Notifying FDA of a Permanent Discontinuance or Interruption in Manufacturing Under Section 506C of the FD&C Act Guidance for Industry In light of the Coronavirus Disease 2019 (COVID-19) public health emergency, this guidance is being implemented without prior public comment in accordance with 21 U.S.C. 701(h)(1)(C)(i)) and 21 CFR 10.115(g)(2), but it remains subject to comment in accordance with the Agency’s good guidance practices. Comments may be submitted at any time for Agency consideration. Submit written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Submit electronic comments to https://www.regulations.gov. 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 document, contact (CDER) Drug Shortage Staff, 240-402-7770, or (CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) March 2020 Procedural Notifying FDA of a Permanent Discontinuance or Interruption in Manufacturing Under Section 506C of the FD&C Act Guidance for Industry Additional copies are available from: Office of Communications, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993-0002 Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 Email: druginfo@fda.hhs.gov https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and/or Office of Communication, Outreach and Development Center for Biologics Evaluation and Research Food and Drug Administration 10903 New Hampshire Ave., Bldg. 71, Room 3128 Silver Spring, MD 20993-0002 Phone: 800-835-4709 or 240-402-8010 Email: ocod@fda.hhs.gov https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances 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) March 2020 Procedural Contains Nonbinding Recommendations TABLE OF CONTENTS I. INTRODUCTION............................................................................................................. 1 II. BACKGROUND ............................................................................................................... 2 III. NOTIFYING FDA OF A PERMANENT DISCONTINUANCE OR AN INTERRUPTION IN MANUFACTURING .............................................................................. 6 A. Why It Is Important To Notify FDA ............................................................................................ 6 B. Who Should Notify FDA ............................................................................................................... 6 C. When To Notify FDA ..................................................................................................................... 7 D. What Information To Include in Notifications............................................................................ 8 E. How To Notify FDA ..................................................................................................................... 10 F. Failure To Notify FDA................................................................................................................. 11 IV. HOW FDA COMMUNICATES INFORMATION ABOUT DRUGS AND BIOLOGICAL PRODUCTS IN SHORTAGE ........................................................................ 11 Contains Nonbinding Recommendations 1 Notifying FDA of a Permanent Discontinuance or Interruption in 2 Manufacturing Under Section 506C of the FD&C Act 3 Guidance for Industry1 4 5 6 This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 7 this topic. It does not establish any rights for any person and is not binding on FDA or the public. You 8 can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. 9 To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 10 title page. 11 12 13 14 I. INTRODUCTION 15 16 The Food and Drug Administration (FDA or Agency) plays a critical role in protecting the 17 United States from threats including emerging infectious diseases, including the Coronavirus 18 Disease 2019 (COVID-19) pandemic. FDA is committed to providing timely guidance to support 19 response efforts to this pandemic. 20 21 Due to the COVID-19 pandemic, FDA has been closely monitoring the medical product supply 22 chain with the expectation that it may be impacted by the COVID-19 outbreak, potentially 23 leading to supply disruptions or shortages of drug and biological products in the United States. 24 FDA is issuing this guidance to assist applicants and manufacturers in providing FDA timely, 25 informative notifications about changes in the production of certain drugs and biological 26 products that will, in turn, help the Agency in its efforts to prevent or mitigate shortages of such 27 products. 28 29 The guidance discusses the requirement under section 506C of the Federal Food, Drug, and 30 Cosmetic Act (FD&C Act) (21 U.S.C. 356c) and FDA’s implementing regulations for applicants 31 and manufacturers to notify FDA of a permanent discontinuance in the manufacture of certain 32 products or an interruption in the manufacture of certain products that is likely to lead to a 33 meaningful disruption in supply of that product in the United States. 2 This guidance also 34 recommends that applicants and manufacturers provide additional details and follow additional 35 procedures to ensure FDA has the specific information it needs to help prevent or mitigate 36 shortages. In addition, the guidance explains how FDA communicates information about 37 products in shortage to the public. 38 1 This guidance has been prepared by the Drug Shortage Staff and the Office of Regulatory Policy in the Center for Drug Evaluation and Research (CDER), in conjunction with the Office of Compliance and Biologics Quality in the Center for Biologics Evaluation and Research (CBER). 2 This guidance addresses only the notification requirement in section 506C of the FD&C Act; it does not address the contents of other notifications, for example, those that may be required under section 506I of the FD&C Act (21 U.S.C. 356i) when drug products are discontinued. 1 Contains Nonbinding Recommendations 39 Given the public health emergency related to COVID-19 declared by the Department of Health 40 and Human Services (HHS), this guidance is being implemented without prior public comment 41 because the FDA has determined that prior public participation for this guidance is not feasible 42 or appropriate (see section 701(h)(1)(C)(i) of the FD&C Act and 21 CFR 10.115(g)(2)). This 43 guidance document is being implemented immediately, but it remains subject to comment in 44 accordance with the Agency’s good guidance practices. 45 46 This guidance is intended to remain in effect for the duration of the public health emergency 47 related to COVID-19 declared by HHS, including any renewals made by the Secretary in 48 accordance with section 319(a)(2) of the Public Health Service Act (42 U.S.C. 247d(a)(2)). 49 However, the recommendations and processes described in the guidance are expected to assist 50 the Agency more broadly in its efforts to prevent and mitigate shortages, including under 51 circumstances outside of the COVID-19 public health emergency, and reflect the Agency’s 52 current thinking on this issue. Therefore, within 60 days following the termination of the public 53 health emergency, FDA intends to revise and replace this guidance with any appropriate changes 54 based on comments received on this guidance and the Agency’s experience with implementation. 55 56 In general, FDA’s guidance documents, including this guidance, do not establish legally 57 enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic 58 and should be viewed only as recommendations, unless specific regulatory or statutory 59 requirements are cited. The use of the word should in Agency guidances means that something is 60 suggested or recommended, but not required. 61 62 63 II. BACKGROUND 64 65 There is currently an outbreak of respiratory disease caused by a novel coronavirus. The virus 66 has been named “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2) and the 67 disease it causes has been named “Coronavirus Disease 2019” (COVID-19). On January 31, 68 2020, HHS issued a declaration of a public health emergency related to COVID-19 and 69 mobilized the Operating Divisions of HHS. 3 In addition, on March 13, 2020, the President 70 declared a national emergency in response to COVID-19. 4 As explained above, during the 71 COVID-19 outbreak, FDA has been closely monitoring the medical product supply chain with 72 the expectation that it may be impacted by the COVID-19 outbreak, potentially leading to supply 73 disruptions or shortages of drug and biological products in the United States. 74 75 Title X of the Food and Drug Administration Safety and Innovation Act (FDASIA), enacted on 76 July 9, 2012, 5 amended the FD&C Act to help the Agency address the problem of drug shortages 3 Secretary of Health and Human Services Alex M Azar, Determination that a Public Health Emergency Exists. (Jan. 31, 2020), available at https://www.phe.gov/emergency/news/healthactions/phe/Pages/2019-nCoV.aspx). 4 Proclamation on Declaring a National Emergency Concerning the Novel Coronavirus Disease (COVID-19) Outbreak (Mar. 13, 2020), available at https://www.whitehouse.gov/presidential-actions/proclamation-declaring- national-emergency-concerning-novel-coronavirus-disease-covid-19-outbreak/. 5 Public Law 112-144. 2 Contains Nonbinding Recommendations 77 in the United States, including by amending requirements related to notifying FDA about product 78 discontinuances and manufacturing interruptions. While some supply disruptions and shortages 79 cannot be predicted or prevented, early communication and detailed notifications from 80 manufacturers to the Agency play a significant role in decreasing the incidence, impact, and 81 duration of supply disruptions and shortages. 82 83 As explained below, under section 506C of the FD&C Act (as amended by FDASIA) and FDA’s 84 implementing regulations, 6 persons covered by the notification requirement must notify FDA of 85 a permanent discontinuance in the manufacture of covered drugs and biological products or an 86 interruption in the manufacture of covered drugs and biological products that is likely to lead to a 87 meaningful disruption 7 (or, in the case of blood or blood components intended for transfusion, a 88 significant disruption 8) in the supply of such products in the United States, and the reasons for 89 such discontinuance or interruption. 9 The products covered by the notification requirement are 90 prescription drugs and biological products (including blood or blood components for 91 transfusion) 10 that are (1) life supporting, life sustaining, 11 or intended for use in the prevention 6 Section 506C(i) of the FD&C Act required FDA to issue regulations implementing section 506C of the FD&C Act. On July 8, 2015, FDA issued the final rule, “Permanent Discontinuance or Interruption in Manufacturing of Certain Drug or Biological Products” (80 FR 38915) to implement section 506C and other drug shortage provisions of the FD&C Act, as amended by FDASIA (see §§ 310.306, 314.81(b)(3)(iii), and 600.82 (21 CFR 310.306, 314.81(b)(3)(iii), and 21 CFR 600.82)). 7 Meaningful disruption means a change in production that is reasonably likely to lead to a reduction in the supply of a drug by a manufacturer that is more than negligible and affects the ability of the manufacturer to fill orders or meet expected demand for its product, and does not include interruptions in manufacturing due to matters such as routine maintenance or insignificant changes in manufacturing so long as the manufacturer expects to resume operations in a short period of time (see section 506C(h)(3) of the FD&C Act and §§ 314.81(b)(3)(iii)(f) and 600.82(f)). 8 Significant disruption means a change in production that is reasonably likely to lead to a reduction in the supply of blood or blood components by a manufacturer that substantially affects the ability of the manufacturer to fill orders or meet expected demand for its product, and does not include interruptions in manufacturing due to matters such as routine maintenance or insignificant changes in manufacturing so long as the manufacturer expects to resume operations in a short period of time (see § 600.82(f)). FDA intends to consider an interruption in manufacturing that leads to a reduction of 20 percent or more of an applicant’s own supply of blood or blood components over a 1- month period to “substantially affect” the ability of the applicant to fill orders or meet expected demand; accordingly, such an interruption would be considered a “significant disruption” in supply (see 80 FR 38915 at 38920-21). 9 Section 506C(i)(3) of the FD&C Act permitted FDA to apply the section, by regulation, to biological products (as defined in section 351 of the Public Health Service Act), including plasma products derived from human plasma protein and their recombinant analogs, if FDA determined that including these products would benefit the public health. FDA’s 2015 final rule extended drug shortage notification requirements to applicants of certain biological products, including recombinant therapeutic proteins, monoclonal antibody products, vaccines, allergenic products, plasma derived products and their recombinant analogs, blood or blood components for transfusion, and cellular and gene therapy products (see § 600.82 and 80 FR 38915 at 38918). 10 For purposes of the notification requirement, the term product refers to a specific strength, dosage form, and route of administration of a drug or biological product. See 80 FR 38915 at 38919 and 38928. 11 Life supporting or life sustaining means a product that is essential to or that yields information that is essential to, the restoration or continuation of a bodily function important to the continuation of human life (see §§ 314.81(b)(3)(iii)(f) and 600.82(f)). 3 Contains Nonbinding Recommendations 92 or treatment of a debilitating disease or condition, 12 including any such product used in 93 emergency medical care or during surgery; and (2) not radiopharmaceutical drug products or any 94 other products designated by FDA. 13 The persons covered by the notification requirement 95 (collectively referred to in this guidance as “manufacturers”) are as follows: 96 97 • Applicants with an approved new drug application (NDA) or approved abbreviated 98 new drug application (ANDA) for a covered drug product 14 99 100 • Applicants with an approved biologics license application (BLA) for a covered 101 biological product, other than blood or blood components 15 102 103 • Applicants with an approved BLA for blood or blood components for transfusion, if 104 the applicant is a manufacturer of a significant percentage of the U.S. blood 105 supply 16,17 106 107 • Manufacturers of a covered drug product marketed without an approved NDA or 108 ANDA 18 109 110 Under the statute and implementing regulations, the notifications must include, at a minimum: 19 111 112 • Name of the product, including the National Drug Code (NDC) number, or, for 113 biological products, an alternative standard for identification and labeling if one has 114 been recognized as acceptable by the Center Director 20 115 116 • Name of the application holder (for approved products) or manufacturer (for 117 unapproved drugs) 118 12 Intended for use in the prevention or treatment of a debilitating disease or condition means a product intended for use in the prevention or treatment of a disease or condition associated with mortality or morbidity that has a substantial impact on day-to-day functioning (see §§ 314.81(b)(3)(iii)(f) and 600.82(f)). 13 See section 506C(a) of the FD&C Act; §§ 310.306, 314.81(b)(3)(iii)(a), and 600.82(a). 14 See § 314.81(b)(3)(iii). 15 See § 600.82(a)(1). 16 See § 600.82(a)(2). 17 FDA intends to consider an applicant that holds a BLA for blood or blood components to be a manufacturer of a “significant percentage” of the U.S. blood supply if the applicant manufactures 10 percent or more of the U.S. blood supply (see 80 FR 38915 at 38917). 18 See § 310.306, which applies § 314.81(b)(3)(iii) in its entirety to covered drug products marketed without an approved NDA or ANDA. 19 See section 506C(a) of the FD&C Act; §§ 310.306(b), 314.81(b)(3)(iii)(c), and 600.82(c). 20 See § 600.82(c)(1). 4 Contains Nonbinding Recommendations 119 • Whether the notification relates to a permanent discontinuance of or an interruption in 120 manufacturing the product 121 122 • Description of the reason for the permanent discontinuance or interruption in 123 manufacturing 124 125 • Estimated duration of the interruption in manufacturing 126 127 Notifications under section 506C of the FD&C Act must be submitted to FDA at least 6 months 128 in advance of a permanent discontinuance or an interruption in manufacturing. 21 However, if 6 129 months advance notice is not possible because the discontinuance or interruption in 130 manufacturing was not reasonably anticipated, then the notification must be submitted as soon as 131 practicable thereafter, but in no case later than 5 business days after the discontinuance or 132 interruption in manufacturing occurs. 22 133 134 Consistent with section 506E of the FD&C Act (21 U.S.C. 356e) and the implementing 135 regulations, 23 FDA maintains up-to-date lists of drugs and biological products that FDA has 136 determined to be in shortage in the United States. 24 These lists include: 137 138 • Established name of the product in shortage; brand name of the product in shortage, if 139 applicable; the NDC number, presentation, strength(s), and package size, as available 140 141 • Name of each application holder (for approved products) or manufacturer (for 142 unapproved drugs) 143 144 • Name of the distributor, if different from the application holder (for approved 145 products) or manufacturer (for unapproved drugs) 146 147 • Reason for the shortage from the following categories: 148 149 - Requirements related to complying with good manufacturing practices 150 - Regulatory delay 151 - Shortage of an active ingredient 152 - Shortage of an inactive ingredient component 153 - Discontinuation of the manufacture of the product 154 - Delay in shipping 155 - Demand increase 156 - Other reason 21 See section 506C(b) of the FD&C Act; §§ 310.306(b), 314.81(b)(3)(iii)(b)(1), and 600.82(b)(1). 22 See section 506C(b) of the FD&C Act; §§ 310.306(b), 314.81(b)(3)(iii)(b)(2), and 600.82(b)(2). 23 See section 506E of the FD&C Act; §§ 310.306(c), 314.81(b)(3)(iii)(d)(1), and 600.82(d)(1). 24 See https://www.accessdata.fda.gov/scripts/drugshortages/default.cfm for shortages tracked by CDER; see https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Shortages/ucm351921.htm for shortages tracked by CBER. 5 Contains Nonbinding Recommendations 157 158 • Estimated duration of the supply disruption or shortage, anticipated date of 159 availability, and resolution dates 160 161 • Any additional information related to the shortage that the manufacturer chooses to 162 share as described below in section IV 163 164 165 III. NOTIFYING FDA OF A PERMANENT DISCONTINUANCE OR AN 166 INTERRUPTION IN MANUFACTURING 167 168 A. Why It Is Important To Notify FDA 169 170 A critical component of preventing or mitigating drug shortages is for manufacturers to notify 171 FDA as soon as possible of a permanent discontinuance or an interruption in manufacturing that 172 is likely to lead to a meaningful disruption in supply. As well as being timely, it is important that 173 notifications include specific information about the situation that will allow the Agency to 174 evaluate the situation and determine an appropriate course of action. 25 Early, informative 175 notifications are the best tool FDA has to help prevent a shortage from occurring and to mitigate 176 the impact of an unavoidable shortage. When FDA does not receive timely, informative 177 notifications, the Agency’s ability to respond appropriately is limited. 178 179 Notifications regarding discontinuances or potential manufacturing issues that are sent to FDA to 180 meet other reporting requirements, for example, under section 506I of the FD&C Act (reports of 181 marketing status) or 21 CFR 314.81(b)(1) (field alert reports), are not a substitute for the 182 notifications required under section 506C. It is important that notifications pursuant to section 183 506C be submitted to the appropriate staff in CDER and CBER (as described in section III.E) to 184 ensure timely review and action by the Agency. 185 186 187 B. Who Should Notify FDA 188 189 The notification requirement set forth in section 506C of the FD&C Act and implementing 190 regulations applies to the manufacturers of certain drugs and biological products, as discussed in 191 section II. 26 In general, the notification requirement applies to each individual manufacturer 192 regardless of market share, number of other manufacturers marketing products that are 25 See CDER’s Manual of Policies and Procedures (MAPP) 4190.1, Rev. 3, on Drug Shortage Management for information about CDER’s policies and procedures for evaluating and managing drug shortage situations, available at: https://www.fda.gov/media/72447/download. See CBER’s Standard Operating Procedures and Policies 8506: Management of Shortages of CBER-Regulated Products, Version #3, for information about CBER’s policies and procedures for evaluating and managing shortage situations, available at: https://www.fda.gov/media/83301/download 26 The notification requirement applies regardless of any determination with respect to whether the product is medically necessary (see generally CDER’s MAPP 4190.1 Rev. 3). 6 Contains Nonbinding Recommendations 193 therapeutically equivalent, or the amount of product that may be in distribution. 27 If a 194 manufacturer is not certain whether products it manufactures are subject to the notification 195 requirement, we recommend that the manufacturer contact the Agency as described in section 196 III.E below. 197 198 In the case of products that are marketed under approved applications, the applicant is solely 199 responsible for reporting to FDA a permanent discontinuance or an interruption in 200 manufacturing, whether the product is manufactured by the applicant itself or for the applicant 201 under contract with one or more different entities. 28 Accordingly, the applicant should establish a 202 process with any relevant contract manufacturer, active pharmaceutical ingredient supplier, or 203 other entity that ensures that the applicant can provide a complete and accurate notification to 204 FDA within the required time frame. 205 206 C. When To Notify FDA 207 208 Manufacturers must inform FDA at least 6 months in advance of (1) a permanent discontinuance 209 in manufacturing of a product or (2) an interruption in manufacturing of a product that is likely 210 to lead to a meaningful disruption in supply of the product in the United States. 29 If 6 months’ 211 advance notice is not possible because the discontinuance or interruption was not reasonably 212 anticipated, the notification must be submitted as soon as practicable thereafter, but in no case 213 later than 5 business days after the discontinuance or interruption in manufacturing occurs. 30 214 After the initial notification of an interruption in manufacturing, FDA recommends that 215 manufacturers provide updates every 2 weeks on the situation, including the expected timeline 216 for recovery, even if the status remains unchanged. These updates are important to ensure that 217 FDA remains informed and can act on the most current information. We recommend that such 218 updates be submitted until the shortage has been resolved (see section IV for a description of 219 when FDA considers a shortage to be resolved.). 220 221 FDA interprets a permanent discontinuance to be a decision by the manufacturer to cease 222 manufacturing and distributing a product indefinitely for business or other reasons. All such 223 discontinuances are required to be reported within the time frame described above. 31 Upon 224 receiving such notifications, FDA assesses the potential public health impact of the reported 225 discontinuance and, if needed, may request further discussion with the reporting manufacturer. 226 Manufacturers should not delay notifying FDA until after production has ceased; FDA expects to 227 be notified well before any decline in supply occurs. 228 27 But see section II (explaining that the requirement for blood or blood components intended for transfusion only applies to applicants that manufacture a significant percentage of the U.S. blood supply) (emphasis added). 28 See §§ 314.81(b)(3)(iii)(a) and 600.82(a)(1). 29 See section 506C(b) of the FD&C Act; §§ 310.306(b), 314.81(b)(3)(iii)(b)(1), and 600.82(b)(1). 30 See section 506C(b) of the FD&C Act; §§ 310.306(b), 314.81(b)(3)(iii)(b)(2), and 600.82(b)(2). 31 See section 506C(a) of the FD&C Act; §§ 310.306(b), 314.81(b)(3)(iii)(a), and 600.82(a). 7 Contains Nonbinding Recommendations 229 In the case of interruptions in manufacturing, when assessing whether a meaningful disruption in 230 supply is likely to occur, the relevant analysis is whether a change in production is likely to lead 231 to a reduction in the supply of a product by the manufacturer that is more than negligible and 232 would affect the manufacturer’s ability to fill orders or meet expected demand for its product. 32 233 In other words, the assessment is to be based solely on the reporting manufacturer’s capacity and 234 supply. The manufacturer should not consider other manufacturers’ or competitors’ capacities or 235 assumed capacities, or what it understands about market demand for the product. 33 FDA expects 236 that manufacturers will notify the Agency before a meaningful disruption in their own supply 237 occurs. For example, FDA should not first learn of a supply disruption resulting from an 238 interruption in manufacturing from a purchaser whose order could not be filled by the 239 manufacturer. 240 241 If a manufacturer is unsure of whether to notify FDA of an interruption in manufacturing 242 because the firm does not know whether a meaningful disruption in its supply is likely to occur, 243 FDA urges the manufacturer to submit a notification. This would allow FDA to monitor the 244 overall market and take timely steps, as necessary, to help prevent or mitigate any resulting 245 shortage. In addition, if a manufacturer is considering taking an action that may lead to a 246 meaningful disruption in the supply of a product (e.g., holding production to investigate a quality 247 issue or transfer of ownership), FDA requests that the manufacturer notify FDA immediately 248 through the process explained in section III. E. 249 250 As described above, the notification requirement in the FD&C Act and the implementing 251 regulations is triggered by a permanent discontinuance or an interruption in manufacturing of 252 certain products, as discussed in section II; however, there are other circumstances as well where 253 FDA requests that manufacturers submit a notification to the Agency. FDA requests that 254 manufacturers notify the Agency when they are unable to meet demand for products covered by 255 the notification requirement, 34 even in the absence of an interruption in manufacturing, for 256 example, when there is a sudden, unexpected spike in demand. Though manufacturers are not 257 required to report this type of situation to FDA, reporting under these circumstances provides an 258 important signal to the Agency about a potential shortage and allows FDA to take appropriate 259 steps to address the potential shortage. 260 261 D. What Information To Include in Notifications 262 263 As explained above, notifications under section 506C of the FD&C Act are required to include 264 certain information. This information, described in section II, is the minimum that manufacturers 265 must provide. However, to ensure that FDA is better-equipped to help prevent or mitigate a drug 32 See 80 FR 38915 at 38920. Manufacturers are not required to report interruptions in manufacturing due to matters such as routine maintenance or insignificant changes in manufacturing, so long as the manufacturer expects to resume operations in a short period of time (see section 506C(h)(3)(B) of the FD&C Act). 33 See 80 FR 38915 at 38920 (explaining that manufacturers are not required or expected to predict the market-wide impact of an interruption in their own manufacturing). But see section II (explaining that the regulatory requirement for blood or blood components intended for transfusion only applies to applicants that manufacture a significant percentage of the U.S. blood supply) (emphasis added). 34 See section II for a description of products covered by the notification requirement. 8 Contains Nonbinding Recommendations 266 shortage, FDA recommends that manufacturers provide additional details about the situation and 267 has included below questions for manufacturers to consider as they evaluate the situation and 268 prepare to notify FDA. This list is not intended to be exhaustive; it provides questions to 269 consider that may yield information that would help FDA determine appropriate steps to help 270 prevent or mitigate a shortage. The more information manufacturers are able to provide on these 271 topics, the better FDA is able to assist in preventing or mitigating a shortage. 272 273 It is important to note that manufacturers need not have answers to each question before 274 submitting a notification; notifications can be updated at any time to include additional 275 information. Therefore, we recommend that manufacturers not delay notifying the Agency until 276 answers are available, but instead recommend that they provide initial notification as soon as is 277 practicable and additional information as it becomes available. 278 279 We recommend considering the following questions when providing notification to FDA: 280 281 • Is this notification for an unavoidable supply disruption or a supply disruption that 282 may be preventable? 283 284 • What is the underlying reason or root cause leading to this notification? (A detailed 285 and thorough explanation beyond “manufacturing delay” or a recitation of the broad 286 categories of reasons listed above in section II is especially important and allows 287 FDA to identify and use the most appropriate and effective mitigation tools.) 288 289 • What is the estimated date of onset of the interruption in manufacturing or supply 290 disruption for this product? If a supply disruption has occurred, what is the estimated 291 duration? 35 292 293 • If the notification is for a permanent discontinuance, what is the anticipated time 294 frame for all existing product (on hand and in distribution channels) to be exhausted? 295 296 • What is your estimated market share for the product? Is your entire market share 297 affected by this issue? What is the estimated volume of your historic monthly sales, 298 usage, or demand, as applicable, for this product? 299 300 • Is this product manufactured on multiple lines or in multiple facilities? 301 302 • How much current inventory of product is at your facility or warehouse? 303 304 • When will the last batch of finished product be released into distribution? Based on 305 the current demand, how long do you expect the supply to last in the market without 306 additional releases? 307 35 Notifications of interruptions in manufacturing must include the estimated duration of the interruption in manufacturing. See §§ 310.306(b), 314.81(b)(3)(iii)(c)(5), and 600.82(c)(5). 9 Contains Nonbinding Recommendations 308 • Do you have an emergency or reserve supply of this product? Is allocation 36 of supply 309 on hand or your reserve supply an option? 310 311 • Have you provided, or will you provide, public information for your stakeholders and 312 patients regarding this actual or potential shortage (e.g., Dear Healthcare Provider 313 (DHCP) Letters, supply or shortage information posted on your website)? 314 315 • Do you have a proposal for FDA to review to expedite availability of your product? 316 What do you think FDA can do to help prevent or mitigate a supply disruption? 317 318 This information is intended to help FDA assess the situation and take appropriate action. As 319 described further in section IV below, information that is submitted to FDA will not be disclosed 320 except in accordance with applicable disclosure law, which includes restrictions on the release of 321 confidential commercial information and trade secrets. 37 If FDA determines that a product is in 322 shortage, the Agency intends to work with manufacturers to confirm the accuracy and 323 appropriateness of information regarding the shortage before posting publicly on FDA’s website. 324 325 E. How To Notify FDA 326 327 Notifications under section 506C of the FD&C Act must be submitted to FDA electronically in a 328 format that FDA can process, review, and archive. 38 For products regulated by the Center for 329 Drug Evaluation and Research (CDER), manufacturers should submit initial notifications either 330 via email at drugshortages@fda.hhs.gov or through the CDER Direct NextGen Portal at 331 https://edm.fda.gov/wps/portal/. Initial notifications regarding products regulated by the Center 332 for Biologics Evaluation and Research (CBER) should be submitted to FDA electronically via 333 email at cbershortage@fda.hhs.gov. All additional updates should be submitted by email to the 334 applicable Center (CDER or CBER), not through the NextGen Portal. 335 336 Manufacturers should submit a separate notification for each permanent discontinuance or 337 interruption in manufacturing. A single initial notification may include a list of all affected 338 products. 39 Manufacturers should not provide notification about a newly affected product (e.g., a 339 new strength) in an update, even if the issue is related to a previously reported interruption in 340 manufacturing. Rather, a separate initial notification should be submitted to ensure the newly 341 affected product is tracked appropriately. In addition, as explained in section III.A, notifications 342 submitted to FDA to satisfy other reporting requirements (e.g., under section 506I of the FD&C 343 Act) are not a substitute for the notifications required under section 506C. 344 36 Allocation generally refers to limiting the quantity distributed to customers to extend the life of the existing supply. 37 See section 506C(d) of the FD&C Act. 38 See §§ 310.306(b), 314.81(b)(3)(iii)(b), and 600.82(b); see also 80 FR 38915 at 38922. 39 See note 10 10 Contains Nonbinding Recommendations 345 F. Failure To Notify FDA 346 347 If a manufacturer fails to provide notification of a permanent discontinuance or an interruption in 348 manufacturing as required by section 506C(a) of the FD&C Act and in accordance with the 349 timelines set forth in section 506C(b) and the implementing regulations, 40 FDA will issue a letter 350 to that manufacturer stating that the notification requirement was not met (a “noncompliance 351 letter”). 41 Note that if FDA determines that an applicant experienced a reportable interruption in 352 manufacturing that it could not reasonably anticipate 6 months in advance, but the applicant 353 failed to notify FDA “as soon as practicable,” FDA will issue a noncompliance letter. 42 354 The manufacturer must respond to FDA’s letter within 30 calendar days, providing the reason for 355 noncompliance and the required information on the discontinuance or interruption. 43 Within 45 356 calendar days of sending the noncompliance letter to the manufacturer, FDA will post that letter 357 and any response received on FDA’s website, 44 with appropriate redactions to protect trade 358 secrets or confidential commercial information. 45 However, FDA will not post the 359 noncompliance letter and response if the Agency determines that the noncompliance letter was 360 issued in error or, after review of the manufacturer’s response, that the manufacturer had a 361 reasonable basis for not notifying FDA as required. 46 362 363 364 IV. HOW FDA COMMUNICATES INFORMATION ABOUT DRUGS AND 365 BIOLOGICAL PRODUCTS IN SHORTAGE 366 367 FDA maintains public, up-to-date lists of drugs and biological products that the Agency has 368 determined to be in shortage. 47 These lists include, among other information, the established 369 name of the product in shortage, the reason for the shortage, and the estimated duration of the 370 shortage based on information provided by the manufacturer. The reason for the shortage 371 identified on the list is determined by FDA using the notification submitted and any 372 supplementary information gathered, such as from manufacturing facility reviews conducted by 373 FDA. Posted information may also include information that a manufacturer intends to provide or 374 has provided to its stakeholders and patients regarding an actual or potential shortage (e.g., 375 DHCP Letters, informed consent forms, or patient letters). The Agency does not include 376 confidential commercial information or trade secrets. 48 377 40 Section 506C(b) of the FD&C Act; §§ 310.306(b), 314.81(b)(3)(iii)(b)(1) and (2), and 600.82(b)(1) and (2). 41 See section 506C(f)(1) of the FD&C Act. 42 Id. 43 See section 506C(f)(2) of the FD&C Act. 44 Links to noncompliance letters can be found at http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm403902.htm. 45 See section 506C(d), (f)(3) of the FD&C Act. 46 See section 506C(f)(3) of the FD&C Act. 47 See note 24. 48 See section 506E(c)(2) of the FD&C Act. 11 Contains Nonbinding Recommendations 378 FDA updates its lists regularly and strives to communicate in real-time so that patients and 379 healthcare providers have the most current information on product shortages in the United States. 380 A product is added to the CDER- or CBER-maintained list only after the Agency determines that 381 it is in shortage; products are not added to the list(s) immediately upon receipt of a notification 382 regarding a discontinuance or interruption in manufacturing. In cases where a shortage does not 383 occur or is prevented through FDA or stakeholder intervention, the product will not be posted on 384 the list. FDA generally considers a shortage to be resolved and removes the product from the 385 “current shortage” section of the list based on an evaluation of the entire market, assessing 386 whether all backorders have been filled and supply is meeting or exceeding demand. In making 387 this evaluation, FDA may consider, among other factors, affected market share, ability of 388 alternate manufacturers to cover the demand, and confirmed market stabilization. 389 390 In general, FDA works with manufacturers to confirm the accuracy and appropriateness of 391 information before posting publicly on its website(s). FDA will continue to post information on 392 its website(s) consistent with section 506E of the FD&C Act and the implementing regulations 393 (see section II of this guidance), regardless of any additional information manufacturers provide 394 to the Agency based on the recommendations in this guidance. 12