Drug and Device Manufacturer

Communications With Payors,

Formulary Committees, and Similar

Entities

Questions and Answers

Guidance for Industry and Review Staff

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to http://www.regulations.gov. Submit written
comments to the Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with
the docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this draft document, contact (CDER) Elaine Hu Cunningham at 301-
796-1200; (CBER) Office of Communication, Outreach and Development at 800-835-4709 or
240-402-8010; (CDRH) Paul Gadiock at 301-796-5736; or (OC) Kristin Davis at 301-796-0418.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

Center for Devices and Radiological Health (CDRH)

Office of the Commissioner (OC)

January 2017

Procedural

15422dft.doc
 Drug and Device Manufacturer

Communications With Payors, Formulary Committees, and Similar

Entities

Questions and Answers

Guidance for Industry and Review Staff

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Center for Devices and Radiological Health (CDRH)

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January 2017

Procedural

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TABLE OF CONTENTS

I. INTRODUCTION............................................................................................................. 1

II. BACKGROUND ............................................................................................................... 2

III. QUESTIONS AND ANSWERS....................................................................................... 3

A. Communication of HCEI by Firms to Payors Regarding Approved Drugs............................. 3

B. Communications by Firms to Payors Regarding Investigational Drugs and Devices ........... 15

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1 Drug and Device Manufacturer Communications With Payors,

2 Formulary Committees, and Similar Entities Questions and
3 Answers
4 Guidance for Industry and Review Staff1
5
6
7 This draft guidance, when finalized, will represent the current thinking of the Food and Drug
8 Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not
9 binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the
10 applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible
11 for this guidance as listed on the title page.
12
13
14
15
16 I. INTRODUCTION
17
18 This guidance provides answers to common questions regarding firms2 communication of health
19 care economic information (HCEI) regarding their prescription drugs3 to payors, formulary
20 committees, or other similar entities4 with knowledge and expertise in the area of health care
21 economic analysis (collectively referred to as payors). This guidance also addresses common
22 questions relating to dissemination of information about investigational drugs and devices5
23 (medical products6) to payors before FDA approval or clearance of such products.
24
25 The questions and answers are grouped in the following categories:
26

1
This guidance has been prepared by the Office of Prescription Drug Promotion 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, and the Office of the Commissioner at the Food and Drug Administration.
2
The term firms refers to medical product manufacturers, packers, and distributors and their representatives.
3
Each biological product that also meets the definition of drug under the Federal Food, Drug, and Cosmetic Act
(FD&C Act) is subject to provisions of the FD&C Act applicable to drugs, except that a biological product licensed
under section 351 of the Public Health Service Act (PHS Act) is not required to have an approved new drug
application under section 505 of the FD&C Act (21 U.S.C. 355). See section 351(j) of the PHS Act (42 U.S.C.
262(j)). For the purposes of this guidance, the term drugs means human prescription drugs, including those that
are licensed as biological products.
4
The terms payors, formulary committees, or other similar entities are discussed in Q.A.2/A.A.2 of this guidance.
5
The term device refers to a medical device intended for human use, including a device that is licensed as a
biological product.
6
The term medical products refers to both drugs and devices.

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27 Communication of HCEI to payors regarding approved drugs

28 Communications to payors about investigational drugs and devices (investigational
29 products)7
30
31 This guidance describes FDAs current thinking on these topics.
32
33 In general, FDAs guidance documents do not establish legally enforceable responsibilities.
34 Instead, guidances describe the Agencys current thinking on a topic and should be viewed only
35 as recommendations, unless specific regulatory or statutory requirements are cited. The use of
36 the word should in Agency guidances means that something is suggested or recommended, but
37 not required.
38
39
40 II. BACKGROUND
41
42 A number of FDAs statutory and regulatory provisions potentially impact firms
43 communications with payors.8 This guidance provides FDAs thinking on frequently asked
44 questions regarding such communications in order to provide clarity for firms and payors.

7
As used in this guidance, the term investigational products refers to drugs and devices that are not yet
approved/cleared by FDA for any use (but which must be approved/cleared to be legally marketed), including
products for which firms have submitted or plan to submit a new drug application (NDA), a biologics license
application (BLA) (including an application submitted under the 351(k) pathway), an abbreviated new drug
application (ANDA), a premarket approval application (PMA), a 510(k) submission, a de novo submission under
section 513(f)(2) of the FD&C Act (21 U.S.C. 360c(f)(2)), or a Humanitarian Device Exemption (HDE) application.
8
For example, section 502(a), as amended by section 114 of the Food and Drug Administration Modernization Act
of 1997 (FDAMA) (Public Law 105-115) and section 3037 of the 21st Century Cures Act (Public Law 114-255),
includes the following provision regarding communication of HCEI to payors about approved drugs:
Health care economic information provided to a payor, formulary committee, or other similar entity
with knowledge and expertise in the area of health care economic analysis, carrying out its
responsibilities for the selection of drugs for coverage or reimbursement, shall not be considered to be
false or misleading under this paragraph if the health care economic information relates to an
indication approved under section 505 or under section 351(a) of the Public Health Service Act [42
U.S.C. 262(a)] for such drug, is based on competent and reliable scientific evidence, and includes,
where applicable, a conspicuous and prominent statement describing any material differences between
the health care economic information and the labeling approved for the drug under section 505 or
under section 351 of the Public Health Service Act. The requirements set forth in section 505(a) or in
subsections (a) and (k) of section 351 of the Public Health Service Act shall not apply to health care
economic information provided to such a payor, committee or entity in accordance with this
paragraph. Information that is relevant to the substantiation of the health care economic information
presented pursuant to this paragraph shall be made available to the Secretary [of Health and Human
Services] upon request . For purposes of this paragraph, the term health care economic
information means any analysis (including the clinical data, inputs, clinical or other assumptions,
methods, results, and other components underlying or comprising the analysis) that identifies,
measures, or describes the economic consequences, which may be based on the separate or aggregated
clinical consequences of the represented health outcomes, of the use of a drug. Such analysis may be
comparative to the use of another drug, to another health care intervention, or to no intervention.
Such term does not include any analysis that relates only to an indication that is not approved under
section 505 or under section 351 of the Public Health Service Act for such drug.

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45 Specifically, section III.A provides FDAs thinking on frequently asked questions regarding
46 communication of HCEI to payors about approved prescription drugs. Payors seek a range of
47 information on effectiveness, safety, and cost-effectiveness of approved prescription drugs,
48 including information from firms, to help support their drug selection, formulary management,
49 and/or coverage and reimbursement decisions on a population basis. Often, this information
50 differs from and can be provided in addition to the information FDA reviews in order to make
51 approval decisions. Because coverage and reimbursement decisions by payors impact a large
52 number of patients, FDA believes it is essential that information provided by firms to payors
53 about their drugs be truthful and non-misleading.
54
55 Section III.B provides FDAs thinking on frequently asked questions regarding communications
56 to payors about investigational products. Payors have also indicated that due in part to their need
57 to, in some situations, plan for and make coverage and reimbursement decisions far in advance
58 of the effective date of such decisions, they are also interested in receiving information from
59 firms about medical products that are still under investigation or review by FDA. For the
60 reasons described above, it is essential that information provided by firms about their
61 investigational products be truthful and non-misleading.
62
63
64 III. QUESTIONS AND ANSWERS
65
66 A. Communication of HCEI by Firms to Payors Regarding Approved Drugs
67
68 Q. A.1. What is HCEI, and how can it be presented?
69
70 A. A.1. HCEI is defined in section 502(a) of the FD&C Act (21 U.S.C. 352(a)) (section
71 502(a)) as any analysis (including the clinical data, inputs, clinical or other
72 assumptions, methods, results, and other components underlying or comprising
73 the analysis) that identifies, measures, or describes the economic consequences,
74 which may be based on the separate or aggregated clinical consequences of the
75 represented health outcomes, of the use of a drug. Such analysis may be
76 comparative to the use of another drug, to another health care intervention, or to
77 no intervention.9 HCEI pertains to the economic consequences related to the
78 clinical outcomes of treating a disease (or specific aspect of a disease) or of
79 preventing or diagnosing a disease.10 HCEI may include comparative analyses of
80 the economic consequences of a drugs clinical outcomes to alternative options
81 (including the use of another drug) or to no intervention.
82
9
See section 502(a), as amended by section 114 of the Food and Drug Administration Modernization Act of 1997
and section 3037 of the 21st Century Cures Act. As used in this guidance, the term section 502(a) refers to the
part of that section specific to HCEI.
10
Ibid. Section 502(a) further provides that HCEI provided to a payor, formulary committee, or other similar
entity (payors) that relates to an approved indication and is based on competent and reliable scientific evidence
will not be considered false or misleading. Those terms are discussed in Q.A.2/A.A.2, Q.A.4/A.A.4, and
Q.A.5/A.A.5 of this guidance.

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83 HCEI can be presented in a variety of ways that can include, but are not limited
84 to, an evidence dossier, a reprint of a publication from a peer-reviewed journal, a
85 software package comprising a model with user manual, or a budget-impact
86 model.
87
88 Q. A.2. What is the appropriate scope of the audience for the communication of HCEI
89 about approved drugs under section 502(a)?
90
91 A. A.2. Section 502(a) specifies that HCEI can be provided to a payor, formulary
92 committee, or other similar entity with knowledge and expertise in the area of
93 health care economic analysis, carrying out its responsibilities for the selection of
94 drugs for coverage or reimbursement.11
95
96 This audience includes payors,12 formulary committees13 (e.g., pharmacy and
97 therapeutics committees), drug information centers, technology assessment
98 panels, pharmacy benefit managers, and other multidisciplinary entities that
99 review scientific and technology assessments to make drug selection, formulary
100 management, and/or coverage and reimbursement decisions on a population basis
101 for health care organizations.14,15
102
103 Such entities are constituted to consider HCEI (and other types of information)
104 through a deliberative process and should have the appropriate range of
105 knowledge and expertise in the area of health care economic analysis needed to
106 interpret HCEI presented to them to inform their population-based decision-
107 making process.16,17 Expertise in this area is essential to understand and evaluate
108 health care economic analyses and their limitations.
109
110 This guidance does not apply to dissemination of HCEI to other audiences, such
111 as health care providers who are making individual patient prescribing decisions
11
Ibid.
12
The term payors refers to entities that are responsible for the financing or reimbursement of costs associated
with health care services (e.g., third-party payers, health plan sponsors).
13
The term formulary committees refers to multidisciplinary committees that have the responsibility for the
selection of drugs and the management of a drug formulary.
14
The term health care organizations may include entities such as integrated health care delivery networks,
hospitals, and hospital systems.
15
See page 65 of the House Report on Prescription Drug Use Reauthorization and Drug Regulatory Modernization
Act of 1997 (H.R. 1411), H.R. Rep. No. 105-310. The report is available at
https://www.congress.gov/congressional-report/105/house-report/310.
16
Ibid.
17
See section 502(a).

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112 or consumers (e.g., dissemination via a public Web site). Dissemination of HCEI
113 to these audiences is not covered by the recommendations of this guidance.18
114
115 Q. A.3. How does FDA intend to implement this guidance for HCEI disseminated in
116 accordance with section 502(a)?
117
118 A. A.3. If a firm disseminates to an appropriate audience HCEI that is the type of
119 information within the scope of section 502(a) (i.e., HCEI that relates to an
120 approved indication and is based on competent and reliable scientific evidence
121 (CARSE), as each of these elements is described in this guidance), FDA does not
122 intend to consider such information false or misleading. HCEI should clearly and
123 prominently present the information discussed in Q.A.7/A.A.7 and Q.A.8/A.A.8
124 in this section, including study design and methodology, generalizability,
125 limitations, sensitivity analyses, and information relevant to providing a balanced
126 and complete presentation. If HCEI includes material differences from the FDA-
127 approved labeling, it must present a conspicuous and prominent statement
128 describing any material differences between the health care economic information
129 and the labeling approved for the drug,19 as discussed in Q.A.7/A.A.7.
130
131 In addition, FDA does not intend to use HCEI disseminated consistent with this
132 guidance as providing evidence of a new intended use.
133
134 Q. A.4. Section 502(a) provides that HCEI shall not be considered false or misleading
135 if, among other things, it relates to an [approved] indication.20 What types of
136 information does FDA consider to relate to an approved indication?
137
138 A. A.4. To be considered related to an approved indication, HCEI analyses should relate
139 to the disease or condition, manifestation of the disease or condition, or symptoms
140 associated with the disease or condition in the patient population for which the
141 drug is indicated in the FDA-approved labeling.
142

18
The scope of the audience for HCEI is important because it will ensure that the information is presented only to
parties who have established procedures and skills to interpret the methods and limitations of economic studies.
[Section 502(a)] is not intended to permit manufacturers to provide such health care economic information to
medical practitioners who are making individual prescribing decisions nor is it intended to permit the provision of
such information in the context of medical education. See page 65 of H.R. Rep. No. 105-310.
19
See section 502(a).
20
Section 502(a)(2)(B) of the FD&C Act also provides that the term HCEI does not include any analysis that
relates only to an indication that is not approved under section 505 or under section 351 of the Public Health Service
Act. If an analysis is consistent with the recommendations in Q.A.4/A.A.4, FDA would consider it to be within the
scope of HCEI as defined in section 502(a). On the other hand, if an analysis does not relate to an approved
indication for a drug, as illustrated by the examples at the end of Q.A.4/A.A.4, FDA would not consider it to be
within the scope of HCEI as defined in this section.

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143 The table below provides examples of HCEI analyses that FDA believes could be
144 considered related to an approved indication of a drug, despite incorporating
145 information that does not appear within, and may vary in certain respects from,
146 information presented in the FDA-approved labeling. These examples are for
147 illustrative purposes only and are not intended to be comprehensive or restrictive.
148
149 Examples of HCEI Analyses That Relate to the Approved Indication
Example Description
Duration of Treatment Where the approved indication for a drug does not limit
the duration of use, HCEI analyses may incorporate
information about the long-term use of the drug for that
indication over a period that is different from that
addressed in the studies described in the FDA-approved
labeling (e.g., if a drug is approved for a chronic
condition with no limitation on its duration of use based
on 24-week studies, economic consequences beyond 24
weeks can be modeled).

Practice Setting HCEI analyses may be based on use of the drug for its
approved indication in practice settings that differ from
the settings of the clinical trials submitted to FDA in
the application (e.g., results of clinical trials conducted
in a fee-for-service setting could be extrapolated to a
managed care or other setting).

Burden of Illness HCEI analyses may be derived from studies of broad

management of a disease for which the drug is
indicated, including economic consequences of
treatment on clinical outcomes (e.g., economic
consequences of absent work days as a result of signs
and symptoms associated with a disease).

Dosing HCEI analyses may be based on data or studies of

approved dosage forms and strengths of a drug for its
approved indication, where the dosing regimen varies
from the FDA-approved labeling (e.g., an observational
study based on drug utilization data from a health plan
database, where actual patient use of an approved
dosage form and strength of a drug for an approved
indication falls outside the recommended dosing
regimen in the label, such as by taking at a different
frequency or a different total dose than recommended).

Patient Subgroups HCEI analyses may be derived from analyses of

treatment effects in patient subgroups (e.g.,
demographics, disease severity, co-morbidities) that are

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Example Description
within the patient population for the approved
indication, even if these subgroup analyses were not
pre-specified in the studies that formed the basis for
approval of the drug.

Length of Hospital Stay HCEI analyses may be derived from studies of

treatment impacts on length of hospital stay.

Validated Surrogate HCEI analyses may be derived from clinical data

Endpoints demonstrating an effect on a surrogate endpoint that is
known to predict clinical benefit (i.e., a validated
surrogate endpoint).21 For example, blood pressure
reduction is a validated surrogate endpoint for
reduction in certain cardiovascular events (e.g., stroke,
myocardial infarction) pertaining to antihypertensive
drugs (e.g., calcium channel blockers, angiotensin
converting enzyme inhibitors).22

Clinical Outcome HCEI analyses may be derived from studies involving

Assessments (COAs)23 or the approved indication of a drug that assess COAs
Other Health Outcome (e.g., patient-reported outcomes (PROs), such as
Measures (e.g., Quality- compliance/adherence, work productivity, basic
Adjusted Life Year activities of daily living) or other health outcome
(QALY))24 measures (e.g., QALY) when they are evaluated using
valid and reliable measures (as determined by experts
who are familiar with evaluating the merits of a
particular COA or other health outcome measure).

21
See FDAs guidance for industry Expedited Programs for Serious Conditions Drugs and Biologics. We update
guidances periodically. To make sure you have the most recent version of a guidance, check the FDA guidance
Web page at http://www.fda.gov/RegulatoryInformation/Guidances/. If there is insufficient evidence to demonstrate
that a particular surrogate endpoint is capable of predicting clinical benefit, it generally should not be used as a basis
for HCEI.
22
See FDAs guidance for industry Labeling for Outcome Claims for Drugs to Treat Hypertension.
23
A COA is any assessment of a patients clinical state by the patient or a clinician. There are four types of COA
measures (i.e., patient-reported outcomes, clinician-reported outcomes, observer-reported outcomes, and
performance outcomes). See FDAs guidance for industry Patient-Reported Outcome Measures: Use in Medical
Product Development to Support Labeling Claims.
24
A QALY is a measure of the value of a health outcome that is typically scored on a scale from zero (corresponds
to death) to one (corresponds to perfect or optimal health), integrating the life expectancy and treatment impact on
morbidity of the compared interventions that may be used in HCEI.

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Example Description
Persistence25 HCEI analyses may be based on data estimating patient
persistence on a drug for its approved indication (e.g.,
estimates based on drug utilization data from a health
plan database).

Comparisons HCEI analyses may be derived from studies comparing

the safety or effectiveness of a drug for its approved
indication to another drug or intervention or to no
treatment.

150
151 The following are examples of HCEI analyses that are not considered to relate to
152 an approved indication:
153
154 1. An economic analysis of disease course modification related to use of a
155 drug that is approved only to treat the symptoms of the disease would not
156 be considered related to the approved indication.26 Thus, for example, if
157 an analysis for a drug indicated for the acute relief of angina discussed the
158 effect of the drug on delaying the worsening of coronary artery disease
159 (disease course modification), FDA would not consider this to relate to the
160 approved indication. Similarly, an analysis based on prolonging patient
161 survival (disease course modification) for patients with heart failure would
162 not be considered related to an indication for a drug approved only for the
163 treatment of the signs and symptoms of heart failure.27 As illustrated by
164 these examples, if a drug is approved only to relieve the symptoms of a
165 disease, HCEI analyses regarding use of the drug to prevent, cure, or
166 mitigate/change the course of the disease would not be considered related
167 to the drugs approved indication.
168
169 2. HCEI analyses derived from studies in patient populations that are not
170 within the indicated patient population are not related to the approved
171 indication of the drug. For example, an analysis regarding the treatment of
172 cystic fibrosis (CF) in patients with any mutation in the CF gene would
173 not be considered to relate to the approved indication for a drug approved
174 to treat only one specific CF gene mutation.
175

25
The term persistence refers to the duration of time from initiation to discontinuation of therapy. See Cramer
JA, Roy A, Burrell A, et al., Medication Compliance and Persistence: Terminology and Definitions, Value Health,
2008;11(1):4447.
26
See page 66 of H.R. Rep. No. 105-310.
27
Ibid.

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176 Q. A.5. What evidentiary support should firms have for their HCEI under section
177 502(a)?
178
179 A. A.5. Section 502(a) states that HCEI shall not be considered false or misleading if,
180 among other things, it is based on competent and reliable scientific evidence.
181 FDA considers HCEI to be based on CARSE if the HCEI has been developed
182 using generally-accepted scientific standards, appropriate for the information
183 being conveyed, that yield accurate and reliable results. In evaluating whether the
184 amount and type of evidence that forms the basis for a particular communication
185 of HCEI meets the generally-accepted scientific standards for such information,
186 FDA will consider the merits of existing current good research practices for
187 substantiation developed by authoritative bodies (e.g., International Society for
188 Pharmacoeconomic and Outcomes Research (ISPOR), Patient-Centered
189 Outcomes Research Institute). For example, when evaluating HCEI based on
190 indirect treatment comparisons in the absence of data from head-to-head
191 controlled clinical trials, FDA may refer to guidelines issued by external expert
192 bodies regarding current rigorous methodologies and best practices for such
193 comparisons (e.g., network meta-analyses).
194
195 HCEI should clearly and prominently present the information discussed in
196 Q.A.7/A.A.7 and Q.A.8/A.A.8 of this guidance, including study design and
197 methodology, generalizability, limitations, sensitivity analyses, and information
198 relevant to providing a balanced and complete presentation.
199
200 Q. A.6. Does the CARSE standard apply only to the economic components of HCEI, or
201 does it also apply to the other components?
202
203 A. A.6. Under section 502(a), HCEI includes the clinical data, inputs, clinical or other
204 assumptions, methods, results, and other components underlying or comprising
205 the analysis of a drugs economic consequences. FDA considers the CARSE
206 standard in section 502(a) to apply to all components of HCEI, including inputs
207 and assumptions related to both economic consequences and clinical outcomes
208 (i.e., safety and/or effectiveness). As discussed previously in Q.A.4/A.A.4, such
209 information must also relate to an approved indication.
210
211 Q. A.7. What information should firms include when disseminating HCEI?
212
213 A. A.7. To enable payors to make informed coverage and reimbursement decisions and to
214 help ensure that the information is not false or misleading under section 502(a),
215 firms should include appropriate background and contextual information
216 necessary to allow payors to fully understand the HCEI, including the elements
217 discussed briefly below. This information, if applicable, should be presented
218 clearly and prominently.
219
220 1. Study Design and Methodology
221

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222 Firms should include an accurate overview of the design of the economic
223 analysis, including a statement of the study objectives. For example, a clear
224 description of the hypothesis tested should be provided and potential biases and/or
225 confounders should be acknowledged. In addition, the following information
226 about the study and/or methodology should be presented:
227
228 Type of Analysis: The type of economic analysis selected (e.g., cost-
229 minimization analysis, cost-effective analysis, cost-utility analysis, cost-
230 benefit analysis, cost-consequence analysis) should be stated and the reason
231 for its choice should be explained.28
232
233 Modeling: The type of modeling technique should be disclosed, with an
234 explanation of the model choice, its scope, and its key variables/parameters.29
235 The rationale and consequences of including and excluding specific variables
236 in economic models should be discussed in the analysis.
237
238 Patient Population: Details about the patient population should be specified,
239 including the number of patients and relevant demographic information, such
240 as age, gender, ethnicity, clinical characteristics, and socioeconomic
241 status.30,31
242
243 Perspective/Viewpoint: The perspective or viewpoint of the economic analysis
244 should be clearly stated so that payors can understand the rationale for the
245 selection of inputs (e.g., outcome measures, time periods, costs) and can,
246 therefore, determine whether the HCEI is relevant to their particular health
247 care organizations. Possible viewpoints can include those of the patient,
248 employer, health care provider (e.g., clinician, institution), payor, regulatory
249 body (e.g., government agency), or society (i.e., everyone impacted by the
250 treatment).32,33
251

28
Drummond MF, Jefferson TO, Guidelines for Authors and Peer Reviewers of Economic Submissions to BMJ,
BMJ, 1996;313:(7052):275283.
29
Husereau D, Drummond M, Petrou S, et al., Consolidated Health Economic Evaluation Reporting Standards
(CHEERS) Explanation and Elaboration: A Report of the ISPOR Health Economic Evaluation Publication
Guidelines Good Reporting Practices Task Force, Value Health, 2013;16:231250.
30
Gold MR, Siegel JE, Russell LB, et. al., editors, Cost-Effectiveness in Health and Medicine, New York, NY:
Oxford University Press, 1996.
31
Husereau, et al., op cit.
32
Gold, et al., op cit.
33
Drummond, et al., op. cit.

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252 Treatment Comparator: The choice of comparator treatment (e.g., other

253 drugs, other medical care, no treatment) should be fully explained.34,35
254
255 Time Horizon: The choice of time horizon should be clearly stated and
256 explained, including its relation to the major and relevant clinical outcomes
257 (e.g., safety and effectiveness) and economic consequences related to the
258 treatment of interest and its comparators.36,37
259
260 Outcome Measures: The outcome measure(s) chosen should be fully
261 described, as should the sources of clinical and/or nonclinical data. For
262 example, clinical outcomes chosen could include PROs (e.g.,
263 compliance/adherence, work productivity, basic activities of daily living) or
264 QALYs. Data sources may include clinical and nonclinical studies or other
265 sources, such as administrative databases (e.g., health plan databases),
266 electronic health records (EHRs), and registries.
267
268 Cost Estimates: All of the relevant resource items for measurement and
269 valuation for a treatment pathway in an economic analysis should be
270 identified. Reference should be made to the source of cost data, including the
271 date of the pricing.38 In addition, full disclosure of and explanation for any
272 data manipulations and methods (e.g., discount rates, adjustments for
273 inflation, currency conversion) should be included.39
274
275 Assumptions: A comprehensive listing of all assumptions (clinical and
276 nonclinical) and associated rationales should be made explicit in the
277 explanation of the methodology for the economic analysis.40 Assumptions
278 may include, for example, information related to patient demographics or
279 characteristics, natural disease course, disease management/clinical practice,
280 and cost of clinical events. All evidence to support assumptions made should
281 be provided.
282

34
Gold, et al., op. cit.
35
Husereau, et al., op. cit.
36
Gold, et al., op. cit.
37
Husereau, et al., op. cit.
38
Ibid.
39
Ibid.
40
Ibid.

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283 2. Generalizability
284
285 Generalizability refers to the applicability of HCEI obtained in one health care
286 setting or patient population to another. Any factors which may limit the
287 generalizability of the economic analysis should be disclosed.41
288
289 3. Limitations
290
291 A discussion of the limitations of the economic analysis should be made
292 explicit.42 Factors that may affect the interpretability and reliability of an
293 economic analysis include, but are not limited to, limitations of the study design,43
294 limitations of the data sources, incomplete data, assumptions made, choice of
295 comparators, and exclusion of certain clinical outcomes. For example, regarding
296 study design, limitations and methodological issues associated with observational
297 studies44 and indirect treatment comparisons45 should be fully described, as they
298 may inform conclusions that can be reliably made based on these analyses.
299
300 4. Sensitivity Analysis
301
302 Uncertainty may arise from data sources, extrapolation, or analytical methods
303 employed in an economic analysis. Therefore, uncertainties that could affect the
304 conclusions in HCEI should be identified, and a sensitivity analysis should be
305 performed. HCEI should include adequate disclosures and rationales regarding
306 the method used for the sensitivity analysis, the variables chosen, and the ranges
307 for those variables.46
308
309 5. Additional Material Information for a Balanced and Complete Presentation
310

41
Siegel JE, Weinstein MC, Russell LB, et al., Recommendations for Reporting Cost-Effectiveness Analyses, Panel
on Cost Effectiveness in Health and Medicine, JAMA, 1996;276(16):13391341.
42
Gold, et al., op. cit.
43
Regarding study design limitations, firms should disclose whether the study lacked randomization, blinding, or a
control group; lacked assay sensitivity; failed to include pre-specified endpoints; failed to include endpoints that are
valid and reliable measures of the outcomes of interest; failed to identify dosing, patient population, patient drop
outs, selection and timing of endpoints; failed to meet the primary endpoint; etc.
44
Berger ML, Martin BC, Husereau D, et al., A Questionnaire to Assess the Relevance and Credibility of
Observational Studies to Inform Health Care Decision Making: An ISPOR-AMCP-NPC Good Practice Task Force
Report, Value Health, 2014;17(2):143156.
45
Song F, Loke YK, Walsh T, et al., Methodological Problems in the Use of Indirect Comparisons for Evaluating
Healthcare Interventions: Survey of Published Systemic Reviews, BMJ, 2009;338:b1147.
46
Husereau, et al., op. cit.

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311 A balanced and complete presentation includes material information such as the
312 following:
313
314 Conspicuous and Prominent Statement Describing Material Differences:
315 If HCEI includes material differences from the FDA-approved labeling,
316 including assumptions that vary in certain respects from the information
317 presented in the FDA-approved labeling, a conspicuous and prominent
318 statement describing any material differences between the health care
319 economic information and the labeling approved for the drug47 must be
320 presented.
321
322 Furthermore, firms should not misleadingly represent that the clinical
323 assumptions that vary from the FDA-approved labeling have been found by
324 FDA to be safe and effective.
325
326 FDA-Approved Indication/FDA-Approved Labeling: HCEI should
327 include a statement regarding the FDA-approved indication of the drug and be
328 accompanied by the most current FDA-approved labeling.
329
330 Disclosure of Omitted Studies or Data Sources: As a general matter, the
331 presentation of HCEI would not be considered to be balanced and complete if
332 relevant data or information is available but was not considered and included
333 in the analysis. This is especially true if the omitted data or information is
334 from rigorous studies (e.g., adequate and well-controlled trials). It is,
335 therefore, recommended that firms perform a comprehensive literature search
336 and that their HCEI include an explanation of the methods used in the
337 literature search (e.g., databases or sources used, time period covered, and
338 criteria/keywords used to search the databases and sources and to determine
339 what data or information to include/exclude). If HCEI is created without
340 using all available relevant data, HCEI should clearly explain that certain
341 studies or data sources were omitted from the analysis, the reasons they were
342 not included, and how such a selective inclusion of studies or data sources
343 may change or affect the conclusions.
344
345 Risk Information: HCEI should disclose important risk information
346 associated with the approved use of the drug and, under section 502(a), must
347 disclose any additional risk information related to clinical assumptions in
348 economic analyses that vary from the FDA-approved labeling (e.g., risks
349 observed in a particular patient subgroup).
350

47
See section 502(a). Factors that can influence the conspicuous and prominent presentation of a statement include,
but are not limited to, the location of the statement; the font size and style of the statement text; the contrast between
text and background; and the white space between and around text.

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351 Financial/Affiliation Biases: HCEI should disclose potential financial or

352 affiliation biases, such as the disseminating firms role in funding underlying
353 research or in drafting underlying publications or presentations or the names
354 of any authors of studies or analyses who received compensation from the
355 firm or who had a significant financial interest in the firm, to the extent
356 reasonably known by the firm at the time of dissemination.
357
358 Q. A.8. If HCEI is based on COAs or other health outcome measures, are there any
359 additional considerations of which firms should be aware?
360
361 A. A.8. When HCEI includes COAs (e.g., PROs, including compliance/adherence, work
362 productivity, basic activities of daily living) or other measures of health outcomes
363 (e.g., QALYs), information regarding the validity and reliability of the measures
364 used in assessments of the COA (as determined by experts familiar with
365 evaluating the merits of a particular COA)48 or the health outcome measure
366 should be included.
367
368 Regarding health outcome measures such as QALYs, the following should be
369 considered to facilitate interpretability and comprehensibility of the information:
370 (1) the methods by which the patients health status is captured should be
371 disclosed, and the rationale for the health status measures included in the analysis
372 (e.g., physical function, psychological function, social function, impairment, pain)
373 should be provided and (2) the methods for the valuation of health outcomes
374 should be disclosed, and their appropriateness for the patient population and the
375 disease or condition being studied should be explained.
376
377 Q. A.9. Is HCEI for prescription drugs disseminated in accordance with section 502(a)
378 considered to be promotion? Do FDAs requirements for promotional
379 materials apply to HCEI?
380
381 A. A.9. HCEI disseminated in accordance with section 502(a) is promotion, and,
382 therefore, is subject to FDAs requirements for submission of promotional
383 materials. These include, but are not limited to, the post-marketing requirement at
384 21 CFR 314.81(b)(3)(i) to submit such materials to FDA at the time of initial
385 publication or dissemination (using Form FDA 2253 (Transmittal of
386 Advertisements and Promotional Labeling for Drugs and Biologics for Human
387 Use)) and, for HCEI about drugs submitted for approval under the accelerated
388 approval pathway or about drugs approved based on animal studies,49 the
389 requirements regarding pre-dissemination submission of promotional materials.

48
For further guidance regarding characteristics of valid and reliable assessments of COAs, please see FDAs
guidance for industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support
Labeling Claims.
49
See 21 CFR 314.550, 314.640, 601.45, and 601.94.

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390 All supporting information for HCEI should be referenced and be made available
391 upon request.50
392
393 Q. A.10. What are the Agencys policies for communication of HCEI regarding
394 unapproved uses of approved drugs?
395
396 A. A.10. FDA has issued a draft guidance describing our thinking on how firms can
397 respond to unsolicited requests, including requests from payors, for unapproved
398 use information related to their FDA-approved prescription drugs and FDA-
399 approved or cleared medical devices.51 In addition, FDA has provided separate
400 guidances describing recommended practices for the dissemination by firms of
401 scientific and medical publications discussing unapproved uses of approved drugs
402 or approved or cleared medical devices.52,53
403
404 Q. A.11. What are the Agencys policies regarding risk-sharing and other value-based
405 contracts between firms and payors?
406
407 A. A.11. This guidance addresses the communication of HCEI to payors, which may
408 include communication of HCEI in the course of discussions between firms and
409 payors related to risk-sharing and other value-based contracts. This guidance,
410 however, is not intended to address the terms of contracts between firms and
411 payors. FDA does not regulate the terms of contracts between firms and payors.
412
413 B. Communications by Firms to Payors Regarding Investigational Drugs and
414 Devices
415
416 Medical product firms may wish to provide certain types of information to payors regarding
417 their investigational products. Such information may help payors plan and budget for future
418 coverage and/or reimbursement decisions prior to FDA approval or clearance of
419 investigational products. This section provides answers to frequently asked questions on this
420 topic.
421

50
In addition, under section 502(a), if FDA requests submission of information that is relevant to the substantiation
of HCEI, firms are required to provide FDA such information, which may include the primary data and analysis
methods used to support the HCEI.
51
FDAs draft guidance Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs
and Medical Devices.
52
FDAs guidance Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or
Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical
Devices (January 2009), available at http://www.fda.gov/RegulatoryInformation/Guidances/ucm125126.htm.
53
FDAs revised draft guidance Distributing Scientific and Medical Publications on Unapproved New Uses
Recommended Practices (February 2014).

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422 Q. B.1. What are the types of information covered by this section of the draft guidance
423 and what is FDAs approach with respect to firms that wish to provide such
424 information prior to FDA approval or clearance of an investigational product?
425
426 A. B.1. FDA does not intend to object, under 21 CFR 312.7(a) or 21 CFR 812.7(a) or
427 otherwise, to the following types of information about investigational products (as
428 defined in this guidance) provided by firms to payors prior to FDA approval or
429 clearance, that is unbiased, factual, accurate, and non-misleading and when
430 presented with information discussed in Q.B.2/A.B.2:
431
432 Product information (e.g., drug class, device design)
433
434 Information about the indication sought, such as information from the clinical
435 study protocol(s) about endpoint(s) being studied and the patient population
436 under investigation (e.g., number of subjects enrolled, subject enrollment
437 criteria, subject demographics)
438
439 Factual presentations of results from clinical or preclinical studies (i.e., no
440 characterizations or conclusions should be made regarding the safety or
441 effectiveness of the product)
442
443 Anticipated timeline for possible FDA approval/clearance
444
445 Product pricing information
446
447 Targeting/marketing strategies (e.g., outreach activities planned to generate
448 prescriber awareness about the product)
449
450 Product-related programs or services (e.g., patient support programs)
451
452 Q.B.2. What other information should firms provide to payors when communicating
453 information about their investigational products?
454
455 A. B.2. FDA recommends that firms provide the following information to payors when
456 communicating information about investigational products:
457
458 A clear statement that the product is under investigation and that the safety or
459 effectiveness of the product has not been established
460
461 Information related to the stage of product development (e.g., the phase of
462 clinical trial in which a product is being studied and how it relates to the
463 overall product development plan)
464
465 FDA also suggests that firms provide follow-up information to payors if
466 previously communicated information becomes outdated as a result of significant
467 changes or as a result of new information regarding the product (e.g., failure to

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468 meet primary effectiveness endpoint in the phase 3 trial) or its review status (e.g.,
469 an application is determined to not be ready for approval upon completion of the
470 review cycle, a study is placed on a clinical hold).
471
472 Q. B.3. What types of information would be considered inappropriate to communicate
473 to payors about investigational products?
474
475 A. B.3. Communications between firms and payors that represent that an investigational
476 product is FDA-approved/cleared or otherwise safe or effective for the purpose(s)
477 for which it is under investigation would not be appropriate.

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