, and the Office of the
Commissioner at the Food and Drug Administration.
2
The scope of the italicized terms, for the purposes of this guidance, is further explained in section II of this
guidance.

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36 These communication types are further described in Q4 of this guidance.

37
38 For the purposes of this guidance, these specific types of communications from firms to HCPs of
39 scientific information on unapproved uses of approved/cleared medical products in combination
40 with the disclosures recommended in this guidance are referred to as SIUU communications.
41 Other communications by firms are not specifically addressed by this draft guidance, and we do
42 not intend to convey any views on such communications in issuing this draft guidance.
43
44 The Federal Food, Drug, and Cosmetic Act (FD&C Act), the Public Health Service Act (PHS
45 Act), and their implementing regulations (collectively, the FDA Authorities) prohibit, among
46 other things, the introduction (or causing the introduction) into interstate commerce of a medical
47 product that fails to comply with applicable premarket requirements or is otherwise misbranded
48 or adulterated. 3 This prohibition includes introducing (or causing the introduction) into interstate
49 commerce a medical product that is intended for a use that has not been approved or cleared by
50 FDA, even if that same product is approved or cleared for a different use. These premarket
51 requirements further multiple important government interests and distributing approved/cleared
52 medical products for unapproved uses can undermine these interests.
53
54 In certain circumstances, however, HCPs may be interested in scientific information about
55 unapproved uses of approved/cleared medical products to inform clinical practice decisions for
56 the care of an individual patient. In developing this draft guidance, FDA has sought to strike a
57 careful balance between supporting HCP interest in scientific information about unapproved
58 uses of approved/cleared medical products to inform clinical practice decisions for the care of an
59 individual patient, and mitigating the potential that the government interests advanced by these
60 statutory requirements will be undermined.
61
62 In light of those goals, FDA believes it is critical that SIUU communications be truthful, non-
63 misleading, factual, and unbiased and provide all information necessary for HCPs to interpret the
64 strengths and weaknesses and validity and utility of the information in the SIUU communication.
65 In addition, any study or analysis described in a source publication that serves as the basis for an
66 SIUU communication should be scientifically sound. The study or analysis should also provide
67 information that is relevant to HCPs engaged in making clinical practice decisions for the care of
68 an individual patient (as used in this guidance, clinically relevant). 4 The manner of presentation
69 of SIUU communications is also critical to consider. This guidance provides recommendations
70 addressing all of these considerations.
71
3
See FDA Memorandum: Public Health Interests and First Amendment Considerations Related to Manufacturer
Communications Regarding Unapproved Uses of Approved or Cleared Medical Products (January 2017
Memorandum) (available at https://www.regulations.gov/document/FDA-2016-N-1149-0040). Appendix A of that
document provides an overview of legal frameworks relevant to firms’ communications regarding unapproved uses
of medical products, which include provisions directly governing the premarket review processes as well as certain
related adulteration and misbranding provisions (collectively, premarket requirements). In addition, we note that,
since FDA issued the January 2017 Memorandum, Congress has amended the relevant authorities in certain
respects, see, e.g., sections 505G, 502(a), and 502(gg) of the FD&C Act, 21 U.S.C. 355h, 352(a), and 352(gg).
4
The term clinically relevant is further explained in Q1 of this guidance.

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72 If a firm shares an SIUU communication with HCPs in a manner that is consistent with the
73 recommendations in this guidance, FDA does not intend to use such communication standing
74 alone as evidence of a new intended use. For the purposes of this guidance, we refer to this
75 enforcement policy for SIUU communications as “the enforcement policy outlined in this
76 guidance.” In addition, we note that this guidance does not describe the only circumstances in
77 which FDA does not intend to consider a firm’s dissemination of information about an
78 unapproved use of its approved/cleared medical product to be evidence of the firm’s intent that
79 the medical product be used for an unapproved use. For example, FDA has issued other
80 guidance documents that address circumstances when FDA would not consider a firm’s
81 dissemination of information regarding an unapproved use of its approved/cleared medical
82 product to be evidence of intended use. 5 We also note that nothing in this draft guidance is
83 intended to convey new policy regarding a firm’s existing obligations under the FDA Authorities
84 to update FDA-required labeling to accurately reflect what is known about the safety profile of
85 the drug, to ensure that the FDA-required labeling is not false or misleading, or for other
86 reasons. 6
87
88 This guidance includes examples to illustrate some of the recommendations and general
89 considerations for firms engaged in sharing SIUU communications with HCPs. The examples in
90 this guidance do not describe every aspect of the SIUU communication.
91
92 In developing this draft guidance, FDA considered stakeholder feedback from ongoing efforts,
93 including comments received on the guidance entitled Distributing Scientific and Medical

5
FDA issued a draft guidance with recommendations for firms on responding to unsolicited requests for information
about unapproved uses of approved medical products (see the draft guidance for industry Responding to Unsolicited
Requests for Off-Label Information About Prescription Drugs and Medical Devices (December 2011)). When final,
that guidance will represent FDA’s current thinking on this topic. We update guidances periodically. To make sure
you have the most recent version of a guidance, check the FDA guidance web page at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. FDA has also provided
recommendations for industry support of scientific or educational activities (such as Continuing Medical Education
programs) without being subject to FDA regulation (see the guidance Industry-Supported Scientific and Educational
Activities (December 1997)). In June 2018, FDA issued a final guidance that provides recommendations for firms’
communications with payors and similar entities (see the guidance Drug and Device Manufacturer Communications
With Payors, Formulary Committees, and Similar Entities – Questions and Answers (June 2018) (superseded in part
by section 502(gg) of the FD&C Act enacted in December 2022 as part of the Consolidated Appropriations Act,
2023 (Public Law No. 117-328)). Furthermore, in amending FDA’s regulations regarding evidence of intended use
in 2020–2021, FDA provided several examples of evidence that, standing alone, are not determinative of intended
use. See Proposed Rule (NPRM): Regulations Regarding “Intended Uses” (2020 Intended Use NPRM) (85 FR
59718 at 59725–26, September 23, 2020); Final Rule: Regulations Regarding “Intended Uses” (2021 Intended Use
Final Rule) (86 FR 41383, 41397, August 2, 2021). In addition, it has long been FDA policy not to consider a
firm’s presentation of truthful and non-misleading scientific information about unapproved uses at the planned
sessions and presentations at medical or scientific conferences to be evidence of intended use when the presentation
is made in non-promotional settings and not accompanied by promotional communications. (See January 2017
Memorandum (cited in footnote 3 of this guidance) at 20–21).
6
See, e.g., section 502(a) of the FD&C Act; 21 CFR 201.56(a)(2) (“labeling must be updated when new information
becomes available that causes the labeling to become inaccurate, false, or misleading”), 21 CFR 314.70 and 601.12
(concerning supplements and other changes to an approved application, including labeling), and 21 CFR 514.8(c)
(concerning supplements and other changes to an approved application for a new animal drug, including labeling).

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94 Publications on Unapproved New Uses – Recommended Practices (2014 revised draft guidance).
95 This draft guidance will supersede the 2014 revised draft guidance. Changes include a revised
96 title, a question-and-answer format, and certain changes in scope.
97
98 In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
99 Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
100 as recommendations, unless specific regulatory or statutory requirements are cited. The use of
101 the word should in Agency guidance means that something is suggested or recommended, but
102 not required.
103
104
105 II. SCOPE
106
107 As previously noted, the SIUU communications addressed by this draft guidance relate to
108 scientific information on an unapproved use of an approved/cleared medical product. This is
109 one of several important aspects of the scope of this guidance that are further described in this
110 section. We begin by describing the scope of unapproved use, approved/cleared medical
111 product, and related terms as those terms are used in this guidance:
112
113 • The term medical product refers to a medical device for human use (including one that is
114 a biological product), a human drug (including one that is a biological product), or an
115 animal drug.
116
117 • The term approved/cleared medical product 7 refers only to certain medical products that
118 may be introduced into interstate commerce for at least one use under the FDA
119 Authorities as a result of having satisfied applicable premarket requirements, as follows:
120
121 - With respect to a device, the term refers only to a device that is the subject of an
122 approved premarket application (PMA) under section 515 of the FD&C Act, a 510(k)
123 clearance, or a De Novo classification; to a device that is licensed under PHS Act
124 section 351; or to a device that is exempt from premarket notification.
125
126 - With respect to a human drug, the term refers only to a drug that is the subject of an
127 approved application under section 505 of the FD&C Act or section 351 of the PHS
128 Act, or it is marketed in compliance with section 505G of the FD&C Act.
129
130 - With respect to an animal drug, the term refers only to a drug that is the subject of an
131 approved application under section 512 of the FD&C Act; it does not include a
132 conditionally approved or indexed animal drug.

7
This term has been chosen for ease of reference within this guidance and its use in this guidance is not intended to
indicate that every medical product covered by this term is referred to as “approved” or “cleared” under the
language of the FDA Authorities. For example, nonprescription drugs that satisfy requirements for marketing under
Section 505G of the FD&C Act are not “approved” under Section 505. The use of the term “approved/cleared
medical product” also does not convey that the introduction of the medical product into interstate commerce for an
unapproved use would be legal.

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133 Note, this guidance does not apply to communications about a use that is an “unapproved
134 use of an approved product” for the purposes of section 564 of the FD&C Act and that is
135 an authorized emergency use under that section (see sections 564(a)(2)(B) and (a)(4)(E)
136 of the FD&C Act). 8
137
138 • The term approved use 9 refers to a use that is lawfully included as an indication or use in
139 the FDA-required labeling of an approved/cleared medical product (as that term is
140 defined in this guidance) as a result of having satisfied applicable premarket
141 requirements.
142
143 • The term unapproved use refers to a use that is not lawfully included as an indication or
144 use in the FDA-required labeling of an approved/cleared medical product (as that term is
145 defined in this guidance).
146
147 • The term FDA-required labeling includes, but is not necessarily limited to, the labeling
148 reviewed and approved by FDA as part of the medical product premarket review process.
149 FDA-required labeling includes, for example:
150
151 - for a prescription human drug (including a drug that is licensed as a biological
152 product), the FDA-approved prescribing information that meets the requirements of
153 21 CFR 201.100
154
155 - for a nonprescription human drug that is the subject of an approved drug application
156 under section 505 of the FD&C Act, the FDA-approved Drug Facts labeling that
157 meets the requirements of 21 CFR 201.66
158
159 - for a nonprescription drug that is not the subject of an approved drug application
160 under section 505 of the FD&C Act but instead is marketed under section 505G of the
161 FD&C Act, the labeling that must be provided in order for that drug to comply with
162 section 505G
163
164 - for an animal drug, the FDA-approved prescribing information
165
166 - for a device, the labeling approved during the review of a premarket approval
167 application or De Novo classification
168

8
In addition, this guidance does not apply to any communications about a medical product that is an “unapproved
product” as that term is used in section 564 of the FD&C Act, including communications about a use that is an
authorized emergency use under that section. (See sections 564(a)(2)(A) and (a)(4)(D) of the FD&C Act.)
9
This term is chosen for ease of reference within this guidance. We note that for certain categories of medical
products, the FDA Authorities use terms other than “approved” to describe satisfaction of applicable premarket
requirements.

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169 - for a device subject to premarket notification (510(k)) requirements or exempt from
170 premarket review, the labeling that provides indications for use and adequate
171 directions for use and other information required to appear on the label or in labeling
172
173 We next describe the meaning, as used in this guidance, of additional key terms that relate to the
174 scope of this draft guidance:
175
176 • The term firm or firms refers to the persons legally responsible for the labeling of medical
177 products, and includes applicants, sponsors, requestors, 10 manufacturers, packers, and
178 distributors of medical products, and licensees of such persons, and any persons
179 communicating on behalf of these entities.
180
181 • The term health care providers (HCPs) refers to individuals such as physicians,
182 veterinarians, dentists, physician assistants, nurse practitioners, pharmacists, or registered
183 nurses who are licensed or otherwise authorized by law to prescribe, order, administer, or
184 use medical products in a professional capacity. The recommendations in this guidance
185 are specific to communications by firms to HCPs engaged in making clinical practice
186 decisions for the care of an individual patient. 11
187
188 • The term SIUU communications refers to specific types of communications (see section I
189 of this guidance) from firms to HCPs of scientific information on unapproved uses of
190 approved/cleared medical products in combination with the disclosures recommended in
191 this guidance. We acknowledge that firms share these communications through different
192 media (e.g., paper, digital). The recommendations in this guidance apply regardless of
193 the medium of the communication. We also acknowledge that firms communicate with
194 other audiences, and we do not intend to convey any views on communications with
195 other audiences in issuing this draft guidance.
196
197 • The term source publication refers to the published reprint, CPG, reference text, or
198 material from an independent clinical practice resource that serves as the basis of a firm’s
199 SIUU communication.
200
201 This draft guidance does not cover a firm’s communications of scientific information in response
202 to unsolicited requests, which are addressed in the draft guidance for industry Responding to

10
See section 505G(q)(3) of the FD&C Act.
11
FDA has separate recommendations for a firm’s communications with the payor audience, which could include
HCPs serving on formulary committees or other entities carrying out responsibilities for medical product selection
or acquisition, formulary management, and/or coverage and reimbursement decisions on a population basis (payors).
(See the guidance for industry Drug and Device Manufacturer Communications With Payors, Formulary
Committees, and Similar Entities – Questions and Answers. See also section 502(a) and (gg) of the FD&C Act, 21
U.S.C. 352(a) and (gg).) Additionally, while HCPs may serve as researchers, a firm’s communications with HCPs
in their capacities as researchers are not within the scope of this guidance. The Agency is separately soliciting
public comment on the topic of a firm’s communications with researchers.

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203 Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices
204 (December 2011). 12
205
206
207 III. BACKGROUND
208
209 The evolution of medical product regulation in the United States has been shaped by experience
210 with the real and substantial risks to the public from uses of medical products not shown to be
211 both safe and effective. Congress developed the premarket review frameworks for medical
212 products in response to public health tragedies, realizing that (1) safety and effectiveness for
213 each intended use needs to be appropriately studied by firms and then independently evaluated
214 by FDA before a medical product is introduced into interstate commerce for that use because the
215 evidence that demonstrates effectiveness and safety for one use of a product provides no
216 guarantee of the effectiveness or safety of additional uses; and (2) exclusive reliance on post-
217 market remedies (e.g., enforcement actions for false or misleading labeling) is unacceptable as a
218 public health strategy because it does not prevent consumers from experiencing harm from
219 unsafe and/or ineffective treatments. 13
220
221 Accordingly, the FDA Authorities prohibit the introduction (or causing the introduction) into
222 interstate commerce of a medical product that fails to comply with applicable premarket
223 requirements. 14 This prohibition includes the introduction (or causing the introduction) into
224 interstate commerce of a medical product that is intended for a use that has not been approved
225 (an unapproved use), even if that same medical product is approved by FDA for a different use. 15
226
227 The intended use of a medical product can be established from, among other things, its label,
228 accompanying labeling, promotional claims, advertising, and any other relevant source. 16 For
229 example, claims or statements made by or on behalf of a firm that explicitly or implicitly

12
When final, that guidance will represent FDA’s current thinking on this topic.
13
See January 2017 Memorandum (cited in footnote 3 of this guidance) at 1, 4, and footnote 8.
14
For a more detailed discussion of many relevant statutory provisions and implementing regulations related to
premarket review of medical products, see Appendix A of the January 2017 Memorandum.
15
The concept of intended use is fundamental to the regulatory approach for medical products embodied in the FDA
Authorities. Intended use is an element in the definitions of drug and device, helping to define the scope of FDA’s
authority over medical products and subjecting the medical products to the drug or device provisions of the FDA
Authorities, as applicable. In addition, intended use may affect the appropriate premarket review pathway for a
medical product and is a separate element in establishing certain violations under the FDA Authorities. (See,
generally, 2020 Intended Use NPRM, 85 FR 59718 at 59724; 2021 Intended Use Final Rule, 86 FR 41383 at
41385.)
16
See, e.g., 2021 Intended Use Final Rule, 86 FR 41383 at 41386-41388 (citing cases).

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230 promote a medical product for a particular use may be taken into account. 17 Accordingly, a
231 firm’s communications may be relevant to establishing whether its medical product is subject to
232 the FDA Authorities and whether particular statutory or regulatory provisions apply to the
233 medical product.
234
235 The premarket requirements of the FDA Authorities advance substantial government interests
236 that include increasing the availability of medical products that have been shown to be safe and
237 effective for a particular use and in preventing direct and indirect harm from uses of medical
238 products that have not been shown to be safe and effective. Maintaining the premarket review
239 process for safety and effectiveness of each intended use advances these and other interests,
240 including protecting against fraud, misrepresentation, and bias, and preventing the diversion of
241 health care resources toward ineffective treatments.
242
243 The premarket requirements of the FDA Authorities advance further substantial government
244 interests, including motivating the development of robust scientific data on safety and
245 effectiveness; ensuring that the FDA-required labeling is accurate and informative; protecting the
246 integrity and reliability of promotional information regarding medical product uses; protecting
247 human subjects receiving experimental treatments; ensuring informed consent; maintaining
248 incentives for clinical trial participation; protecting innovation incentives, including statutory
249 grants of exclusivity; and promoting the development of products for underserved patients. 18
250
251 Generally, FDA’s premarket review process focuses on determining whether a medical product
252 is safe and effective for the specified use(s) in an identified population. However, after the
253 premarket review process is complete and a product is approved/cleared, questions may arise in
254 clinical practice relating to the use of the medical product for a particular patient.
255
256 HCPs prescribe and use approved/cleared medical products for unapproved uses when they judge
257 that the unapproved use is medically appropriate for their particular patient—whose
258 characteristics and needs may differ from the characteristics of the population(s) reflected in the
259 approved use(s). 19 This practice may be most common in patients with diseases for which there
260 is no medical product that is a proven treatment or in patients who have exhausted all approved
261 uses of medical products. 20 In such instances, HCPs may be interested in communications about
262 unapproved uses of approved/cleared medical products. However, especially because such
263 communications may be used to inform clinical practice decisions for the care of an individual
264 patient, it is critical that these communications be truthful, non-misleading, factual, and unbiased
265 and include all information necessary for HCPs to interpret the strengths and weaknesses and

17
See, e.g., 21 CFR 201.128 (drugs); 21 CFR 801.4 (devices); 2020 Intended Uses NPRM, 85 FR 59718 at 59721;
2021 Intended Use Final Rule, 86 FR 41383 at 41386–41397, footnote 3.
18
See January 2017 Memorandum at 3–16.
19
The extra-label use of approved veterinary or human drugs in animals is permitted only if it complies with section
512(a)(4) and (a)(5) of the FD&C Act, 21 U.S.C. 360b(a)(4) and 360b(a)(5), and 21 CFR part 530.
20
See January 2017 Memorandum at 17.

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266 validity and utility of the information about the unapproved use. It is also critical that such
267 communications be based on studies and analyses that are scientifically sound and provide
268 clinically relevant information. In contrast, patient harm could result from communicating
269 information about unapproved uses of approved/cleared medical products to HCPs who are
270 engaged in prescribing or administering those medical products to an individual patient if that
271 information is false, misleading, biased, or not based on studies and analyses that are
272 scientifically sound and able to provide clinically relevant information. 21 And where firms
273 choose to use persuasive marketing techniques (as that term is described below) in
274 communications regarding unapproved uses, this suggests an improper intent to market the
275 relevant products for unapproved uses.
276
277 Cognizant of all these factors, FDA, in implementing the premarket requirements of the FDA
278 Authorities and, more specifically, in developing this draft guidance, has sought to strike a
279 careful balance, supporting HCP interest in scientific information about unapproved uses of
280 approved/cleared medical products to inform clinical practice decisions for the care of an
281 individual patient, but without undermining the other government interests described elsewhere
282 in this guidance document. This includes the government interest in incentivizing the
283 development of and satisfaction of applicable premarket requirements for medical products,
284 which reduces the need to rely on unapproved use(s), and in protecting patients from medical
285 product uses that have not been shown to be safe and effective.
286
287 This draft guidance represents a continuation of FDA’s ongoing efforts to consider, develop, and
288 refine its policies and recommendations relating to communications by firms about unapproved
289 uses of their approved/cleared medical products. In 2009, FDA issued the guidance for industry
290 Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or
291 Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or
292 Cleared Medical Devices to provide guidance to firms on distributing “journal articles” and
293 “scientific or medical reference publications.” Then, FDA issued the 2014 revised draft
294 guidance to clarify the Agency’s position on a firm’s dissemination of scientific or medical
295 reference texts and CPGs that include information on unapproved uses of the firm’s medical
296 products and to provide additional explanation on these topics.
297
298 In 2016, FDA held a public hearing and requested comments on the topic of “Manufacturer
299 Communications Regarding Unapproved Uses of Approved or Cleared Medical Products” (2016
300 public hearing) (81 FR 60299, September 1, 2016). In response to comments at the hearing,
301 FDA developed and placed in the docket (FDA-2016-N-1149-0040) a memorandum to provide
302 additional background on the issues it is considering as part of its review of its rules and policies
303 relating to communications by firms regarding unapproved uses of approved or cleared medical
304 products. (See FDA Memorandum: Public Health Interests and First Amendment
305 Considerations Related to Manufacturer Communications Regarding Unapproved Uses of

21
As an example, FDA generally does not consider preliminary scientific data to be clinically relevant because
“[w]hen what exists is preliminary scientific data, the ultimate relevance and utility of that data is often unknown.
That is, one might truthfully summarize the data generated by a preliminary study without being able to determine
whether any inferences or conclusions drawn from the data would ultimately be shown to be correct . . . .” (See
January 2017 Memorandum (cited in footnote 3 of this guidance) at 7.)

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306 Approved or Cleared Medical Products (January 2017 Memorandum), cited at footnote 3 of this
307 guidance; see also 82 FR 6367, January 19, 2017 (announcing the addition of the January 2017
308 Memorandum to the 2016 public hearing docket and extending the comment period).) FDA also
309 revised its intended use regulations, publishing the final rule in 2021. See 2021 Intended Use
310 Final Rule, 86 FR 41383 (August 2, 2021), codified at 21 CFR 201.128 and 801.4. The
311 preambles to the proposed and final rules address some related topics. In addition, the guidance
312 for industry Drug and Device Manufacturer Communications With Payors, Formulary
313 Committees, and Similar Entities – Questions and Answers (June 2018) and subsequent
314 legislation address related topics (see footnote 5 of this guidance).
315
316
317 IV. QUESTIONS AND ANSWERS
318
319 Q1. What should firms consider when determining whether a source publication is
320 appropriate to serve as the basis for an SIUU communication?
321
322 Source publications that serve as the basis for SIUU communications should describe studies or
323 analyses that are scientifically sound and provide clinically relevant information. To be
324 scientifically sound, the studies or analyses, at a minimum, should meet generally accepted
325 design and other methodological standards for the particular type of study or analysis performed,
326 taking into account established scientific principles and existing scientific knowledge. 22 To be
327 clinically relevant, the studies or analyses, in addition to being scientifically sound, should
328 provide information that is pertinent to HCPs engaged in making clinical practice decisions for
329 the care of an individual patient.
330
331 For human and animal drugs, randomized, double-blind, concurrently controlled superiority
332 trials are usually regarded as the most rigorous design and informative to clinical practice, and
333 therefore the most likely to provide scientifically sound and clinically relevant information;
334 however, other well-designed and well-conducted trials are also able to generate scientifically
335 sound and clinically relevant information. For medical devices, the types of studies, information,
336 and analyses that are considered valid scientific evidence are described in 21 CFR 860.7 and may
337 include well-controlled investigations, partially controlled studies, studies and objective trials
338 without matched controls, well-documented case histories conducted by qualified experts, and
339 reports of significant human experience with a marketed device. For medical devices, these
340 types of studies, information, and analyses are most likely to be scientifically sound and
341 clinically relevant.
342
343 Real-world data and associated real-world evidence about medical products may be scientifically
344 sound and clinically relevant depending on the characteristics of the data and the nature of the

22
Statistical robustness is generally necessary, but not sufficient, to determine if a study or analysis is appropriate
for an SIUU communication. Although statistical robustness factors into the rigor of the design and methodology,
statistical robustness does not assure that the study or analysis relates to outcomes of clinical relevance to HCPs.

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345 analyses. 23 Other types of well-designed and well-conducted studies and analyses can also be
346 informative to HCPs, but any study or analysis described in a source publication should be
347 evaluated in light of its limitations to determine whether the study or analysis is scientifically
348 sound and provides clinically relevant information.
349
350 Certain studies without an adequate comparison or control group, isolated case reports about
351 medical products, and other reports that lack enough detail to permit scientific evaluation would
352 generally not be scientifically sound or clinically relevant and, therefore, use of such reports
353 alone as the basis for an SIUU communication would not be consistent with the enforcement
354 policy outlined in this guidance.
355
356 Similarly, communications that distort studies as well as communications based on publications
357 that distort studies 24 or include fraudulent data would not be consistent with the enforcement
358 policy outlined in this guidance and may also violate provisions of the FDA Authorities, such as
359 section 502(a) of the FD&C Act. In situations where flaws of a study or analysis render the data
360 unreliable, 25 such study or analysis should also be excluded from serving as the basis of an SIUU
361 communication as even full disclosure of the limitations of such study or analysis would not
362 permit interpretation of results or attribution of the results to an effect of the medical product.
363
364 Of note, scientific data generated in early stages of medical product development can produce
365 results that are not borne out in later studies, as demonstrated by the failure of some clinical
366 studies 26 to support the use of a medical product for the treatment of a disease or condition for

23
For example, analyses of real-world data should be prespecified, protocols and statistical analysis plans should be
finalized prior to conducting the prespecified analyses, and data integrity should be carefully monitored and
maintained. For more information on considerations relevant to real-world data and real-world evidence, see, for
example, the guidance for industry and Food and Drug Administration staff Use of Real-World Evidence to Support
Regulatory Decision-Making for Medical Devices (August 2017) and the guidance for industry Considerations for
the Use of Real-World Data and Real-World Evidence To Support Regulatory Decision-Making for Drug and
Biological Products (August 2023).
24
Studies may be distorted by, for example, inaccurately describing or interpreting results.
25
For example, studies or analyses that fail to control for confounding factors, fail to enroll the appropriate spectrum
of patients, or fail to include clear definitions of study endpoints are unlikely to produce reliable results.
Additionally, studies or analyses based on, for example, poorly extracted data or data that is transferred with errors,
is not source verified, or is inaccurately collected and documented would not provide reliable information. For
further discussion of common weaknesses in study design, see, e.g., Appendix D, Common Weaknesses in Study
Designs. Institute of Medicine (US) and National Research Council (US) Committee on New Approaches to Early
Detection and Diagnosis of Breast Cancer; Joy JE, Penhoet EE, Petitti DB, editors. (2005). Saving Women's Lives:
Strategies for Improving Breast Cancer Detection and Diagnosis. Washington (DC): National Academies Press
(US). Available from https://www.ncbi.nlm.nih.gov/books/NBK22323/.
26
For example, the failure rate during the process of new prescription drug development exceeds 95 percent (see
National Center for Advancing Translational Sciences. About New Therapeutic Uses. U.S. Department of Health
and Human Services, National Institutes of Health. Retrieved August 14, 2023, from
https://ncats.nih.gov/ntu/about). Similarly, medical devices have a very high failure rate in their first prototype tests,
with a reported 90 percent of medical devices failing in their first prototype tests (see Intertek (2010). The Top 10

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367 which the medical product initially appeared promising. 27,28 Such scientific data generated in
368 early stages of product development are unlikely to be sufficiently reliable by themselves to
369 allow for a determination of clinical relevance. As a result, a communication based on this type
370 of data alone is unlikely to be within the scope of the enforcement policy outlined in this
371 guidance.
372
373 Finally, it would not be consistent with the enforcement policy outlined in this guidance to
374 continue to share an SIUU communication that is based on a study or analysis that is no longer
375 clinically relevant. A study or analysis may no longer be clinically relevant because, for
376 example, subsequent research has established that the findings from the study or analysis are not
377 reliable. Accordingly, when a firm has shared on the internet an SIUU communication that is
378 based on a study or analysis that is later determined to no longer be clinically relevant and the
379 firm has the ability to remove their SIUU communication, we recommend the firm remove their
380 SIUU communication. 29
381
382 Q2. What information should firms include as part of SIUU communications?
383
384 It is critical that SIUU communications be truthful, non-misleading, factual, and unbiased and
385 provide all information necessary for HCPs to interpret the strengths and weaknesses and
386 validity and utility of the information in the SIUU communication. Accordingly, FDA

Reasons Medical Devices Fail Product Certification Testing the First Time. Available at
https://www.intertek.com/medical/10-reasons-medical-devices-fail-testing-paper/).
27
One report evaluated 22 case studies of drugs, vaccines, and medical devices from 1999 to 2017 in which
promising phase 2 clinical trial results were not confirmed in phase 3 clinical trials. Phase 3 studies did not confirm
phase 2 findings of effectiveness in 14 cases, safety in 1 case, and both safety and effectiveness in 7 cases. These
unexpected results could occur even when the phase 2 study was relatively large and even when the phase 2 trials
assessed clinical outcomes. In two cases, the phase 3 studies showed that the experimental product increased the
frequency of the problem it was intended to prevent (see U.S. Food and Drug Administration Report. (2017). 22
Case Studies Where Phase 2 and Phase 3 Trials Had Divergent Results. Available at
https://www.fda.gov/media/102332/download).
28
Further study is often needed to demonstrate safety and effectiveness for an intended use because the ultimate
relevance and utility of scientific data generated in early stages of product development often cannot be ascertained
from that early-stage data alone. See, e.g., Echt DS, Liebson PR, Mitchell LB et al. (1991). Mortality and Morbidity
in Patients Receiving Encainide, Flecainide, or Placebo: The Cardiac Arrhythmia Suppression Trial. New Eng. J.
Med., 324(12): 781-88. The Cardiac Arrhythmia Suppression Trial (CAST) was a well-controlled study that
examined the widely held belief (in the absence of well-controlled studies showing this to be true) that treating
minor rhythm abnormalities (frequent ventricular premature beats) with anti-arrhythmics after an acute myocardial
infarction would improve survival. To test this belief, the National Institutes of Health conducted the CAST study
which demonstrated that, although the drugs did indeed treat minor rhythm abnormalities, the patients who took
those drugs had a 2 ½ fold increase in mortality. See also National Academy of Sciences (1969), Drug Efficacy
Study: Final Report to the Commissioner of Food and Drugs, Food and Drug Administration, which found that
approximately one-third of all pre-1962 marketed drugs did not have a single effective use.
29
While it would not be consistent with the enforcement policy outlined in this guidance for a firm to continue to
share a communication based solely on a study or analysis that is no longer clinically relevant, a communication that
includes some discussion of or reference to a source publication containing historical information, such as to
describe the historical context and evolution of clinical knowledge in a subject area, would be consistent with the
recommendations of this guidance if it makes clear that the historical information is no longer clinically relevant.

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387 recommends that firms include all of the following information as part of SIUU
388 communications: 30
389
390 • A statement that the unapproved use(s) of the medical product has not been approved by
391 FDA and that the safety and effectiveness of the medical product for the unapproved
392 use(s) has not been established

393 - For example, a statement that “[Medical Product X] has not been approved by FDA
394 for use in [Condition Y] and the safety and effectiveness of [Medical Product X] for
395 [Condition Y] has not been established.”

396 • A statement disclosing the FDA-approved use(s) of the medical product, including any
397 limitations of use specified in the FDA-required labeling

398 • A statement disclosing any limitations, restrictions, cautions, or warnings described in the
399 FDA-required labeling about the unapproved use(s)

400 • A copy of the most current FDA-required labeling (or a mechanism for obtaining this
401 labeling, as appropriate)

402 • A statement describing any contraindication(s) in the FDA-required labeling for the
403 medical product

404 • A statement describing any serious, life-threatening, or fatal risks posed by the medical
405 product that are in the FDA-required labeling for the medical product or known by the
406 firm and that are relevant to the unapproved use(s) 31

407 • A statement identifying any authors, editors, or other contributors to publication(s)

408 included in the SIUU communication who were employees of or consultants to or who
409 received compensation from the firm 32 at the time of writing, editing, or contributing to
410 the publication, to the extent a firm acting reasonably would know of such relationship

See item 2 in Q4 of this guidance for information on limited exceptions to the recommendations in this section
30

when SIUU communications in the form of certain unabridged CPGs or reference texts in their entirety are shared.
31
If a risk evaluation and mitigation strategy (REMS) has been established under 21 U.S.C. 355-1, the statement
should disclose that fact and should describe the goal(s) of the REMS.
32
Systematic reviews of studies funded and/or conducted by the firm or its representatives demonstrate bias
favoring a firm’s medical product. See, e.g., Lexchin, J., Bero, L. A., Djulbegovic, B., & Clark, O. (2003).
Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ (Clinical research
ed.), 326(7400), 1167–1170. https://doi.org/10.1136/bmj.326.7400.1167 (reviewing 30 studies finding that
“[s]ystematic bias favours products which are made by the company funding the research.”); Lundh, A., Lexchin, J.,
Mintzes, B., Schroll, J. B., & Bero, L. (2017). Industry sponsorship and research outcome. The Cochrane database
of systematic reviews, 2(2), MR000033. https://doi.org/10.1002/14651858.MR000033.pub3 (reviewing 48 studies

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411 • In the case of an SIUU communication that is based on a source publication that is
412 primarily focused on a particular scientific study or studies, 33 for each such study 34 where
413 the following information is not included in the publication, provide a description of: 35

414 - All material aspects of study design, methodology, and results

415 - All material limitations related to the study design, methodology, and results 36

416 - Any conclusions from other relevant studies, when applicable, that are contrary to or
417 cast doubt on the results shared, including citations for any such studies

418 • The publication date of any referenced or included publication(s) (if not specified in the
419 publication or citation)

420 Q3. What presentational considerations should firms take into account for SIUU
421 communications?
422
423 As noted above, the premarket requirements of the FDA Authorities further multiple important
424 government interests. In developing this draft guidance, FDA has sought to strike a careful
425 balance between supporting HCP interest in scientific information about unapproved uses of
426 approved/cleared medical products to inform clinical practice decisions for the care of an
427 individual patient, and mitigating the potential that the government interests advanced by these
428 statutory requirements will be undermined. There are several presentational considerations that
429 can help achieve the appropriate balance, in part by helping to ensure that SIUU communications
430 are conveyed in a manner that enhances and does not interfere with HCP understanding and
431 evaluation of the underlying scientific information, including its limitations. In addition to the
432 information being truthful and non-misleading, it is critical that the presentation is factual and
433 unbiased. To that end, FDA recommends the following:
434
435 1. SIUU communications should clearly and prominently present all disclosures
436 recommended in this guidance.
437
438 All recommended disclosures should be clearly and prominently presented. This helps to ensure
439 that HCPs have the information necessary to interpret the scientific information and the SIUU

showing that “[s]ponsorship of drug and device studies by the manufacturing company leads to more favorable
results and conclusions than sponsorship by other sources”).
33
FDA anticipates that most SIUU communications of CPGs or reference texts would not be subject to this
recommendation because they are not focused primarily on a specific study or studies.
34
For example, if an SIUU communication includes a reprint that describes two studies in detail, this
recommendation applies to each study, even if the SIUU communication does not address them in identical detail.
35
See item 3 in Q4 for specific recommendations for the presentation of such material information in firm-generated
presentations of scientific information from an accompanying reprint.
36
See Q1 for further discussion of limitations of studies and analyses.

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440 communication as a whole. Factors FDA considers when determining whether information is
441 clearly and prominently presented may include type size, font style, layout, contrast, graphic
442 design, headlines, spacing, volume, articulation, pace, and any other techniques to achieve
443 emphasis or notice. 37 For SIUU communications that have both audio and visual components, to
444 help HCPs notice and comprehend the information, FDA recommends that disclosures be
445 presented in both the audio and in text at the same time using the same words (key terms and
446 phrases or a full transcript). 38 Note, for SIUU communications that have both audio and visual
447 components, it would be consistent with the disclosure recommendations of this guidance for
448 both the audio and visual components to include a statement about how to obtain a copy of the
449 most current FDA-required labeling for the medical product that is the subject of the SIUU
450 communication.
451
452 2. SIUU communications should not use persuasive marketing techniques.
453
454 When communicating about the approved uses of their medical products, firms often use
455 marketing techniques to influence the views of their audience. Some of these marketing
456 techniques influence use of the products based on elements other than the scientific content of
457 the communication (as used herein, “persuasive marketing techniques”). Examples of these
458 persuasive marketing techniques include the use of celebrity endorsements, premium offers, and
459 gifts. 39 In the context of a firm’s communications to HCPs in support of an unapproved use, a
460 firm’s choice to use persuasive marketing techniques suggests an effort to convince the HCP to
461 prescribe or use the product for the unapproved use, and FDA therefore considers such
462 communications to be evidence of an intended use of the product for purposes of relevant
463 requirements of the FDA Authorities. 40 And because such communications attempt to influence
464 HCPs to reach positive conclusions about the unapproved use based on elements other than the
465 scientific content, such communications are outside the scope of the enforcement policy outlined
466 in this guidance.
467

37
FDA assesses disclosure clarity and prominence on a case-by-case basis.
38
For example, if a firm posts a reprint on a web page and also includes a firm-generated video presentation of
scientific information from the accompanying reprint on that web page (see item 3 in Q4), the firm should present
recommended disclosures in the video in both the audio and in text at the same time, using the same words.
39
See, e.g., Datta, A., & Dave, D. (2017). Effects of physician‐directed pharmaceutical promotion on prescription
behaviors: longitudinal evidence. Health economics, 26(4), 450-468; Meffert, J. (2009). Key opinion leaders: where
they come from and how that affects the drugs you prescribe. Dermatol Ther, 22, 262-268; Naylor, C., Chen, E.,
Strauss, B. (1992). Measured enthusiasm: does the method of reporting trial results alter perceptions of therapeutic
effectiveness? Ann Intern Med. 117(11): 916-21; Price, S., O’Donoghue, A., Rizzo, L., Sapru, S., Aikin, K. (2021).
What influences healthcare providers’ prescribing decisions? Results from a national survey. Research in Social and
Administrative Pharmacy, 17(10), 1770-1779; Sismondo, S. (2015). How to make opinion leaders and influence
people. CMAJ: Canadian Medical Association journal = journal de l'Association medicale canadienne, 187(10),
759–760.
40
See 2021 Intended Use Final Rule, 86 FR at 41388 (“Courts have repeatedly held that . . . promotional claims are
one source of evidence of intended use”).

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468 Because an SIUU communication may be used to inform clinical practice decisions about
469 whether to use an approved/cleared medical product for an unapproved use in an individual
470 patient, it is also important that the communication be presented in a manner that is unlikely to
471 lead HCPs to base those decisions on conclusions about the safety or effectiveness of the
472 unapproved use that are not in alignment with, or that go beyond what is justified by, the
473 underlying scientific information. 41 Research demonstrates that promotional communications
474 about medical products often employ marketing techniques that are effective at influencing
475 attitudes and behaviors of HCPs, 42 and that how information is presented can impact HCP
476 impressions of that information. 43 These marketing techniques can influence attitudes and
477 behavior, independent of the quality of the information, even among highly educated medical
478 professionals. 44

41
See, e.g., Eguale, T., Buckeridge, D. L., Verma, A., Winslade, N. E., Benedetti, A., Hanley, J. A., & Tamblyn, R.
(2016). Association of Off-label Drug Use and Adverse Drug Events in an Adult Population. JAMA internal
medicine, 176(1), 55–63; Radley, D. C., Finkelstein, S. N., & Stafford, R. S. (2006). Off-label prescribing among
office-based physicians. Archives of internal medicine, 166(9), 1021–1026. See also the January 2017 Memorandum
at 13 (“Marketing activities and communications regarding the safety and effectiveness of a medical product for a
particular use that are not properly supported by scientific evidence may thus create a false or misleading impression
about the safety and efficacy of the medical product for that use, which can lead to prescribing or use decisions that
harm patients. Examples of some marketing activities that caused such harm are described in Appendix C.”).

42
See e.g., Austad, K. E., Avorn, J., & Kesselheim, A. S. (2011). Medical students’ exposure to and attitudes about
the pharmaceutical industry: a systematic review. PLoS Med, 8(5), e1001037; Austad, K. E., Avorn, J., Franklin, J.
M., Campbell, E. G., & Kesselheim, A. S. (2014). Association of Marketing Interactions With Medical Trainees’
Knowledge About Evidence-Based Prescribing: Results From a National Survey. JAMA Internal Medicine,
174(8):1283-1290; Avorn, J., Chen, M., & Hartley, R. (1982). Scientific versus commercial sources of influence on
the prescribing behavior of physicians. The American Journal of Medicine, 73(1), 4-8; and Spurling, G. K.,
Mansfield, P. R., Montgomery, B. D., Lexchin, J., Doust, J., Othman, N., & Vitry, A. I. (2010). Information from
pharmaceutical companies and the quality, quantity, and cost of physicians' prescribing: A systematic review. PLoS
Med, 7(10), e1000352.
43
See, e.g., Bobbio, M., Demichelis, B., & Giustetto, G. (1994). Completeness of reporting trial results: effect on
physicians' willingness to prescribe. Lancet, 343(8907), 1209–1211; Bucher, H. C., Weinbacher, M., & Gyr, K.
(1994). Influence of method of reporting study results on decision of physicians to prescribe drugs to lower
cholesterol concentration. BMJ (Clinical research ed.), 309(6957), 761–764; Kahwati, L., Carmody, D., Berkman,
N., Sullivan, H. W., Aikin, K. J., & DeFrank, J. (2017). Prescribers' knowledge and skills for interpreting research
results: a systematic review. The Journal of Continuing Education in the Health Professions, 37(2), 129–136;
Marcatto, F., Rolison, J.J., & Ferrante, D. (2013). Communicating clinical trial outcomes: effects of presentation
method on physicians’ evaluations of new treatments. Judgment and Decision Making, 8(1), 29-33.
44
See e.g., Chaiken, S., Liberman, A., & Eagly, A.E. (1980). Heuristic and systematic information processing within
and beyond the persuasion context. In Unintended Thought (ed. J.E. Uleman). New York: Guilford Press, 212-252;
DeJong, C., Aguilar, T., Tseng, C-W., Lin, GA., Boscardin, WJ., Dudley, RA. (2016). Pharmaceutical industry–
sponsored meals and physician prescribing patterns for Medicare beneficiaries. JAMA Intern Med., 176(8):1114-
1122; Hadland, SE., Cerdá, M., Li, Y., Krieger, MS., Marshall, BDL. (2018). Association of pharmaceutical
industry marketing of opioid products to physicians with subsequent opioid prescribing. JAMA Intern Med.,
178(6):861-863; Inoue, K., Tsugawa, Y., Mangione, CM., Duru, OK. (2021). Association between industry
payments and prescriptions of long-acting insulin: An observational study with propensity score Matching. PloS
Med, 18(6): e1003645; Petty, R. E. & Cacioppo, J. T. (1986); Communication and Persuasion: Central and
Peripheral Routes to Attitude Change. New York: Springer-Verlag; Sah, S., & Fugh-Berman, A. (2013). Physicians

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479 As explained above, this guidance strives to balance (1) HCP interest in scientific information
480 about unapproved uses of approved/cleared medical products to inform clinical practice
481 decisions for the care of an individual patient and (2) the various government interests in
482 incentivizing the development of and satisfaction of applicable premarket requirements for
483 medical products. A firm’s use of persuasive marketing techniques in communications that
484 support unapproved uses does not appropriately serve the purpose of informing clinical practice
485 decisions for individual patient care and therefore does not counterbalance the important
486 government interests discussed above. For these reasons, a firm’s communications that support
487 unapproved uses and use persuasive marketing techniques are outside the scope of the
488 enforcement policy outlined in this guidance.
489
490 3. SIUU communications should be separate and distinct from promotional communications
491 about approved uses of medical products.
492
493 As set forth in this guidance, the medical products that are discussed in SIUU communications
494 are approved/cleared for at least one use, and, as such, it is likely that firms regularly disseminate
495 promotional communications for those approved uses. However, including information about
496 unapproved uses in those promotional communications has the potential to undermine the
497 government interests in the premarket requirements of the FDA Authorities. In this guidance,
498 FDA has sought to strike a careful balance, supporting HCPs interested in scientific information
499 about unapproved uses of approved/cleared medical products to inform clinical practice
500 decisions for the care of an individual patient, while mitigating the potential that the government
501 interests advanced by these statutory requirements will be undermined. To preserve this balance
502 and to avoid misleading HCPs, we strongly recommend that firms avoid sharing an SIUU
503 communication for a medical product together with a promotional communication for that
504 product for its approved use(s) because combining these two types of communications is more
505 likely to lead to conflation of the approved use and unapproved use information. 45 This
506 conflation may lead HCPs to conclude that the firm’s medical product has been demonstrated to
507 be safe and effective for all presented uses, including the unapproved use(s), or to conclude that
508 all presented uses of the medical product are uses for which it may be approved/cleared.
509
510 Additionally, FDA recommends that firms use dedicated vehicles, channels, and venues for
511 sharing SIUU communications that are separate from the vehicles, channels, and venues used for
512 promotional communications about approved uses of medical products to reduce the risk of

under the influence: social psychology and industry marketing strategies. The Journal of law, medicine & ethics: a
journal of the American Society of Law, Medicine & Ethics, 41(3), 665–672; Yeh, JS., Franklin, JM., Avorn, J.,
Landon, J., Kesselheim, AS. (2016). Association of industry payments to physicians with the prescribing of brand-
name statins in Massachusetts. JAMA Intern Med., 176(6):763-768.
45
Research indicates that combining multiple communications can prompt conflation of the messages conveyed by
each communication. See, e.g., Sullivan, H. W., O’Donoghue, A. C., Rupert, D. J., Willoughby, J. F., Amoozegar,
J. B., & Aikin, K. J. (2016). Are Disease Awareness Links on Prescription Drug Websites Misleading? A
Randomized Study. Journal of health communication, 21(11), 1198–1207; Aikin, K. J., Sullivan, H. W., & Betts, K.
R. (2016). Disease Information in Direct-to-Consumer Prescription Drug Print Ads. Journal of health
communication, 21(2), 228–239.

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513 HCPs conflating the approved and unapproved use information. In cases where there is only one
514 vehicle, venue, or channel available for the sharing of information, a firm should ensure that
515 SIUU communications are clearly identified and distinct from promotional communications
516 about approved uses.
517
518 For example, firms may be interested in sharing information about both the approved and
519 unapproved uses of their medical products online through websites. In these cases, FDA
520 recommends that SIUU communications be on a separate web page from the web page that hosts
521 promotional communications about the approved uses of the medical product. FDA also
522 recommends that firms not include direct links from web pages that host promotional
523 communications about approved uses to webpages that host SIUU communications. Similarly,
524 FDA recommends that email messages used to share SIUU communications be separate and
525 distinct from email messages used to share promotional communications about approved uses of
526 the medical product.
527
528 Medical or scientific conferences also represent a venue where information about both approved
529 and unapproved uses of medical products is shared. Although conference organizers generally
530 select the content to be shared for the planned sessions and presentations at the conference (e.g.,
531 poster sessions), 46 these same conferences also offer venues (e.g., booths in commercial exhibit
532 halls) where firms can independently select and share information with conference attendees,
533 which could include both promotional communications about approved uses of medical products
534 and SIUU communications. When sharing information in commercial exhibit halls and similar
535 venues where programming is not selected and determined by the conference organizers, firms
536 should ensure that SIUU communications are clearly identified and distinct from promotional
537 communications about approved uses. 47 For example, in commercial exhibit halls, FDA strongly
538 recommends that firms divide booth space to allow for a dedicated space where SIUU
539 communications can be shared, separate and distinct from promotional communications about
540 approved uses.
541
542 4. SIUU communications should be shared through media and via platforms that enable
543 firms to implement the recommendations in this guidance.
544
545 Different media types and platforms are available to firms interested in sharing SIUU
546 communications, and each medium and platform may prompt unique presentational challenges
547 and considerations. For example, certain online platforms may impose character-space

46
FDA does not consider a firm’s presentation of truthful and non-misleading scientific information about
unapproved uses in the planned sessions and presentations selected by conference organizers at medical or scientific
conferences to be evidence of intended use when the presentation is made in non-promotional settings and not
accompanied by promotional communications.
47
This recommendation applies even to those SIUU communications that include the same substantive content as
presented in planned sessions at the conference. Courts have recognized that a different level of First Amendment
scrutiny can apply to the same speech depending on how the speech is communicated. See, e.g., Washington Legal
Foundation v. Friedman, 13 F. Supp. 2d 51, 64 (D.D.C. 1998), vacated in part sub nom. Washington Legal
Foundation v. Henney, 202 F.3d 331, 336-37 (D.C. Cir. 2000).

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548 limitations or other presentational limitations that would not enable a firm to include within their
549 communications on that platform all of the disclosures that are recommended for an SIUU
550 communication. To be consistent with the recommendations in this guidance, such platforms
551 should not be used to host SIUU communications but could be used to direct HCPs to an SIUU
552 communication. For example, it would be consistent with the recommendations in this guidance
553 for a communication on a character-space limited platform to direct HCPs to an SIUU
554 communication through a statement that does not mention the name of any specific medical
555 product, such as “New publication for Health Care Providers—phase 3 trial results for an
556 investigational treatment for [disease X],” followed by a link to a website where the SIUU
557 communication appears.
558
559 Firms should carefully consider the limitations of different media types and platforms to ensure
560 that the medium and platform used for sharing an SIUU communication allows the firm to
561 include all information consistent with the recommendations in this guidance.
562
563 5. Firms should consider using plain language in the content they develop for SIUU
564 communications to facilitate comprehension.
565
566 Although HCPs have specialized training and experience in evaluating scientific information,
567 research indicates that HCPs may nonetheless have difficulty understanding some types of
568 scientific information, including clinical trial data, and the design and methodological limitations
569 of studies. 48 To aid in comprehension and encourage careful consideration of the information
570 shared in an SIUU communication, firms should consider using plain language for any firm-
571 generated portions of the SIUU communication, including recommended disclosures. Plain
572 language is language that is clear, concise, well-organized, and where possible, avoids
573 complexities such as technical jargon, passive voice, and long sentences and paragraphs. 49
574 Clearly explaining scientific or technical terms and avoiding or appropriately introducing
575 acronyms and abbreviations can facilitate comprehension.
576

48
See, e.g., Anderson, B.L., Schulkin, J. (2014). Numerical Reasoning in Judgments and Decision Making about
Health. Cambridge University Press; Kahwati, L., Carmody, D., Berkman, N., Sullivan, H. W., Aikin, K. J., &
DeFrank, J. (2017). Prescribers' Knowledge and Skills for Interpreting Research Results: A Systematic Review. The
Journal of Continuing Education in the Health Professions, 37(2), 129–136; Moynihan, C. K., Burke, P. A., Evans,
S. A., O'Donoghue, A. C., & Sullivan, H. W. (2018). Physicians' Understanding of Clinical Trial Data in
Professional Prescription Drug Promotion Journal of the American Board of Family Medicine. JABFM, 31(4), 645–
649; Weir, I. R., Marshall, G. D., Schneider, J. I., Sherer, J. A., Lord, E. M., Gyawali, B., Paasche-Orlow, M. K.,
Benjamin, E. J., & Trinquart, L. (2019). Interpretation of time-to-event outcomes in randomized trials: an online
randomized experiment. Annals of oncology: official journal of the European Society for Medical Oncology, 30(1),
96–102.

See the U.S. General Services Administration (GSA) Plain Language Action and Information Network (PLAIN)
49

website at https://www.plainlanguage.gov/.

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577 Q4. What additional recommendations apply to specific types of SIUU communications?
578
579 This draft guidance addresses a number of different types of SIUU communications. This
580 section offers specific recommendations for firms to take into account for these different types of
581 SIUU communications, in addition to the recommendations outlined in Q1, Q2, and Q3.
582
583 1. Reprints:
584
585 In this guidance, we use the term reprint to refer to a copy of an article originally published by a
586 medical or scientific journal. When firms share SIUU communications in the form of a reprint,
587 FDA recommends that the reprint have all of the following characteristics:
588
589 • The article is published in a journal managed by an independent organization with an
590 editorial board comprised of persons who have demonstrated expertise in the subject of
591 the articles under review by the organization (through education or experience), and a
592 publicly stated policy regarding the disclosure of conflicts of interest or biases for all
593 authors, contributors, or editors
594
595 • The article is peer-reviewed by experts in the subject of the article, as established by
596 education or experience
597
598 • The article is generally available (or the journal from which the article is taken is
599 generally available) through independent distribution channels (e.g., internet sources,
600 book retailers, subscriptions, libraries) where periodicals and reprints are sold or are
601 accessible
602
603 • The article describes studies or analyses that are scientifically sound and provide
604 information that is clinically relevant (see Q1); specifically:
605
606 - To be scientifically sound, the scientific studies or analyses described in the article
607 should meet generally acceptable design and other methodological standards for the
608 type of study or analysis being performed (e.g., provide a clear description of the
609 hypothesis stated and tested, acknowledge and account for potential bias, and
610 otherwise meet generally accepted scientific standards for the type of study or
611 analysis performed). Meta-analyses, cohort or case-control studies, open-label
612 studies, single-arm studies, or epidemiological studies can be scientifically sound if
613 these studies and analyses meet generally acceptable design and other methodological
614 standards for the type of study or analysis being performed and take into account any
615 limitations of the selected design and methodology. For some devices, well-
616 documented case histories conducted by qualified experts may also be scientifically
617 sound and provide information that is clinically relevant.
618
619 - To be clinically relevant, the scientific studies or analyses described in the article
620 should, in addition to being scientifically sound, provide information that is pertinent
621 to HCPs engaged in making clinical practice decisions for the care of an individual

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622 patient. Generally, sharing articles focused on a nonclinical study or analysis alone
623 would not be consistent with the enforcement policy outlined in this guidance because
624 this nonclinical study or analysis alone is unlikely to provide information that is
625 clinically relevant.
626
627 - Articles that misrepresent or overstate findings in light of the limitations of the study
628 or analysis would not be consistent with the enforcement policy outlined in this
629 guidance.
630
631 • Reprints should be unaltered/unabridged as the sharing of unaltered/unabridged articles is
632 less likely to introduce bias or result in the omission of material information. 50
633
634 2. Clinical Reference Resources:
635
636 In this draft guidance, we address the following clinical reference resources:
637
638 • Clinical Practice Guidelines (CPGs):
639
640 - In this guidance, we use the term CPG to refer to a statement or document from
641 a professional or academic organization that includes recommendations focused
642 on a specific disease or condition intended to help HCPs make decisions for
643 individual patient care, including decisions in circumstances where there are few
644 or no approved/cleared medical products indicated for the patient’s condition or
645 the approved/cleared medical products have not proven successful for the
646 individual patient. 51
647
648 • Reference Texts:
649
650 - In this guidance, we use the term reference text to refer to medical or scientific
651 textbooks that typically discuss a wide range of topics (e.g., medical diagnosis,
652 pathophysiology and treatments, pharmacology, surgical techniques, and other
653 scientific or medical information).
654
655 • Materials from Independent Clinical Practice Resources:
656
657 - In this guidance, we use the term independent clinical practice resource to refer
658 to a digital resource that contains medical and scientific information on a wide

50
A firm could develop a truthful, non-misleading, factual, and unbiased presentation of scientific information from
an accompanying reprint and not be inconsistent with this recommendation. See item 3 in Q4 for recommendations
regarding firm-generated presentations of scientific information from an accompanying reprint.
51
CPGs can provide a resource for HCPs who may not have the time or capacity to review the full range of primary
source publications and make an independent, evidence-based assessment to inform their clinical practice decisions.
CPGs provide recommendations for care for a disease or condition, in addition to offering potential alternatives for
certain patient subgroups.

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659 range of topics developed by subject matter experts in various medical specialty
660 fields. The information is typically searchable by topic or keyword and
661 produces materials in response to the HCP’s search terms.
662
663 These clinical reference resources often contain information about unapproved uses of medical
664 products. Therefore, when sharing SIUU communications in the form of CPGs, reference texts,
665 or materials from independent clinical practice resources, FDA recommends that firms follow
666 the recommendations in Q1, Q2, and Q3, subject to the following additions and modifications.
667
668 When a firm shares an SIUU communication in the form of one or more individual section(s) of
669 any of these clinical reference resources, the SIUU communication should include all
670 information from the clinical reference resource necessary for HCPs to interpret the strengths
671 and weaknesses and validity and utility of the information. This may involve the sharing of
672 multiple sections of the clinical reference resource that contain related or linked information.
673 When a firm shares individual section(s) from these clinical reference resources, those
674 individual section(s) should be unaltered/unabridged and extracted directly from the clinical
675 reference resource.
676
677 Because unabridged CPGs and reference texts in their entirety generally discuss a wide range
678 of topics and medical products, FDA notes the following exceptions to the recommendations in
679 Q2. When a firm shares an SIUU communication in the form of an unabridged CPG or
680 reference text in its entirety that discusses a wide range of medical products and that discussion
681 is not primarily focused on one or more of a firm’s medical products, FDA does not expect a
682 firm to include any of the following:
683
684 • A statement disclosing the FDA-approved use(s), including any limitations of use
685 specified in the FDA-required labeling, for each of the firm’s medical products
686 mentioned in the CPG or reference text
687
688 • A statement disclosing any limitations, restrictions, cautions, or warnings described in
689 the FDA-required labeling about the unapproved use(s) for each of the firm’s medical
690 products mentioned in the CPG or reference text
691
692 • A copy of or mechanism to obtain the FDA-required labeling for each of the firm’s
693 medical products mentioned in the CPG or reference text
694
695 • A statement describing the contraindications in the FDA-required labeling for each of
696 the firm’s medical products mentioned in the CPG or reference text
697
698 • A description of the serious, life-threatening, or fatal risks that are in the FDA-required
699 labeling or are known by the firm and that are relevant to the unapproved use(s) posed
700 by each of the firm’s medical products mentioned in the CPG or reference text
701 (including whether a REMS has been established for any of the firm’s medical
702 products mentioned in the CPG or reference text and a description of the goal(s) of the
703 REMS)

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704 Instead, FDA recommends that firms include a more general statement in the SIUU
705 communication, such as, “This [CPG/reference text] describes some uses of medical products
706 that are not approved by the FDA, and the safety and effectiveness of any unapproved use(s)
707 have not been established.”
708
709 a. Specific Recommendations for CPGs:
710
711 CPGs are generally based on a wide range of evidence, with the goal of making treatment
712 recommendations and describing the different levels of evidence that support those
713 recommendations. When firms share SIUU communications in the form of a CPG, FDA
714 recommends that the CPG have all of the following characteristics:
715
716 • The CPG is based on rigorous reviews of the existing evidence conducted according to
717 a clear, established procedure and following a transparent process that minimizes biases
718 and conflicts of interest
719
720 • The CPG includes ratings of the recommendations to reflect the quality and strength of
721 evidence that supports each recommendation
722
723 • The CPG is revised when important new evidence warrants modifications of current
724 recommendations
725
726 • The CPG is generally available through independent distribution channels (e.g., internet
727 sources, book retailers, subscriptions, libraries) where CPGs are sold or are accessible
728
729 One helpful resource when considering whether a particular CPG is appropriate to serve as the
730 basis for an SIUU communication is the National Academy of Medicine (NAM) 52 standards for
731 CPG “trustworthiness.” 53 CPGs that are consistent with the NAM standards would also be in
732 alignment with the standards FDA has articulated. The NAM standards recommend that CPGs

NAM was formerly known as the Institute of Medicine (IOM) and is one of three academies that make up the
52

National Academies of Sciences, Engineering, and Medicine.

53
Through the Medicare Improvements for Patients and Providers Act of 2008, Congress required the Secretary of
Health and Human Services (HHS) to contract with IOM (through the Agency for Healthcare Research and Quality)
to undertake a study that focused on “the best methods used in developing clinical practice guidelines in order to
ensure that organizations developing such guidelines have information on approaches that are objective,
scientifically valid, and consistent” (Public Law No. 110-275, 122 Stat. 2595). Also, in this legislation, Congress
required IOM to submit a report to the Secretary of HHS and the appropriate committees of Congress containing the
results of the study, together with recommendations for such legislation and administrative action as IOM
determines appropriate. The standards for CPG “trustworthiness,” as referred to in this guidance, are taken directly
from IOM’s study results (as articulated in its report, Robin Graham, et al. eds., Institute of Medicine of the National
Academies, Committee on Standards for Developing Trustworthy Clinical Practice Guidelines, Clinical Practice
Guidelines We Can Trust (2011)), available at https://nap.nationalacademies.org/catalog/13058/clinical-practice-
guidelines-we-can-trust.

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733 (1) be based on a systematic review 54 of the existing evidence; (2) be developed by a
734 knowledgeable, multidisciplinary panel of experts and representatives from key affected
735 groups; (3) consider important patient subgroups and patient preferences, as appropriate; (4) be
736 based on an explicit and transparent process by which the CPG is developed and funded that
737 minimizes distortions, 55 biases, and conflicts of interest; (5) provide a clear explanation of the
738 logical relationships between alternative care options and health outcomes, provide clearly
739 articulated recommendations in standardized form, and provide ratings of both quality of
740 evidence and the strength of recommendations; and (6) be reconsidered and revised when
741 important new evidence warrants modifications of recommendations.
742
743 Numerous professional organizations develop and disseminate CPGs that are pertinent to their
744 members’ clinical practices. In an era of rapidly increasing amounts of scientific information
745 about medical products, CPGs can be a tool to manage this information. However, in light of
746 the proliferation of professional organizations promulgating CPGs and the variations in scope
747 and evidence used for CPG recommendations by these organizations, it is important that firms
748 assess CPGs in a medical practice area to ensure they are consistent with the recommendations
749 in this guidance, including that CPG recommendations have ratings to reflect the strength and
750 quality of evidence supporting those CPG recommendations and that any CPG
751 recommendations are updated when new evidence warrants modification.
752
753 b. Specific Recommendations for Reference Texts and Independent Clinical
754 Practice Resources:
755
756 When firms share SIUU communications in the form of a reference text or material from
757 independent clinical practice resources, FDA recommends that the reference text or material
758 from an independent clinical practice resource have all of the following characteristics:
759
760 • It is published by an independent publisher that is in the business of publishing
761 scientific or medical educational content 56
762
763 • It is published in a manner consistent with current standards for medical content
764 creation and review that are generally accepted by the medical publishing industry and
765 in accordance with any specific peer-review procedures of the publisher

54
The NAM has defined a systematic review as “a scientific investigation that focuses on a specific question and
uses explicit, prespecified scientific methods to identify, select, assess, and summarize the findings of similar but
separate studies.” Institute of Medicine, Finding What Works in Health Care: Standards for Systematic Reviews
(Jill Eden et al. eds., The National Academies Press 2011), available at
https://nap.nationalacademies.org/catalog/13059/finding-what-works-in-health-care-standards-for-systematic-
reviews.
55
Per NAM, distortion may result from, for example, reliance on incomplete data.
56
It would be consistent with this recommendation for a firm to fund the production of copies of a reference text or
material from an independent clinical practice resource that is already generally available and to provide those
copies to HCPs.

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766 • It is authored, edited, and contributed to by experts who have demonstrated expertise in
767 the subject area(s) through education or experience
768
769 • It is generally available or sold through independent distribution channels 57 (e.g.,
770 internet sources, book retailers, subscriptions, libraries) for medical and scientific
771 educational content
772
773 3. Specific Recommendations for Firm-Generated Presentations of Scientific Information
774 from an Accompanying Reprint
775
776 In addition to sharing reprints, some firms develop firm-generated presentations of scientific
777 information from an accompanying reprint. Consistent with the above recommendations in this
778 guidance, an SIUU communication in the form of a firm-generated presentation of scientific
779 information from an accompanying reprint should be truthful, non-misleading, factual, and
780 unbiased and provide all information necessary for HCPs to interpret the strengths and
781 weaknesses and validity and utility of the presented information, as further explained in this
782 section.
783
784 First, the full reprint(s) should accompany the firm-generated presentation and should be
785 consistent with the recommendations in item 1 in Q4. However, firms should not rely upon the
786 accompanying reprint(s) to provide information that is material to the representations made in
787 the firm-generated presentation; all information material to the representations made in the firm-
788 generated presentation should be included with those representations within the firm-generated
789 presentation, notwithstanding the recommendations in Q2. For example, if a firm-generated
790 presentation includes information about study results, the firm-generated presentation should
791 include all material aspects of and limitations related to the study design, methodology, and
792 results necessary to interpret the presented information directly with the presented information.
793
794 Second, firm-generated presentations should include the disclosures recommended in Q2 of this
795 guidance 58 and should also clearly disclose what portions of the communication are firm-
796 generated. For example, a firm-generated presentation could include the following statement:
797 “This presentation was developed by FIRM X.”
798
799 Third, firm-generated presentations should be consistent with the recommendations in this
800 guidance regarding presentational considerations (see Q3).
801

57
FDA recognizes that individual chapters of reference texts may not be generally available through these channels;
this language is referring to general availability of the complete reference text.
58
To the extent that recommended disclosures apply to both the firm-generated presentation and the reprint, FDA
does not generally expect that firms repeat the recommended disclosures in both the firm-generated presentation and
separately in an attachment to the reprint(s). However, firms should ensure that all recommended disclosures that
are material to specific representations made in the firm-generated presentation are at a minimum included with such
representations in the firm-generated presentation.

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802 Fourth, to ensure that an SIUU communication in the form of a firm-generated presentation of
803 scientific information from an accompanying reprint is truthful, non-misleading, factual, and
804 unbiased, the firm-generated presentation should not, for example, do any of the following:
805
806 • Imply that the study, analysis, or underlying data or information from the reprint(s)
807 represents larger or more-general experience with the medical product than it actually
808 does
809
810 • Present information (e.g., excerpts, quotes, paraphrases, conclusions) from the reprint(s)
811 out of context, without the information necessary for HCPs to interpret the strengths and
812 weaknesses and validity and utility of the information
813
814 • Include representations or suggestions about the safety or effectiveness of the medical
815 product for the unapproved use(s) that are not consistent with the reprint
816
817 • Present conclusions or representations about safety or effectiveness for the unapproved
818 use, even if an accurate reflection of the statements in the reprint, without attributing that
819 statement expressly to the reprint and without immediately following it with the
820 statement identifying any authors, editors, or other contributors to the reprint(s) who were
821 employees of or consultants to or who received compensation from the firm at the time of
822 writing, editing, or contributing to the reprint
823
824 • Use statistical analyses or techniques to indicate clinical significance or validity of a
825 finding not supported by the data or information in the reprint
826
827 • Use tables or graphs or other presentational elements to distort or misrepresent the
828 relationships, trends, differences, or changes among the outcomes evaluated in the reprint

26