Guidance for industrious

Guidance for Industry
Format and Content of
Proposed Risk Evaluation and
Mitigation Strategies (REMS),
REMS Assessments, and
Proposed REMS Modifications
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit 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) Kathleen Frost 301-796-2380, or (CBER) the Office of Communication, Outreach, and Development (OCOD) at 301-827-1800 or 800-835-4709.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
September 2009
Drug Safety
Guidance for Industry
Format and Content of
Proposed Risk Evaluation and
Mitigation Strategies (REMS),
REMS Assessments, and
Proposed REMS Modifications
Additional copies are available from:
Office of Communications
Division of Drug Information, WO51, Room 2201
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
Phone: 301-796-3400; Fax: 301-847-8714
druginfo@fda.hhs.gov
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
and/or
Office of Communication, Outreach, and Development (OCOD)
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448
Phone: 800-835-4709 or 301-827-1800
E-mail: ocod@fda.hhs.gov
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
September 2009
Drug Safety
TABLE OF CONTENTS
I.
INTRODUCTION
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1
II.
BACKGROUND
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2
A.
FDAAA and REMS: Initial Approval and Postapproval Requirements
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2
B.
Relationship Between REMS and RiskMAPs
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3
C.
Products Deemed to Have in Effect an Approved REMS
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4
D.
Content of a REMS
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5
E.
Assessments and Modifications of Approved REMS
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6
F.
REMS Are Enforceable
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7
III.
CONTENT OF A PROPOSED REMS SUBMISSION TO FDA
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A.
Content of the Proposed REMS
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7
B.
Content of the REMS Supporting Document
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16
C.
Foreign Language REMS
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21
IV.
REMS ASSESSMENT AND PROPOSED REMS MODIFICATION
SUBMISSIONS TO FDA
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22
V.
COMMUNICATING WITH FDA REGARDING REMS
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23
A.
Submission Type
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23
B.
Document Identification
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23
C.
Questions about REMS
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26
GLOSSARY
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28
ATTACHMENT A
: EXAMPLE OF A REMS DOCUMENT
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30
FOR A FICTITIOUS DRUG
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Contains Nonbinding Recommendations
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1
2 Guidance for Industry1
3 Format and Content of Proposed Risk Evaluation and
4 Mitigation Strategies (REMS), REMS Assessments,
5 and Proposed REMS Modifications
6
7
8
This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current 9
thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 10
bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 11
the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 12
staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 13
the appropriate number listed on the title page of this guidance. 14
15 16 17 I. INTRODUCTION 18 19 This document provides guidance to industry on: 20 • The format and content of a proposed risk evaluation and mitigation strategy (REMS), 21 including REMS supporting documentation; 22 • The content of assessments and proposed modifications of approved REMS; 23 • What identifiers to use on REMS documents; and 24 • How to communicate with FDA about a REMS. 25 26 This guidance applies to certain drug and biological products submitted for approval or approved 27 under sections 505(b) or 505(j) of the Federal Food, Drug, and Cosmetic Act (FDCA), or section 28 351 of the Public Health Service Act (PHS Act), that are required by FDA to have a REMS. The 29 information on the content of a proposed REMS submission (section III of this document) also 30 applies to proposed REMS that are voluntarily submitted by applicants or holders of approved 31 applications (see section II.A of this document). 32 33 This guidance will address REMS elements and provisions that are broadly applicable to 34 proposed REMS and to assessments and modifications of approved REMS. Other provisions, 35 such as those that pertain only to abbreviated new drug applications (ANDAs), or expanded 36 information about REMS assessments and proposed modifications, will not be fully addressed, 37 but will be the subject of future guidance. 38 39 FDA’s guidance documents, including this guidance, do not establish legally enforceable 40 responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should 41 be viewed only as recommendations, unless specific regulatory or statutory requirements are
1 This guidance has been prepared by the FDAAA Title IX Working Group in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.
Contains Nonbinding Recommendations
Draft — Not for Implementation
42 cited. The use of the word should in Agency guidances means that something is suggested or 43 recommended, but not required. 44 45 II. BACKGROUND 46 47 A. FDAAA and REMS: Initial Approval and Postapproval Requirements 48 49 On September 27, 2007, the President signed into law the Food and Drug Administration 50 Amendments Act of 2007 (FDAAA) (Public Law 110-85).2 Title IX, Subtitle A, section 901 of 51 this statute created new section 505-1 of the FDCA, which authorizes FDA to require persons 52 submitting certain applications (applicants) to submit a proposed REMS as part of such 53 application if the FDA determines that a REMS is necessary to ensure that the benefits of a drug 54 outweigh the risks of the drug.3 Section 505-1 applies to applications for approval of 55 prescription drugs submitted under FDCA subsections 505(b) or (j) and applications submitted 56 under section 351 of the Public Health Service Act. These applications are termed covered 57 applications and refer to new drug applications (NDAs), abbreviated new drug applications 58 (ANDAs), and biologics license applications (BLAs). Please note that the term “drug” is used in 59 this guidance to refer to prescription drug and biologic products for which there are pending or 60 approved applications. 61 62 Section 505-1 also authorizes FDA to require holders of covered applications approved without a 63 REMS to submit a proposed REMS if the FDA becomes aware of new safety information as 64 defined in 505-1(b)(3) and determines that such a strategy is necessary to ensure that the benefits 65 of the drug outweigh the risks of the drug. Once the holder of an approved covered application 66 is notified by FDA that a REMS is necessary, the holder must submit a proposed REMS within 67 120 days, or within such other reasonable time as FDA requires to protect the public health 68 (section 505-1(a)(2)(B)). 69 70 In addition, persons with certain covered applications that were approved before the effective 71 date of Subtitle A, March 25, 2008, were deemed to have in effect an approved REMS and were 72 also required to submit a proposed REMS. See section II.C of this document, Products Deemed 73 to Have in Effect an Approved REMS. 74 75 An applicant may voluntarily submit a proposed REMS without having been required to do so by 76 FDA. For instance, without having been notified by FDA to submit a proposed REMS, an 77 applicant may include a proposed REMS in an original application or in a supplemental 78 application, or in an amendment to an existing original or supplemental application, if the 79 applicant believes a REMS would be necessary to ensure that the benefits of the drug outweigh 80 its risks and the other relevant statutory criteria in section 505-1 are met. Section V of this 81 document describes submission types and document identification. If FDA determines that a
2 See
http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmen dmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/default.htm.
3 Subtitle A took effect on March 25, 2008, 180 days after enactment of FDAAA.
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82 REMS is necessary to ensure that the benefits of the drug outweigh the risks, FDA will 83 determine which elements of a REMS are necessary and will approve the REMS once the 84 Agency has determined that the proposed REMS will ensure that the benefits of the drug 85 outweigh the risks, and the other relevant statutory criteria in section 505-1 are met. An 86 approved REMS that was voluntarily submitted is subject to the same requirements and 87 enforcement as a REMS that was originally submitted as a required proposed REMS. If an 88 applicant voluntarily submits a proposed REMS, it will not be approved as a REMS unless and 89 until the FDA determines that it is required to ensure that the benefits of the drug outweigh the 90 risks and that it meets the FDAAA criteria. Proposed REMS that are not approved are not 91 subject to the requirements and enforcement of an approved REMS. FDA will notify applicants 92 who voluntarily submit a proposed REMS whether the REMS will be required. If the FDA 93 determines that a REMS is not required, an applicant may undertake voluntary risk management 94 measures that would be performed outside of a REMS. 95 96 B. Relationship Between REMS and RiskMAPs 97 98 Before FDAAA was enacted, FDA approved a small number of drug and biological products 99 with risk minimization action plans (RiskMAPs). A RiskMAP is a strategic safety program 100 designed to meet specific goals and objectives in minimizing known risks of a product while 101 preserving its benefits. RiskMAPs were developed for products that had risks that required 102 additional risk management strategies beyond describing the risks and benefits of the product in 103 labeling and performing required safety reporting. For the majority of approved products, 104 labeling and routine reporting requirements are sufficient to mitigate risks and preserve benefits. 105 In a small number of cases, when additional measures were needed to ensure that the benefits of 106 a drug outweigh the risks of the drug, FDA approved the drug with a RiskMAP. In 2005, FDA 107 issued a guidance for industry on Development and Use of Risk Minimization Action Plans4 (the 108 RiskMAP guidance), that described how to develop RiskMAPs, select tools to minimize risks, 109 evaluate and monitor RiskMAPs and monitoring tools, and communicate with FDA about 110 RiskMAPs. 111 112 Now that FDAAA has given FDA the authority to require REMS when necessary to ensure that 113 the benefits of a drug outweigh the risks, FDA anticipates that: 114 115 • A product that would previously have been approved with a RiskMAP will, instead, be 116 approved with a REMS if statutory requirements for a REMS are met.5 117 • Products that would previously have been approved with a Medication Guide or patient 118 package insert that meet the statutory requirements for a REMS will now be required to 119 have a REMS. 120 • While certain products approved with RiskMAPs that included certain types of risk 121 management tools have been deemed to have in effect an approved REMS (see section 122 II.C of this document), all other approved RiskMAPs and approved Medication Guides 123 and patient package inserts that were in place when Subtitle A took effect will continue 124 to be in effect, unless they are replaced by or included in a REMS. They will be
4 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071616.pdf 5 Unless it is an ANDA based on a reference listed drug with an approved RiskMAP.
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125 replaced by or included in a REMS if FDA determines, based on new safety 126 information identified after approval of the product, that a REMS is necessary to ensure 127 that the benefits of the drug outweigh the risks. 128 • ANDAs for which the reference listed drug has an approved RiskMAP will be approved 129 with a comparable RiskMAP that includes the same essential elements. 130 • ANDAs for which the reference listed drug has a REMS will be approved with the 131 elements of that REMS applicable to ANDAs. 132 • Revisions of existing Medication Guides or patient package inserts that meet REMS 133 requirements will be approved as part of a REMS. 134 135 Many of the principles that were included in the RiskMAP guidance are embodied in the 136 FDAAA REMS provisions as implemented by FDA. Many of those principles pertaining to 137 REMS are included in this guidance, and others will be included in future guidance documents 138 related to REMS. The RiskMAP guidance continues to apply to products with existing 139 RiskMAPs (e.g., products with RiskMAPs that were not deemed to have in effect an approved 140 REMS) and to products with new RiskMAPs (e.g., ANDAs for which the reference listed drug 141 has a RiskMAP). 142 143 C. Products Deemed to Have in Effect an Approved REMS 144 145 Section 909(b)(1) of FDAAA addresses products approved before the effective date of Subtitle A 146 that have been deemed to have in effect an approved REMS. 147 148 A drug that was approved before the effective date of this Act is . . . deemed to 149 have in effect an approved risk evaluation and mitigation strategy under section 150 505-1 of the Federal Food, Drug, and Cosmetic Act . . . if there are in effect on 151 the effective date of this Act elements to assure safe use— 152 (A) required under section 314.520 or section 601.42 of title 21, Code of 153 Federal Regulations; or 154 (B) otherwise agreed to by the applicant and the Secretary for such drug. 155 156 Section 909(b)(2) states that the REMS for a drug deemed to have an approved REMS consists 157 of the timetable required under section 505-1(d) and any additional elements under subsections 158 505-1(e) and (f) in effect for the drug on the effective date of FDAAA. 159 160 Section 909(b)(3) of FDAAA states:
161 Not later than 180 days after the effective date of this Act, the holder of an 162 approved application for which a risk evaluation and mitigation strategy is 163 deemed to be in effect . . . shall submit to the Secretary a proposed risk 164 evaluation and mitigation strategy. Such proposed strategy is subject to section 165 505-1 of the Act as if included in such application at the time of submission of 166 the application to the Secretary.6 167
6 121 Stat. 951.
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Contains Nonbinding Recommendations
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168 On March 27, 2008, FDA published in the Federal Register a list of drugs that were identified as 169 deemed to have an approved REMS, and directed holders of approved applications for those 170 products to submit a proposed REMS by September 21, 2008.7 For most of these drugs, the 171 elements of the existing RiskMAPs or restricted distribution and risk management programs 172 were or will be simply converted to the new content and format of a REMS in the proposed 173 REMS. FDA generally does not intend to make substantial changes to these programs during 174 this conversion unless new safety or effectiveness information identified since the drug was 175 approved (including an evaluation of the program identifying deficiencies) suggests that the 176 existing REMS should be modified to ensure that the benefits of the product outweigh the risks. 177 In those cases, FDA has or will require modifications to the REMS. 178 179 D. Content of a REMS 180 181 A REMS for an NDA or BLA product must have a timetable for submission of assessments of 182 the REMS (505-1(d)). In addition, a REMS may include any or all of the other REMS elements, 183 if specified criteria are met. These additional elements are listed below and described in more 184 detail in section III of this document: 185 186 1. Timetable for Submission of Assessments 187 188 Section 505-1(d) requires that all approved REMS for NDA and BLA products have a 189 timetable for submission of assessments of the REMS. FDAAA specifies that the timetable 190 for submission of assessments of the REMS must include an assessment by the dates that 191 are 18 months and 3 years after the strategy is approved, and an assessment in the 7th year 192 after the strategy is approved, or at another frequency specified in the strategy (see section 193 III.A.6 of this document for additional information). 194 195 2. Additional Potential Elements 196 197 Section 505-1(e) lists “Additional Potential Elements” of a REMS that may include the 198 following (see section III.A.3 of this document for additional information): 199 200 • A Medication Guide as provided for under part 208 of title 21, Code of Federal 201 Regulations 202 • A patient package insert if such insert may help mitigate a serious risk of the drug 203 • A communication plan to health care providers if the plan may support 204 implementation of an element of the strategy 205 206 3. Elements to Ensure Safe Use (ETASU) 207
7 See Federal Register Notice “Identification of Drugs and Biological Products Deemed to Have Risk Evaluation and Mitigation Strategies (REMS) for Purposes of the Food and Drug Administration Amendments Act of 2007” (73 FR 16313, March 27, 2008).
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208 Section 505-1(f)8 lists certain Elements to Assure Safe Use that may be required if the drug 209 has been shown to be effective, but is associated with a serious adverse event and can be 210 approved only if, or would be withdrawn unless, such elements are required as part of a 211 strategy to mitigate the specific serious risk(s) listed in the labeling of the product. 212 Elements to assure safe use may be required for approved products when an assessment 213 and Medication Guide, patient package insert, or communication plan are not sufficient to 214 mitigate these risks. The elements to assure safe use must include one or more goals to 215 mitigate the specific serious risk(s). If a REMS includes certain elements to assure safe 216 use, the REMS may also include required implementation systems to enable the applicant 217 to monitor, evaluate, and improve the implementation of the elements (see section III.A.4 218 of this document for additional information). 219 220 This guidance document uses the word tool to describe a process or system designed to 221 implement one or more REMS elements. In some cases, an element itself, such as a Medication 222 Guide, may be viewed as a tool. In other cases, such as for an ETASU that requires that a drug 223 be dispensed to patients with evidence or other documentation of safe-use conditions (505224 1(f)(3)(D)), specific tools are used to implement a REMS element; for example, systems to 225 ensure that certain laboratory test result outcomes are obtained before a drug may be dispensed. 226 227 E. Assessments and Modifications of Approved REMS 228 229 FDAAA includes provisions for the assessment and modification of an approved REMS in 230 section 505-1(g). Additional information on assessments and modifications is included in 231 sections III.B.4 and IV of this document. 232 233 1. Voluntary Assessments and Proposed Modifications (505-1(g)(1) and (4)) 234 235 In addition to required assessments of an approved REMS described below, an 236 applicant may voluntarily submit an assessment of, and propose modifications to, an 237 approved REMS at any time. Proposed modifications may enhance or reduce the 238 approved REMS, and may include additions to or modifications of the timetable for 239 submission of assessments, including a proposal to eliminate assessments, and/or the 240 addition, modification, or removal of a Medication Guide, patient package insert, 241 communication plan or ETASUs. 242 243 2. Required assessments (505-1(g)(2)) 244 245 REMS assessments are required under the following circumstances: 246 247 • When submitting a supplemental application for a new indication for use, unless 248 the approved REMS for the drug includes only a timetable for submission of 249 assessments. FDA anticipates rarely requiring a REMS that includes only a 250 timetable for submission of assessments.
8 FDA is considering the implications of section 505-1(f) on the restricted distribution provisions under 21 CFR 314 Subpart H (drugs) – 314.520, and 21 CFR 601 Subpart E (biologics) – 601.42 and will address this in a future guidance.
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251 • When required by the approved REMS, as provided for in the timetable for 252 submission of assessments 253 • When required by the FDA, within a time period to be determined by the FDA, if 254 the FDA determines that new safety or effectiveness information indicates that the 255 timetable for submission of assessments should be modified and/or that a 256 Medication Guide, patient package insert, communication plan, or ETASUs should 257 be added, modified, or removed 258 • Within 15 days when ordered by the FDA, if the FDA determines that there may 259 be a cause for withdrawal or suspension of approval under section 505(e) of the 260 FDCA 261 262 F. REMS Are Enforceable 263 264 REMS required under section 505-1 are subject to inspection and are enforceable under the 265 FDCA as amended by FDAAA.9 A drug is misbranded under section 502(y) if the responsible 266 person for that drug10 fails to comply with a requirement of the approved strategy. Also, under 267 section 303(f)(4)(A) of the FDCA, a responsible person who violates a REMS requirement is 268 subject to civil monetary penalties of up to $250,000 per violation, not to exceed $1 million in a 269 single proceeding. These penalties increase if the violation continues more than 30 days after 270 FDA notifies the responsible person of the violation. The penalties double for the second 30-day 271 period, and continue to double for subsequent 30-day periods, up to $1 million per period and 272 $10 million per proceeding. In imposing a monetary penalty, FDA will consider the responsible 273 person’s efforts to correct the violation. In addition, under 505(p), a person may not introduce or 274 deliver for introduction into interstate commerce an approved drug that is the subject of a 275 covered application, if a REMS is required with respect to that drug, and the person fails to 276 maintain compliance with the requirements of the approved REMS or with other requirements 277 under 505-1, such as requirements regarding assessments of approved REMS. 278 279 280 III. CONTENT OF A PROPOSED REMS SUBMISSION TO FDA 281 282 A proposed REMS submission to FDA should include two parts: a proposed REMS, which is a 283 concise document that describes the proposed goals and elements of the REMS and, once 284 approved, will be the basis for enforcement; and a REMS supporting document, that expands on 285 information included in the proposed REMS and provides additional information not included in 286 the proposed REMS, including a thorough explanation of the rationale for, and supporting 287 information about, the content of the proposed REMS. These two parts of a proposed REMS 288 submission are described below. 289 290 A. Content of the Proposed REMS 291 292 The proposed REMS should include concise information describing the goal(s) of the REMS and 293 the REMS element(s) proposed for inclusion in the approved REMS for the specified product.
9 See FDAAA Title IX, section 902.
10 The term ‘responsible person’ means the person submitting a covered application or the holder of the approved
such application. Section 505-1(b)(7).
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294 All proposed materials that are included as part of the REMS (e.g., proposed communication and 295 education materials, Medication Guide, patient package insert, enrollment forms, prescriber and 296 patient agreements) should be appended to the proposed REMS. The proposed REMS should be 297 written to clearly describe the responsibilities of the applicant in implementing the REMS; for 298 example, statements will generally begin with, “[Name of the applicant] will…” The proposed 299 REMS should include the date by which each of the REMS elements will be implemented. 300 301 A template for the proposed REMS is available on the FDA’s “Postmarket Drug Safety 302 Information for Patients and Providers” Web site, at 303 http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProvider 304 s/default.htm. Attachment A provides an example of a completed proposed REMS for a 305 fictitious product that an applicant would submit to FDA for review. The preferred template may 306 be periodically updated as we gain more experience with REMS; therefore, applicants should 307 check the Web site for the latest version. Questions should be directed to the FDA contacts 308 described in section V.C of this document. 309 310 Prior to approving a REMS, FDA may require applicants to revise a proposed REMS to ensure 311 that the benefits of the drug will outweigh the risks. 312 313 FDA will append any REMS materials that will be included in the approved REMS, as described 314 above, to the final REMS. The final REMS and appended documents will be referenced in and 315 appended to the approval letter for the application or supplement that contains the proposed 316 REMS, and the approval letter and appended documents will be posted on the following FDA 317 Web sites: 318 319 For products regulated by CDER: 320 321 • The Drugs@FDA Web site at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. 322 • The Postmarket Drug Safety Information for Patients and Providers Web site 323 (http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsand 324 Providers/default.htm). This Web site also includes a list of approved REMS 325 (http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsand 326 Providers/ucm111350.htm). The list of approved REMS includes links to the REMS 327 document and REMS materials, excluding Medication Guides. 328 • Medication Guides can be accessed on the Drugs@FDA Web site and on the Postmarket 329 Drug Safety Information for Patients and Providers Web site through the link to approved 330 Medication Guides (http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm). 331 332 For products regulated by CBER: 333 334 • The Biologics Products and Establishments Web site at 335 http://www.fda.gov/BiologicsBloodVaccines/ucm121134.htm 336 • The Postmarket Drug Safety Information for Patients and Providers Web site (see link 337 above) 338
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339 The elements of an approved REMS are enforceable under FDAAA, Title IX, section 902 (see 340 section II.F of this document), and any changes to the REMS, including to the appended 341 documents, must be submitted as a proposed modification of an approved REMS and approved 342 by FDA before being implemented (see section IV). 343 344 The proposed REMS should contain the following sections as appropriate to manage the risks of 345 the particular product; if an applicant is not proposing one of the elements, the proposed REMS 346 should include a statement that the element is not necessary. 347 348 1. Product and Contact Information 349 350 The proposed REMS should include the application number, proprietary and established names, 351 dosage form of the product, the drug class as described in the product’s label, and the applicant’s 352 name and address. The proposed REMS should also include contact information, including 353 position titles, for those responsible for the REMS policy, management, and implementation. 354 355 2. Goals 356 357 All REMS should include a statement of one or more overall goals. In addition, if the REMS has 358 one or more elements to assure safe use (505-1(f)), the REMS must include one or more goals to 359 mitigate a serious risk listed in the labeling of the drug for which the ETASUs are required. 360 Even when ETASUs are not part of a REMS (e.g., a REMS with a Medication Guide or 361 communication plan only), the goals of the REMS should be identified. Assessments of 362 approved REMS should measure whether the goals are being met. 363 364 As used in this document, a proposed REMS goal is the desired safety-related health outcome or 365 the understanding by patients and/or health care providers of the serious risks targeted by the use 366 of specified REMS elements. REMS goals should target the achievement of particular health 367 outcomes or knowledge related to known safety risks and should be stated in a way that aims to 368 achieve maximum risk reduction. The following are examples of REMS goals: “Patients taking 369 W drug should be aware of the serious risks relative to the potential benefits,” “Patients on X 370 drug should not also be prescribed Y drug,” or “Fetal exposures to Z drug should not occur.” 371 Goals should be stated in absolute terms. Although it might not be possible to ensure that the 372 goal can be met for every patient (i.e., no one on X drug receives Y drug), FDA believes that a 373 goal, as the term implies, is a statement of the ideal outcome of a REMS. 374 375 REMS goals should be associated with pragmatic, specific, and measurable program objectives 376 that result in processes or behaviors leading to achievement of the REMS goals. Objectives can 377 be thought of as intermediate steps to achieving the overall REMS goal. A REMS goal can be 378 associated with more than one objective, depending upon the frequency, type, and severity of the 379 specific risk or risks being minimized. For example, a goal may be the elimination of 380 occurrences of a serious adverse event caused by an interaction of the drug with another drug. 381 The objectives could include lowering physician co-prescribing rates and/or pharmacist co382 dispensing rates for the specific drugs.
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383 384 3. Additional Potential REMS Elements 385 386 (a) Medication Guide and/or Patient Package Insert 387 388 As one element of a REMS, the FDA may require the development of a Medication 389 Guide, as provided for under 21 CFR part 208, which sets forth requirements for patient 390 labeling for human prescription drug products, including biological products, that the FDA 391 determines pose a serious and significant public health concern requiring the distribution 392 of FDA-approved patient information. Medication Guides will be required if the FDA 393 determines that one or more of the following circumstances exist:
394 (1) The drug product is one for which patient labeling could help prevent serious 395 adverse effects.
396 (2) The drug product is one that has serious risks (relative to benefits) of which patients 397 should be made aware because information concerning the risks could affect 398 patients’ decision to use, or to continue to use, the product.
399 (3) The drug product is important to health and patient adherence to directions for use 400 is crucial to the drug's effectiveness.
401 Under 21 CFR part 208 and in accordance with 505-1 of the FDCA, the applicant is 402 responsible for ensuring that the Medication Guide is available for distribution to patients 403 who are dispensed the drug. This section of the REMS should describe the mechanisms 404 the applicant intends to use for distribution of the Medication Guide.
405 In addition, FDA may require a patient package insert as part of a REMS if the FDA 406 determines that the patient package insert may help mitigate a serious risk of the drug. 407 Having both a required patient package insert and a Medication Guide for the same drug 408 is not expected to occur frequently. In most instances, FDA anticipates requiring a 409 Medication Guide (or requiring conversion of an existing PPI to a Medication Guide) if FDA is 410 requiring patient labeling that meets Medication Guide requirements. 411 412 The following types of changes to a PPI would not ordinarily trigger the need to convert 413 a PPI to a Medication Guide: 414 415 • Editorial changes 416 • Changes related to how to use a product (e.g., how to inject the product 417 subcutaneously) unless these changes have the potential to mitigate a serious risk, 418 such as overdose 419 420 Copies of Medication Guides and patient package inserts that are part of a REMS should 421 be appended to the proposed REMS. 422 423 (b) Communication Plan 424
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425 FDA may determine that a communication plan targeted at health care providers is a necessary 426 element of a REMS if it may support implementation of the REMS. The communication plan 427 may include sending letters to health care providers; disseminating information about REMS 428 elements to encourage implementation by health care providers or to explain certain safety 429 protocols, such as medical monitoring by periodic laboratory tests; or disseminating information 430 to health care providers through professional societies about any serious risks of the drug and 431 any protocol to assure safe use (section 505-1(e)(3)). 432 433 Copies of communication plan materials should be appended to the proposed REMS. 434 435 If an NDA has been approved with a REMS with a communication plan, and subsequently an 436 abbreviated new drug application (ANDA) is approved with that NDA product as the reference 437 listed drug, then FDA must undertake the communication plan (section 505-1(i)(2)(A)). Neither 438 the holder of the NDA that is the reference listed drug nor the ANDA holder has to undertake a 439 communication plan once an ANDA is approved. However, many tools that have previously 440 been considered part of a communication plan, such as training materials, specified procedures, 441 patient/physician agreements or other informed consent, patient educational materials, safety 442 protocols, medical monitoring procedures, and data collection forms may fit under one or more 443 elements to assure safe use (ETASU) if specified criteria are met. Both NDA holders and 444 ANDA holders are required to implement ETASUs. 445 446 4. Elements to Assure Safe Use 447 448 Elements to assure safe use are intended to provide safe access for patients to drugs with known 449 serious risks that would otherwise be unavailable. Required ETASUs are put in place to mitigate 450 a specific serious risk listed in the labeling of a drug. Before requiring one or more ETASUs, the 451 FDA must make the following determinations (505-1(f)(1)): 452 453 • That the drug, which has been shown to be effective but is associated with a serious 454 adverse drug experience, can be approved only if, or would be withdrawn unless, 455 such elements were required; and 456 • That for a drug initially approved without ETASUs, other possible elements of a 457 REMS are not sufficient to mitigate such serious risk. 458 459 This subsection of the proposed REMS should describe the ETASUs included in the proposed 460 REMS and any tools designed to implement one or more elements to assure safe use. Copies of 461 all relevant materials should be appended to the proposed REMS. Examples of relevant 462 materials include health care provider attestations; pharmacy, practitioner, health care setting, 463 and patient enrollment forms; training materials; specified procedures; patient/physician 464 agreements or other informed consent; patient educational materials; safety protocols; medical 465 monitoring procedures; and data collection forms. 466 467 The following lists the elements to assure safe use that may be included in the REMS. Note that 468 some of the tools designed to implement the elements to assure safe use may appear in more than 469 one category: 470
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471 A. Health care providers who prescribe the drug have particular training or experience, or 472 are specially certified. 473 474 In general, section 505-1(f)(3)(A) pertains to prescribers of the drug. Elements under this 475 category might require certification of training, or attestation of specific experience or 476 knowledge, before the health care provider is enrolled in a program that allows that 477 provider to prescribe the product. 478 479 For example, in order to be certified, a health care provider may be required to 480 demonstrate that he or she: 481 482 • Can diagnose the condition for which the product is indicated 483 • Understands the risks and benefits of the product and has read the educational 484 materials for prescribers 485 • Can diagnose and treat potential adverse reactions associated with the product 486 487 The program may require periodic recertification and reenrollment. 488 489 The opportunity to obtain this training or certification must be available to any willing 490 provider, for example through an on-line or mail course, at reasonable cost to the 491 provider (505-1(f)(3)(A)). 492 493 B. Pharmacies, practitioners, or health care settings that dispense the drug are specially 494 certified. 495 496 In general, section 505-1(f)(3)(B) pertains to how the drug is dispensed. Elements under 497 this category might require certification of training or attestation of specific experience or 498 knowledge before the pharmacy, practitioner, or health care setting is enrolled in a 499 program that allows the practitioner or staff at the pharmacy or health care setting to 500 dispense the product. 501 502 For example, to be certified, practitioners and staff at pharmacies, hospitals, and infusion 503 sites may be required to demonstrate that they: 504 505 • Understand the risks and benefits of the product and have read the educational 506 materials before the drug is dispensed 507 • Agree to fill a prescription and dispense the drug only after receiving prior 508 authorization 509 • Agree to check laboratory values, or check for the presence of stickers that 510 providers affix to prescriptions for specified products to indicate that the 511 patient has met all criteria for receiving the product (“qualification stickers”), 512 before dispensing a drug 513 • Agree to fill a prescription and dispense the drug only within a specified 514 period of time after the prescription is written 515 • Agree to fill prescriptions only from enrolled prescribers 516
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517 The program may require periodic recertification and reenrollment. 518 519 The opportunity to obtain this certification must be available to any willing provider 520 (505-1(f)(3)(B)). 521 522 C. The drug be dispensed to patients only in certain health care settings, such as hospitals. 523 524 In general, section 505-1(f)(3)(C) pertains to restrictions on dispensing the product to 525 patients in specific health care settings. 526 527 For example, the applicant may be required to 528 529 • Ensure the drug is dispensed only to patients in hospitals that have met 530 certain conditions 531 • Ensure the drug is dispensed only to physicians’ offices equipped to treat the 532 potential risks associated with the drug following administration of the drug 533 (e.g., access to medication and equipment necessary to treat a serious allergic 534 reaction) 535 536 D. The drug be dispensed only to patients with evidence or other documentation of safe-use 537 conditions, such as laboratory test results. 538 539 In general, section 505-1(f)(3)(D) pertains to ensuring that patients meet specified criteria 540 before drug exposure. 541 542 For example, evidence or other documentation of safe use conditions may include the 543 following: 544 545 • Patients have been counseled about the risks and benefits of the product and 546 have signed an acknowledgment that they understand the risks and benefits of 547 the product 548 • Patients have been provided a copy of patient educational materials and 549 demonstrated that they understand the risks and benefits of the product 550 • Patients receive drug only after specified authorization is obtained and 551 verified by the pharmacy. Examples of authorizations include checking 552 laboratory values and checking for physician qualification (stickers) on the 553 prescription 554 555 E. Each patient using the drug be subject to certain monitoring. 556 557 Elements under 505-1(f)(3)(E) might require that patients be monitored or that specific 558 follow-up should occur at specific time points. 559 560 Examples include the following: 561
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562 • Patients’ laboratory tests are monitored on a specified periodic basis to 563 prevent the serious risk 564 • Patients are required to contact the prescriber within a specified period of time 565 after beginning treatment with the drug to ensure they are still appropriate 566 candidates for treatment 567 • Patients are required to contact their prescriber periodically during and 568 following treatment to ensure they did not experience the serious risk 569 associated with the use of the drug 570 571 F. Each patient using the drug be enrolled in a registry. 572 573 In general, section 505-1(f)(3)(F) pertains to enrolling patients into a program as part of 574 an overall strategy to mitigate a specific serious risk listed in the labeling of the drug. 575 The use of a registry may be combined with other ETASUs, such as when a registry is 576 used to document that the drug is dispensed to patients with evidence or other 577 documentation of safe-use conditions; or to document that each patient using the drug is 578 subject to certain monitoring. 579 580 Drug access may be contingent on patient enrollment. The types of information that may 581 be collected on enrolled patients include: 582 583 • Information on clinical outcomes 584 • Clinical and laboratory data 585 • Safety information 586 • Data on compliance with prescribed management and prescribing protocols 587 • Data on the impact of tools on ensuring compliance and outcomes 588 589 Registries that are established with the primary purpose of enrolling patients to mitigate a 590 serious risk associated with a drug would be required under a REMS. Registries may 591 also serve as a repository for clinical data and allow for case finding and follow-up. 592 These registries are not considered PMRs, but studies conducted using the data may be.11 593 594 5. Implementation System 595 596 Section 505-1(f)(4) of the FDCA gives the FDA authority to require an implementation system 597 for a REMS that includes the ETASUs described under 505-1(f)(3)(B), (C), and (D). Through 598 the implementation system, the applicant may be expected to take reasonable steps to monitor 599 and evaluate implementation by health care providers, pharmacists, and other parties in the 600 health care system who are responsible for implementing those elements, and to work to improve 601 their implementation. 602
11 See the draft guidance for industry on Postmarketing Studies and Clinical Trials — Implementation of Section 505(o) of the Federal Food, Drug, and Cosmetic Act, available on the Internet at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
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603 FDA may require the implementation system to include a description of how applicable products 604 will be distributed. In addition, as part of the implementation system, FDA may require the 605 certification of wholesalers and/or distributors who distribute the product to ensure that the 606 product is distributed only to certified or otherwise specified pharmacies, practitioners, or health 607 care settings that dispense the drug, or only to patients who meet the requirements of the REMS. 608 609 Other examples of methods used to monitor and evaluate implementation of REMS with 610 ETASUs described under 505-1(f)(3)(B), (C), and (D) include the following: 611 612 • The applicant maintains a validated and secure database of all certified entities (pharmacies, 613 practitioners, and health care settings) to ensure any certification requirements or other 614 requirements for pharmacies, practitioners, or health care settings are met 615 • The applicant conducts periodic audits of pharmacies, practitioners, and health care settings 616 to ensure compliance with ETASUs (e.g., documentation of safe-use conditions prior to 617 dispensing drug) 618 • If the ETASUs include limits on where and how a drug may be dispensed, the applicant 619 conducts periodic audits of wholesale shipment or distribution systems to determine that the 620 drug is only being distributed to authorized entities 621 622 6. Timetable for Submission of Assessment of the REMS 623 624 This subsection of the proposed REMS should describe the proposed timetable for submission of 625 assessments of the REMS as required by section 505-1(d) of the FDCA. REMS for NDAs and 626 BLAs must include a timetable for submission of assessments of the REMS. REMS for ANDAs 627 do not include a timetable for submission of assessments. Additional information on REMS and 628 ANDAs will be included in future guidance. 629 630 Under section 505-1(d), each timetable for submission of assessments of a REMS must at a 631 minimum include assessments submitted by 18 months and by 3 years after the REMS is initially 632 approved, and in the 7th year after the REMS is initially approved, with additional dates if more 633 frequent assessments are necessary to ensure that the benefits of the drug continue to outweigh 634 the risks. Factors that may influence the need for more frequent assessments of the REMS 635 include, among others, the estimated size of the population likely to use the drug, the seriousness 636 of known or potential risks that may be related to the drug, and knowledge about the 637 effectiveness of REMS elements to mitigate the risks. The requirements for the assessments 638 submitted by 18 months and by 3 years may be met through assessments submitted at specified 639 earlier dates; for example, assessments required in an approved REMS to be submitted at 12 640 months and 24 months would meet the requirements for the assessments submitted by 18 months 641 and 3 years. 642 643 The timetable specifies when the assessment will be submitted to FDA, not when the assessment 644 will be performed. This subsection should specify the interval that each assessment will cover 645 and the planned date of submission to the FDA of the assessment. To facilitate inclusion of as 646 much information as possible while allowing reasonable time to prepare the submission, the 647 reporting interval covered by each assessment should conclude no earlier than 60 days before the 648 submission date for that assessment. For example, the reporting interval covered by an
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649 assessment that is to be submitted by July 31 should conclude no earlier than June 1. The 650 assessment is to be received by the FDA on or before the due date. 651 652 Requests for modification of the timetable for submission of assessments, including eliminating 653 assessments, may be made after approval of the REMS (see 505-1(g)(4)). After the assessment 654 due by 3 years after the REMS is initially approved is submitted, all further assessments, 655 including the 7th-year assessment, may be eliminated if the FDA determines that serious risks of 656 the drug have been adequately identified and assessed and are being adequately managed. 657 658 B. Content of the REMS Supporting Document 659 660 The REMS supporting document should provide a thorough explanation of the rationale for and 661 supporting information about the content of the proposed REMS. A template for the REMS 662 supporting document is available on the FDA’s “Postmarket Drug Safety Information for 663 Patients and Providers” Web site, at 664 http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProvider 665 s/default.htm. The REMS supporting document should include the sections listed in the template 666 for the applicable proposed REMS elements for the specified product, as well as a table of 667 contents. The REMS supporting document should include a description of how and when each 668 REMS element will be implemented and should specify the rationale for the overall timelines 669 and milestones. If any REMS activity will not be implemented at the time of REMS approval, 670 the REMS supporting document should include the rationale for the implementation schedule. 671 For example, the document should address the rationale for whether a communication plan 672 would be implemented before, or concurrently with, other elements. Additional information on 673 each section of the REMS supporting document is described below. 674 675 1. Background 676 677 The Background section of the REMS supporting document should explain why a REMS is 678 necessary and provide a concise summary of how the proposed REMS would ensure that the 679 benefits of the drug outweigh the risks. For a new REMS that is proposed for an already680 approved product, the Background section should also include the description of the new safety 681 information that suggests a REMS is necessary. 682 683 The Background section should describe what is known about the risk to be minimized by the 684 REMS, including the magnitude, severity, and frequency of the adverse events, whether there are 685 particular populations at risk, the background incidence of the risk in the population likely to use 686 the product, whether the adverse event can be prevented or is reversible, and the benefits that 687 would be preserved by the implementation of the REMS. It should also describe the factors that 688 FDA considers when determining whether a REMS is necessary to ensure that the benefits of the 689 drug outweigh the risks: the estimated size of the population likely to use the product, the 690 seriousness of the disease or condition that is to be treated with the product, the expected benefit 691 of the product with respect to such disease or condition, the expected or actual duration of 692 treatment with the drug, the risks and benefits of alternative therapies, and whether the drug is a 693 new molecular entity. The statute specifically requires these factors to be considered for REMS
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694 required at initial approval (505-1(a)(1)), but FDA will also consider these factors in making 695 determinations about postapproval REMS. 696 697 The Background section of the REMS supporting document should include a discussion, if 698 pertinent, about the successes and failures of actions by regulatory authorities, systems of health 699 care, or applicants in mitigating the risks of concern for this product or similar products. 700 Information on risk management plans submitted to other regulators, such as the European 701 Union’s EU Risk Management Plan,12 should be included, with a clear description of how that 702 information supports the proposed REMS, along with reasons for any differences between the 703 proposed REMS and other risk management plans for the product. 704 705 Information provided by the applicant regarding relevant past experiences, domestically or in 706 other countries, will assist in the development of REMS that are compatible with established 707 distribution, procurement, and dispensing systems within the health care delivery system, and 708 that avoid the cost of implementing REMS tools already determined to be unsuccessful. In 709 addition, we encourage applicants to provide applicable information or evaluations from past 710 experiences with products or programs that are similar to the proposed REMS. Brief 711 descriptions of the available evidence regarding the effectiveness of each element and tool 712 included in the proposed REMS may be mentioned in the Background section. Thorough 713 descriptions should be included in the “Supporting Information on Proposed REMS Elements” 714 section. 715 716 2. Goals Section 717 718 This section of the REMS supporting document should describe the rationale for the proposed 719 goals of the REMS and summarize how each proposed element and stated objectives will 720 individually and collectively contribute to achieving the goals. All REMS should include a 721 statement of one or more overall goals. In addition, if the REMS has one or more elements to 722 assure safe use (505-1(f)), the REMS must include one or more goals to mitigate a serious risk 723 listed in the labeling of the drug for which the elements to assure safe use are required. Even if a 724 REMS does not contain elements to assure safe use (e.g., a REMS that includes a Medication 725 Guide or communication plan only), the goals of the REMS should be identified. Additional 726 information about how each particular element and tool will contribute to achieving the goals of 727 the REMS should be included in the “Supporting Information About Proposed REMS Elements” 728 section described immediately below. REMS goals are described in more detail in section 729 III.A.2 of this document. 730 731 3. Supporting Information About Proposed REMS Elements 732 733 This section should include a description of why particular elements and tools were chosen for 734 the proposed REMS and how each particular element and tool will contribute to achieving the 735 goals of the REMS. Each subsection about elements included in the proposed REMS should 736 include a thorough description of the element(s) proposed for mitigating the risk or risks targeted 737 by the proposed REMS; any tools proposed to be implemented under each element; how the
12 GUIDELINE ON RISK MANAGEMENT SYSTEMS FOR MEDICINAL PRODUCTS FOR HUMAN USE, Doc. Ref. EMEA/CHMP/96268/2005 http://www.emea.europa.eu/pdfs/human/euleg/9626805en.pdf.
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738 elements or tools will mitigate the risk; how the elements or tools conform with elements or tools 739 for other products with similar risks; and whether the elements or tools are compatible with 740 established distribution, procurement, and dispensing systems. 741 742 A thorough description of the available evidence regarding the effectiveness of each element or 743 tool should be provided, including, where applicable, results from pretesting of proposed 744 elements or tools or a time frame for when these will be submitted. These subsections should 745 also note whether the applicant sought input from patient or health care interests, and if so, a 746 description of the feedback received regarding the feasibility of its REMS. 747 748 Elements to Assure Safe Use. Section 505-1(f)(2) requires that FDA consider how to ensure 749 access and minimize the burden of a REMS that includes ETASUs. Therefore, for a proposed 750 REMS that includes ETASUs, the Elements to Assure Safe Use subsection of the REMS 751 supporting document should include the following: 752 753 • An explanation of how the proposed ETASUs correspond to the specific serious risks 754 listed in the labeling 755 • An explanation of how the proposed ETASUs will mitigate the observed serious risk 756 • Verification that the proposed elements are not unduly burdensome on patient access to 757 the drug considering the risk being mitigated. Include particular consideration of 758 patients with serious or life-threatening diseases or conditions and patients who have 759 difficulty accessing health care. 760 • A description of how, to the extent practicable, the proposed ETASUs will minimize the 761 burden on the health care delivery system: how the proposed ETASUs conform to 762 those required for other drugs with similar serious risks, and how the proposed elements 763 are designed to be compatible with established distribution, procurement, and 764 dispensing systems for drugs. 765 766 Implementation System. This subsection should include the rationale and supporting information 767 for the proposed implementation system, including each method used to monitor and evaluate 768 implementation of the REMS and any planned ways to improve its implementation. 769 770 Timetable for Submission of Assessments of the REMS. This subsection should include the 771 rationale and supporting information for the proposed timetable for submission of assessments of 772 the REMS. This subsection should also include the rationale for the interval that each 773 assessment will cover and for the planned date the assessment will be submitted to the FDA. 774 775 4. REMS Assessment Plan 776 777 This section should describe the rationale and supporting information for the proposed plan to 778 assess the REMS. Section 505-1(g) of the FDCA describes the requirements for REMS 779 assessments. REMS assessments should include an evaluation of the extent to which each of the 780 REMS elements are meeting the goals and objectives of the REMS, and whether or not the goals, 781 objectives, or REMS elements should be modified. Plans to obtain this information should be 782 included in the REMS supporting document to ensure that sufficient information will be 783 collected to do a valid assessment of the REMS.
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784 785 In accordance with section 505-1(g)(3)(A), for a REMS that includes one or more ETASUs, the 786 REMS assessment shall include an assessment of the extent to which the ETASUs are meeting 787 the goal (see section III.A.2), or whether the goal or such elements should be modified. 788 789 This subsection should describe the proposed REMS assessment plan, including the following: 790 791 • The proposed evaluation methods (including measurements or measures) for assessing 792 the overall effectiveness of the REMS and the effectiveness of each of the REMS 793 elements and tools (e.g., claims-based data systems, surveys, registries) and the rationales 794 for the chosen measures. 795 • Targeted values for each measure and the timeframe for achieving them. Include 796 interpretations of expected results under best- and worst-case scenarios. In addition, this 797 section should specify what values of measures at specific time points will trigger 798 consideration of REMS modification. 799 • The type of data that will be collected, and the nature and timing of data collection, 800 analyses, audits, or monitoring that will be used to assess the performance of each 801 individual REMS element or tool in achieving the REMS’s objectives and goals. 802 • Where applicable and possible, this section should discuss plans to assess unintended 803 and/or unfavorable consequences of the REMS following implementation. 804 805 For example, a REMS may indicate that the following data will be collected to support an 806 assessment: 807 808 • A survey to evaluate knowledge of a labeled serious adverse event to determine whether 809 patients are using the product correctly to prevent the adverse event, or to evaluate use of 810 the product as labeled, particularly when the indicated use is for a restricted population or 811 when numerous contraindications exist. 812 813 • Information about use patterns of the drug including: 814 o Use by prescriber specialty 815 o Patient-level data (age, gender, race) 816 o Length of therapy 817 o Indication 818 819 • Population-based administrative or claims-based data that capture service or payment 820 claims to measure rates of specified serious adverse events. 821 822 • Active surveillance using sentinel reporting sites to determine rates of specified serious 823 adverse events. 824 825 Whenever possible, specific assessment instruments (e.g., surveys) and methodology should be 826 included in the REMS supporting document. If the assessment instruments and methodology are 827 not available when the proposed REMS is submitted to FDA, at least 90 days before the 828 assessments will be conducted, the applicant should update the REMS supporting document to 829 include specific assessment instrument and methodology information. Updates to the REMS
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830 supporting document may be included in a new document that references previous REMS 831 supporting document submission(s) for unchanged portions of the REMS, or updates may be 832 made by modifying the complete previous REMS supporting document, with all changes marked 833 and highlighted. See section V.B.3 for information on how to identify the submission that 834 includes specific assessment instruments when they are submitted after the REMS is approved. 835 836 For a REMS that includes a Medication Guide, information needed for assessment of the REMS 837 should include but may not be limited to the following: 838 839 (a) Survey of patients’ understanding of the serious risks of the drug 840 (b) Report on periodic assessments of the distribution and dispensing of the Medication 841 Guide in accordance with 21 CFR 208.24 842 (c) Report on failures to adhere to distribution and dispensing requirements, and 843 corrective actions taken to address noncompliance 844 845 If a product is distributed in unit-of-use packaging that includes a Medication Guide with a 846 quantity of product dispensed to a single patient and not divided, the reports in (b) and (c) above 847 would not be necessary. 848 849 This subsection of the REMS supporting document might also include information describing the 850 rationale for, and a description of, all elements proposed to be included in the assessments of the 851 REMS, such as the following: 852 853 • Narrative summary and analysis of serious adverse events of interest 854 • Summary of data that will be tracked in a REMS-related database 855 • Summary of wholesaler shipment data 856 • Summary of surveys conducted 857 • Summary of data on drug use 858 • Summary of registry data 859 • Refill frequency and amount 860 861 The assessment should include sufficient detail to identify the need for changes to the REMS. 862 For example, an applicant may be required to assess reports of adverse events associated with the 863 effectiveness of the REMS, each known occurrence of prescriptions written by health care 864 providers who do not have required certification, or dispensing of the product by a pharmacy, 865 practitioner, or health care setting that does not have the required certification. The assessment 866 should also describe any corrective actions taken for these occurrences. 867 868 Requirements for Information on the Status of Any Postapproval Study or 869 Clinical Trial Required Under Section 505(o) or Otherwise Undertaken to 870 Investigate a Safety Issue 871 872 In accordance with section 505-1(g)(3)(B) and (C), all REMS assessments shall include certain 873 information about any postapproval study or clinical trial required under section 505(o) or 874 otherwise undertaken by the applicant to investigate a safety issue.
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875 • For postapproval studies, the REMS assessment shall include the status of each study, 876 including whether any difficulties completing the study have been encountered. 877 • For postapproval clinical trials, the REMS assessment shall include 878 (a) The status of each clinical trial, including whether enrollment has begun, 879 (b) The number of participants enrolled, 880 (c) The expected completion date, 881 (d) Whether any difficulties completing the clinical trial have been encountered, and 882 (e) Registration information with respect to registry and results databank 883 requirements under subsections (i) and (j) of section 402 of the Public Health 884 Service Act. This includes information on whether the data have been 885 submitted to clinicaltrials.gov, and proper certifications have been submitted to 886 the FDA. 887 888 The REMS assessment can satisfy the requirements in section 505-1(g)(3)(B) and (C), for 889 information on the status of any postapproval study or clinical trial required under section 505(o) 890 or otherwise undertaken to investigate a safety issue, by referring to relevant information 891 included in the most recent annual report required under section 506B of the FDCA and 21 CFR 892 314.81(b)(2)(vii) or 21 CFR 601.70, and including any updates to the status information since 893 the annual report was prepared, as long as the information required about postapproval studies 894 and clinical trials described above was provided in the annual report. Failure to submit a 895 complete REMS assessment under 505-1(g)(3) could result in enforcement action. 896 897 5. Other Relevant Information 898 899 This subsection should include information on the positions within the applicant’s company 900 responsible for REMS policy, management, and implementation, including organizational 901 chart(s) that include these REMS-related positions. 902 903 In addition, this subsection should include any other information relevant to the proposed REMS 904 not included elsewhere. 905 906 C. Foreign Language REMS 907 908 Foreign-language versions of REMS, including any materials appended to the REMS such as 909 Medication Guides, patient package inserts, communication and education materials, enrollment 910 forms, prescriber and patient agreements, and others, are not considered part of the approved 911 REMS. FDA will not review foreign-language versions of REMS. 912 913 Consistent with CDER’s approach to foreign-language labeling, when applicants distribute 914 foreign-language versions of a currently approved REMS, they are responsible for ensuring that 915 such materials are complete and accurate.13 Supplemental applications for foreign-language 916 REMS are not required and should not be submitted. 917
13 Note that applicants are required to comply with the requirements regarding distribution of labels and labeling under 21 CFR 201.15(c).
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918 IV. REMS ASSESSMENT AND PROPOSED REMS MODIFICATION 919 SUBMISSIONS TO FDA 920 921 REMS assessments must be submitted according to the timetable for submission of assessments 922 included in the REMS, and as otherwise required (see section II.E of this document and 505923 1(g)). Applicants may also voluntarily submit an assessment of, and propose a modification to, 924 an approved REMS at any time. An applicant’s proposal for modification of an approved REMS 925 must include an assessment of the REMS. 926 927 Under section 505-1(g)(2)(C), when FDA determines that new safety information indicates that 928 an element of the REMS, such as a Medication Guide, should be modified, the application holder 929 is required to assess the REMS. Where the application holder agrees with the Agency's proposed 930 modification to a REMS that consists solely of a Medication Guide and/or a communication 931 plan, that assessment may consist of a statement that the Medication Guide and/or 932 communication plan would be adequate with the proposed modifications to achieve its/their 933 purpose. 934 935 Proposed modifications may include an enhancement or reduction to the approved REMS, and 936 may include additions or modifications to the timetable for submission of assessments, including 937 a proposal to eliminate assessments (after the 3-year period described in 505-1(d)), and/or the 938 addition, modification, or removal of a Medication Guide, patient package insert, communication 939 plan, or ETASU. 940 941 A proposed modification of an approved REMS that is not associated with an existing 942 supplemental application should be submitted as a new prior-approval supplemental application 943 as described in section V of this document. 944 945 Any proposed modification to the approved REMS, including any proposed changes to materials 946 that are included as part of the REMS (e.g., communication and education materials, enrollment 947 forms, prescriber and patient agreements), must be submitted as a proposed modification to an 948 approved REMS in a new prior-approval supplemental application, as described in section V of 949 this document, and must not be implemented until the modified REMS is approved by FDA. 950 951 Each proposed modification submission should include a new proposed REMS (based on the 952 proposed REMS template described in section III.A) that shows the complete previously 953 approved REMS with all proposed modifications highlighted. In addition, the submission should 954 include an update to the REMS supporting document that includes the rationale for and 955 description of all proposed modifications and any impact the proposed modifications would have 956 on other REMS elements. Updates to the REMS supporting document may be included in a new 957 document that references previous REMS supporting document submission(s) for unchanged 958 portions of the REMS, or updates may be made by modifying the complete previous REMS 959 supporting document, with all changes marked and highlighted. The content of the proposed 960 REMS and REMS supporting document are described in section III of this document. 961 Additional information on assessments and modifications to approved REMS is included in 962 section II.E of this document. More complete information on assessments and modifications of 963 approved REMS will be the subject of future guidance.
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964 965 966 V. COMMUNICATING WITH FDA REGARDING REMS 967 968 A. Submission Type 969 970 A proposed REMS may be included in the initial submission of an original or supplemental 971 application, or may be submitted as an amendment to an existing original or supplemental 972 application. All supplemental applications that include a proposed REMS or proposed 973 modifications to an approved REMS should be submitted as prior-approval supplements, not as 974 changes being effected supplements (see 21 CFR 314.70 and 601.12). 975 976 A proposed REMS submitted after approval and not associated with an existing supplemental 977 application should be submitted as a new supplemental application. 978 979 Assessments of approved REMS may be submitted voluntarily at any time and must be 980 submitted as required in the timetable for submission of assessments of the REMS and as 981 otherwise required (see sections II.E and IV of this document). A REMS assessment alone (i.e., 982 not proposing a modification) is not considered a supplemental application. 983 984 REMS assessments that include a proposed modification to the approved REMS should be 985 submitted either as a new supplemental application or included in a related supplemental 986 application. They can be included in a related supplemental application either at the time of 987 submission or as an amendment to the supplemental application. 988 989 A supplemental application for a new indication for use for a product with an approved REMS 990 must include a REMS assessment unless the drug is not subject to section 503(b) and the REMS 991 for the drug includes only the timetable for submission of assessments (505-1(g)(2)(A)). The 992 supplemental application for the new indication should include the required REMS assessment 993 and may propose modifications to the REMS. 994 995 A proposed REMS and proposed modifications to an approved REMS should be submitted using 996 the format in the template for a proposed REMS described in section III.A, and, to facilitate the 997 review process, the submission should include electronic versions of the proposed REMS or 998 proposed modifications to an approved REMS as an Adobe Acrobat pdf document and in a 999 document generated using a word processing program. 1000 1001 As described in section III.C, supplements for foreign-language REMS are not required and 1002 should not be submitted. 1003 1004 Send requests for current information on where REMS-related documents should be included 1005 when submitted as part of an electronic common technical document (eCTD) and questions 1006 about electronic submissions to FDA to the following email address: esub@fda.hhs.gov. 1007 1008 B. Document Identification 1009
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1010 1. Proposed REMS 1011 1012 Regardless of when or how a proposed REMS is submitted, it is critical to provide 1013 identifying information on the submitted REMS document so that it can be tracked, 1014 routed, and reviewed appropriately. In each case, the first page of the submission should 1015 prominently identify the submission as providing a PROPOSED REMS in bold capital 1016 letters at the top of the page. This wording on the first page of the submission should be 1017 combined with any other applicable content identification, for example: 1018 1019 When the proposed REMS is submitted as part of an original application: 1020 1021 NEW ORIGINAL APPLICATION FOR <name of drug> 1022 PROPOSED REMS 1023 1024 When the original proposed REMS is submitted as an amendment to an existing original 1025 or supplemental application: 1026 1027 NDA/BLA/ANDA [assigned #] 1028 PROPOSED REMS 1029 1030 NDA/BLA/ANDA [assigned #] SUPPLEMENT [assigned #] 1031 PROPOSED REMS 1032 1033 When the original proposed REMS is submitted postapproval as a new supplemental 1034 application: 1035 1036 NEW SUPPLEMENT FOR NDA/BLA/ANDA [assigned #] 1037 PROPOSED REMS 1038 1039 When the original proposed REMS is submitted postapproval with a new supplemental 1040 application: 1041 1042 NEW SUPPLEMENT FOR NDA/BLA/ANDA [assigned #] 1043 < other applicable content identification > 1044 PROPOSED REMS 1045 1046 On the first page of subsequent submissions related to an already-submitted proposed 1047 REMS, prominently identify the submission by including this wording in bold capital 1048 letters at the top of the letter: 1049 1050 NDA/BLA/ANDA [assigned #] 1051 PROPOSED REMS-AMENDMENT 1052 1053 NDA/BLA/ANDA [assigned #] SUPPLEMENT [assigned #] 1054 PROPOSED REMS-AMENDMENT 1055
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1056 2. Assessments and Modifications of Approved REMS 1057 1058 On the first page of the submission of an assessment of an approved REMS, prominently 1059 identify its content in bold capital letters at the top of the page: 1060 1061 NDA/BLA/ANDA [assigned #] 1062 REMS ASSESSMENT 1063 1064 If a REMS assessment is submitted as a part of another submission, it is critical to 1065 provide complete identifying information on the submission so that it can be tracked, 1066 routed, and reviewed appropriately. In each case, the first page of the submission should 1067 prominently identify the submission as providing a REMS ASSESSMENT in bold 1068 capital letters at the top of the page. This wording on the first page of the submission 1069 should be combined with any other applicable content identification. 1070 1071 The first page of the submission of an assessment of an approved REMS submitted with a 1072 supplemental application for a new indication for use should prominently identify the 1073 content in bold capital letters at the top of the page. The submission may include 1074 proposed modifications to the approved REMS. This wording on the first page of the 1075 submission should be combined with any other applicable content identification, for 1076 example: 1077 1078 NEW SUPPLEMENT FOR NDA/BLA/ANDA [assigned #] 1079 < other supplement identification > 1080 REMS ASSESSMENT 1081 PROPOSED REMS MODIFICATION (if included) 1082 1083 The first page of the submission of proposed modifications to an approved REMS 1084 submitted as a stand-alone new supplemental application or included with another new 1085 supplemental application should prominently identify the content in bold capital letters at 1086 the top of the page. This wording on the first page of the submission should be combined 1087 with any other applicable content identification, for example: 1088 1089 NEW SUPPLEMENT FOR NDA/BLA/ANDA [assigned #] 1090 < other supplement identification > 1091 PROPOSED REMS MODIFICATION 1092 REMS ASSESSMENT 1093 1094 The first page of the submission of proposed modifications to an approved REMS 1095 submitted as an amendment to a pending supplemental application should prominently 1096 identify the content in bold capital letters at the top of the page: 1097 1098 NDA/BLA/ANDA [assigned #] SUPPLEMENT [assigned #] 1099 PROPOSED REMS MODIFICATION 1100 REMS ASSESSMENT 1101
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1102 The first page of subsequent submissions related to a proposed modification to an 1103 approved REMS should prominently identify the submission by including this wording in 1104 bold capital letters at the top of the page: 1105 1106 NDA/BLA/ANDA [assigned #] SUPPLEMENT [assigned #] 1107 PROPOSED REMS MODIFICATION -AMENDMENT 1108 1109 3. Other REMS Submissions 1110 1111 An applicant may submit REMS submissions that are not proposed REMS, proposed 1112 modifications to an approved REMS, amendments to proposed REMS, proposed 1113 modifications to an approved REMS, or REMS assessments. Such submissions may 1114 include a request for information about what to include in a proposed REMS, information 1115 about the REMS assessment plan for an approved REMS (e.g., assessment instruments 1116 and methodology), general correspondence about an approved REMS that does not 1117 include a proposed modification, amendment to a proposed modification, or a REMS 1118 assessment, or other submissions that do not fall into the categories described above. On 1119 the first page of such submissions, prominently identify its content with the words, 1120 “REMS - OTHER” followed by a concise description of the content in bold capital letters 1121 at the top of the page. For example: 1122 1123 NDA/BLA/ANDA [assigned #] 1124 REMS-OTHER 1125 SURVEY METHODOLOGY 1126 1127 The first page of a submission requesting Agency input on the content of a proposed 1128 REMS that has not yet been submitted should include the following wording in bold 1129 capital letters at the top of the page: 1130 1131 NDA/BLA/ANDA [assigned #] 1132 REMS-OTHER 1133 REQUEST FOR GUIDANCE ON CONTENT OF PROPOSED REMS 1134 1135 If the proposed REMS has already been submitted, such a request should be identified as a 1136 proposed REMS amendment – see section V.B.1. 1137 1138 C. Questions about REMS 1139 1140 In the Center for Drug Evaluation and Research (CDER), the primary contact about a proposed 1141 REMS for a product under an NDA or BLA is the regulatory project manager in the Office of 1142 New Drugs (OND) review division assigned to that product. The primary contact about a 1143 proposed REMS for a product under an ANDA is the Director of the Division of Labeling and 1144 Program Support in the Office of Generic Drugs (OGD). The Office of Surveillance and 1145 Epidemiology, and other program offices as needed, will work with OND and OGD in the 1146 review and development of a proposed REMS. 1147
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1148 In the Center for Biologics Evaluation and Research (CBER), the primary contact about a 1149 proposed REMS is the regulatory project manager in the office with product responsibility. The 1150 Office of Biostatistics and Epidemiology, and other program offices as needed, will work with 1151 the product office in the review and development of a proposed REMS. 1152 1153
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1154 GLOSSARY – applicable to terms as used in this document 1155 1156 Assessment: An assessment of the approved REMS as described in section II.E and III.B.4 of 1157 this document. 1158 1159 Changes Being Effected Supplement: Also called a “changes being effected supplemental 1160 application.” A supplement that includes changes that do not require supplement submission and 1161 approval prior to the changes being implemented; the application holder may commence 1162 distribution of the drug product involved upon receipt by the agency of a supplement for these 1163 changes. A “Changes Being Effected in 30 days” supplement includes changes that do not 1164 require approval prior to the changes being implemented, but requires supplement submission at 1165 least 30 days prior to distribution of the drug product made using the change. If, after review, 1166 FDA disapproves a changes being effected supplement or a changes being effected in 30 days 1167 supplement, FDA may order the manufacturer to cease distribution of the drug products made 1168 using the disapproved change (21 CFR 314.70(c) and 601.12(c)). See section V.A of this 1169 document. 1170 1171 Goal: The desired safety-related health outcome or the understanding of serious risks targeted 1172 by the use of specified REMS elements. See section III.A.2 of this document. 1173 1174 Objective: An intermediate step to achieving the overall goals of the REMS. Objectives should 1175 be pragmatic, specific, and measurable. Objectives may use one or more elements or tools that 1176 result in processes or behaviors leading to achievement of the REMS goals. A REMS goal can 1177 be translated into different objectives, depending upon the frequency, type, and severity of the 1178 specific risk or risks being minimized. See section III.A.2 of this document. 1179 1180 Prior-approval Supplement: Also called a “prior-approval supplemental application.” A 1181 supplemental application that includes changes requiring supplement submission and approval 1182 prior to the distribution of the product made using the change. (21 CFR 314.70(b) and 1183 601.12(c)). See section V.A of this document. 1184 1185 Qualification Stickers: Stickers given by the applicant to providers to affix to prescriptions for 1186 specified products to indicate that the patient has met all criteria for receiving the product. 1187 1188 REMS: Stands for “Risk Evaluation and Mitigation Strategy,” and is the enforceable document 1189 that describes the elements that an applicant is required to implement. See section III.A of this 1190 document. 1191 1192 REMS Supporting Document: A document that includes a thorough explanation of the 1193 rationale and supporting information for the content of the proposed REMS. See section III.B of 1194 this document. 1195 1196 Tool: A process or system designed to implement one or more REMS elements. In some cases 1197 an element itself, such as a Medication Guide, may be viewed as a tool. In other cases, such as 1198 for an ETASU that requires that a drug be dispensed to patients with evidence or other 1199 documentation of safe-use conditions (505-1(f)(3)(C)), specific tools are used to implement a
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1200 REMS element. Examples of such tools include systems that ensure certain laboratory test result 1201 outcomes are obtained before a drug may be dispensed. 1202
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1203 ATTACHMENT A: EXAMPLE OF A REMS DOCUMENT FOR A FICTITIOUS DRUG 1204 1205 NDA ##-### Drug X
1206 RISK EVALUATION AND MITIGATION STRATEGY (REMS)
1207 1208 Class of Product as per label 1209 ABCD Pharmaceuticals
1210 123 Fake Street 1211 City, State Zip 1212 Contact Information for those responsible for 1213 REMS policy, management, and implementation 1214 1215 (555)-xxx-xxxx 1216 www.emailaddress.xxx 1217 1218 I. GOAL
1219 To minimize the risk of drug exposure during pregnancy in women of child-bearing potential 1220 taking Drug X. Because Drug X is teratogenic, ABCD Pharmaceuticals (ABCD) will mitigate 1221 this risk by: 1222 1223 • Ensuring that only females of childbearing potential with a negative pregnancy test 1224 begin therapy with Drug X and only females of childbearing potential with a monthly 1225 negative pregnancy test continue therapy with Drug X.
1226 • Ensuring that females of childbearing potential understand the risks to the fetus and 1227 know what precautions are necessary to prevent pregnancy.
1228 • Ensuring that all patients and health care providers understand the risks associated 1229 with Drug X.
1230 This drug is contraindicated in female patients who are or may become pregnant.
1231 II. REMS ELEMENTS 1232 1233 A. Medication Guide (FDCA Section 505-1(e)(2)) 1234 1235 A Medication Guide will be dispensed with each Drug X prescription. To ensure compliance 1236 with 21 CFR 208.24, ABCD will attach a Drug X Medication Guide to each unit-of-use 1237 package of Drug X to ensure that the Medication Guide is given to each patient with each new 1238 prescription and refill. A copy of the Medication Guide is appended to the REMS Document. 1239 The Medication Guide will be available on the ABCD Web site within 10 days of approval of 1240 the Medication Guide.
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1241 B. Communication Plan (FDCA Section 505-1(e)(3)) 1242 1243 ABCD will implement a communication plan to health care providers to support implementation 1244 of this REMS: 1245 1246 1. The audience for this communication plan is health care professionals (HCPs)— 1247 especially neurologists, endocrinologists, and pharmacists. 1248 1249 2. ABCD will provide physicians and pharmacists with educational materials listed below 1250 that describe the key risks and benefits of Drug X: 1251 1252 a. Prescriber Materials — Dear Health Care Professional Letter 1253 b. Pharmacist Materials — Dear Pharmacist Letter 1254 c. Additional Resources — Drug X REMS Program Internet Site 1255 1256 The printed communication and educational materials listed above are appended. 1257 1258 3. Distribution of materials: Communication plan materials will be distributed within 60 1259 days of approval of the Drug X REMS. 1260 1261 a. At the time the Drug X REMS elements to assure safe use are implemented, ABCD 1262 will send the Dear Health Care Professional Letter by mass mailing to targeted Drug 1263 X prescribers to announce the REMS program and the requirements of the program. 1264 The mailing will include the materials listed in 2a above. Copies of these materials 1265 will be available through the product Web site. 1266 1267 b. At the time the Drug X REMS elements to assure safe use are implemented, ABCD 1268 will send the Dear Pharmacist Letter by mass mailing to targeted pharmacies who 1269 currently order Drug X, to announce the REMS program and the requirements of the 1270 program. The mailing will include the materials listed in 2b above. Copies of these 1271 materials will be available through the product Web site. 1272 1273 C. Elements To Assure Safe Use (FDCA Section 505-1(f)(3)) 1274 1275 ABCD will implement the following elements to ensure safe use to mitigate the risk of drug 1276 exposure during pregnancy by women of child-bearing potential. The elements to assure safe 1277 use will be implemented within 60 days of approval of the Drug X REMS. 1278 1279 1. Drug X will be prescribed only by prescribers who are specially certified under 1280 505-1(f)(3)(A) by enrollment in the Drug X REMS program. 1281 1282 a. ABCD will ensure that physicians and other appropriately licensed health care 1283 providers who prescribe Drug X are specially certified. ABCD will ensure that, to 1284 become certified, each prescriber, on the prescriber enrollment form, attests to the 1285 following: 1286
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1287 • To have read and understood the communication and educational materials for 1288 prescribers regarding the risks and benefits of Drug X, including the Drug X 1289 Prescriber Guide and the Prescriber Contraception Counseling Guide 1290 • To have knowledge of the high risk of severe birth defects associated with 1291 Drug X 1292 • To know the risk factors for unplanned pregnancy and the effective measures to 1293 avoid pregnancy 1294 • To prescribe Drug X after ensuring documentation of safe use conditions 1295 described below 1296 • To submit information about any pregnancy they learn about to the pregnancy 1297 registry 1298 • To monitor patients treated with Drug X as described below 1299 1300 b. ABCD will maintain a list of all certified prescribers and will provide the list to those 1301 needing to verify that a prescriber has obtained the required certification. 1302 1303 c. ABCD will ensure that prescribers will be recertified in the Drug X REMS program 1304 annually. 1305 1306 The following materials are part of the REMS and are appended: 1307 1308 • Prescriber enrollment form, 1309 • Prescriber Guide 1310 • Prescriber Contraception Counseling Guide 1311 1312 2. Drug X will be dispensed only by pharmacies that are specially certified under 1313 505-1(f)(3)(B) by enrollment in the Drug X REMS program. 1314 1315 a. ABCD will ensure that responsible pharmacy personnel from pharmacies that dispense 1316 Drug X are specially certified. ABCD will ensure that, to be certified, responsible 1317 pharmacy personnel will attest to the following: 1318 1319 • To have read and understood the communication and educational materials for 1320 pharmacists regarding the risks and benefits of Drug X, including the Drug X 1321 Pharmacist Guide 1322 • To have knowledge of the high risk of severe birth defects associated with 1323 Drug X 1324 • To train all pharmacists to fill and dispense Drug X only after ensuring 1325 documentation of safe-use conditions described below 1326 • To ensure that all pharmacists who fill and dispense Drug X comply with 1327 required documentation of safe-use conditions described below 1328 • To agree not to sell, borrow, lend, or otherwise transfer Drug X to or from 1329 another pharmacy 1330
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1331 b. ABCD maintains a list of all certified pharmacies and will provide the list to those 1332 needing to verify that a pharmacy has obtained the required certification. 1333 1334 c. Drug X will be distributed to certified pharmacies. 1335 1336 d. Pharmacies will be recertified in the Drug X REMS program annually. 1337 1338 The pharmacy enrollment form and Pharmacist Guide are part of the REMS and are 1339 appended. 1340 1341 3. Drug X will only be dispensed to patients with documentation of safe-use conditions 1342 under 505-1(f)(3)(D)) described below: 1343 1344 a. ABCD will ensure that prescribers of Drug X will: 1345 1346 • Register each patient in the Drug X REMS program (patient enrollment form 1347 is appended) 1348 • Determine the childbearing status of all female patients 1349 • Counsel each female of childbearing potential (FCBP) before beginning 1350 therapy with Drug X and on a monthly basis to avoid pregnancy by using 1351 effective contraceptive forms or refer the patient for contraception 1352 counseling 1353 o Provide them with the following educational materials: Guide for Patients 1354 Who Can Become Pregnant (appended) 1355 o Confirm that FCBP have signed the appropriate informed consents — 1356 Informed consent for Patients Who Can Become Pregnant (appended) 1357 • Counsel males and females not of child bearing potential about the risks and 1358 benefits of Drug X before beginning therapy with Drug X. 1359 o Provide them with the following educational materials: Guide for Patients 1360 Who Cannot Become Pregnant (appended) 1361 o Confirm that males and females not of childbearing potential have signed the 1362 appropriate informed consents — Informed consent for Patients Who Cannot 1363 Become Pregnant (appended) 1364 • Complete for each patient either the Drug X Prescriber Checklist for Patients 1365 Who Can Become Pregnant, or the Drug X Prescriber Checklist for Patients 1366 Who Cannot Become Pregnant (appended) 1367 • For female patients of childbearing potential prior to each prescription: 1368 o Indicate patient’s chosen contraceptive forms each month by telephone or 1369 secure Internet Web site 1370 o Order CLIA-certified pregnancy test for each patient prior to each 1371 prescription and enter results of pregnancy test each month by telephone 1372 or secure Internet Web site 1373 1374 b. ABCD will ensure that pharmacies that dispense Drug X will: 1375
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1376 • Obtain authorization from the Drug X REMS program by telephone or 1377 secure Internet Web site for every Drug X prescription and write the 1378 authorization number on each prescription 1379 • Dispense only a 30-day supply 1380 • Dispense within 7 days of a last negative pregnancy test 1381 • Dispense the Drug X Medication Guide with each prescription 1382 1383 c. ABCD will ensure that Drug X is dispensed only to patients who have met the 1384 following conditions: 1385 1386 • All patients have: 1387 o Signed the informed consent prior to beginning therapy with Drug X 1388 • Females of childbearing potential (before each prescription) have: 1389 o Obtained a CLIA-certified pregnancy test 1390 o Indicated chosen contraceptive forms each month by telephone or secure 1391 Internet Web site 1392 o Completed a questionnaire each month through a secure Internet Web site 1393 1394 4. ABCD will ensure that patients who are treated with Drug X are monitored by their 1395 prescribers monthly for the duration of Drug X therapy and for 1 month following Drug 1396 X discontinuation under section 505-1(f)(3)(E). Monitoring will include the following 1397 elements: 1398 1399 • Re-counseling all patients about the risks and benefits of Drug X therapy and 1400 determining whether they are still appropriate for Drug X therapy 1401 • Determining whether the childbearing status of female patients has changed 1402 • Obtaining a CLIA-certified pregnancy test prior to each Drug X prescription 1403 • Ensuring FCBP are still on appropriate contraception and re-counseling 1404 FCBP of the importance of complying with contraceptive methods during 1405 and for 1 month following therapy with Drug X 1406 1407 5. ABCD will ensure that Drug X will only be dispensed to patients who are enrolled in the 1408 REMS program registry under 505-1(f)(3)(F) and who meet the following conditions: 1409 1410 • Patient must understand that severe birth defects can occur with the use of 1411 Drug X by female patients. 1412 • Patient must be reliable in understanding and carrying out instructions. 1413 • Patient must agree to not share Drug X with anyone. 1414 • Patient must agree to not donate blood while on Drug X and for 1 month after 1415 Drug X discontinuation. 1416 • Females of child-bearing potential (FCBP) must: 1417 o Not be pregnant and understand the importance of avoidance of 1418 pregnancy 1419 o Be capable of following mandatory contraceptive measures 1420
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1421 The following information will be collected on enrolled patients: 1422 1423 • Age, gender, and childbearing status 1424 • Documentation of counseling 1425 • Prescription data (e.g., dates RX filled, quantity dispensed) 1426 • For FCBP: 1427 o Baseline and monthly pregnancy test (dates and results) 1428 o Chosen methods of contraception 1429 • For females who become pregnant 1430 o Maternal and fetal outcomes 1431 o Information on circumstances that led to failure to prevent 1432 pregnancy 1433 1434 D. Implementation System (FDCA Section 505-1(f)(4)) 1435 1436 The implementation system will include the following components: 1437 1438 1. ABCD will maintain a validated and secure database of all entities enrolled under 1439 505-1(f)(3)(B) and (D) and 505-1(f)(4), including wholesalers/distributers, 1440 pharmacies and patients. 1441 2. ABCD will ensure that wholesalers/distributers who distribute Drug X are specially 1442 certified. To become certified, wholesalers/distributers will be enrolled in the Drug X 1443 REMS program. 1444 1445 a. The Drug X REMS Program wholesaler/distributor enrollment process is 1446 composed of the following three steps that must be completed prior to 1447 receiving Drug X inventory for distribution:
1448 i. The Distributor’s Authorized Representative reviews the 1449 Wholesaler/Distributor Program Materials.
1450 ii. Prior to receiving Drug X, the Distributor’s Authorized Representative 1451 completes and signs the Distributor Enrollment Form and faxes it to the 1452 Drug X REMS Program. In signing the Enrollment Form, the 1453 Representative is required to indicate they understand that Drug X is 1454 available only through the Drug X REMS Program, agree to comply with 1455 program requirements, and acknowledge that:
1456 A. I will ensure that relevant staff are trained about the Drug X REMS 1457 Program for Drug X procedures.
1458 B. I will ensure that relevant staff distribute Drug X only to Drug X 1459 REMS pharmacies that are active in the database.
1460 C. I will provide monthly records of Drug X shipments to each Drug 1461 X REMS pharmacy.
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1462 D. I will permit a program-related audit of our shipping records to 1463 corroborate that we are shipping Drug X only to Drug X REMS 1464 pharmacies.
1465 iii. A Drug X REMS Program professional reviews the form, requests any 1466 missing or illegible information, and, when the form has been verified to 1467 be accurate and successfully completed, the distributor is notified of 1468 activation.
1469 b. Upon initial activation, wholesalers/distributors remain active until a 1470 corrective action of inactivation occurs or expiration of the enrollment period.
1471 c. If a previously active wholesaler becomes inactive, the wholesaler/distributor 1472 can become active again by completing the standard wholesaler enrollment 1473 process in its entirety.
1474 d. Wholesalers/distributors are re-educated and re-enrolled following substantial 1475 changes to the program or at least every 2 years. Substantial changes to the 1476 Drug X REMS Program are defined as changes that modify the operation of 1477 the Drug X REMS Program in a way that changes Drug X REMS Program 1478 procedures for distributors.
1479 e. The Distributor Enrollment Form is part of the REMS and is appended.
1480 1481 3. ABCD will monitor wholesaler distribution data to ensure that only registered entities 1482 are dispensing Drug X. 1483 4. ABCD will monitor pharmacies to ensure these entities are dispensing Drug X to 1484 patients only after receiving authorization. 1485 5. ABCD will correct pharmacy noncompliance with program requirements. 1486 6. ABCD will conduct periodic audits of registered pharmacies to determine whether the 1487 data collected is in the manner and frequency agreed upon with FDA. 1488 7. ABCD will maintain a Call Center (1-800-ABCD411) to respond to questions from 1489 practitioners, pharmacists, and patients (FDAAA Section 505-1(f)(3)(B), and (D)). 1490 1491 E. Timetable for Submission of Assessments 1492 1493 ABCD will submit REMS Assessments to FDA every 6 months from the date of the approval of 1494 the REMS. To facilitate inclusion of as much information as possible while allowing reasonable 1495 time to prepare the submission, the reporting interval covered by each assessment should 1496 conclude no earlier than 60 days before the submission date for that assessment. ABCD will 1497 submit each assessment so that it will be received by the FDA on or before the due date. 1498 1499 [Attachments are not included in this example.]
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