Source: http://www.pharmafacts.com/guidances/fda-guidances/nonprescription-sunscreen-drug-products%EF%A3%A7content-and-format-of-data-submissions-to-support-a-grase-determination-under-the-sunscreen-innovation-act-guidance-for-industry
Timestamp: 2017-06-26 13:56:05
Document Index: 16126869

Matched Legal Cases: ['§ 330', '§ 330', 'art 330', 'art 314', 'art 330', 'art 330']

Nonprescription Sunscreen Drug ProductsContent and Format of Data Submissions To Support a GRASE Determination Under the Sunscreen Innovation Act Guidance for Industry - PharmaFacts
Nonprescription Sunscreen Drug ProductsContent and Format of Data Submissions To Support a GRASE Determination Under the Sunscreen Innovation Act Guidance for Industry DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document, contact Kristen Hardin at 240-402-4246. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) November 2015 OTC Nonprescription Sunscreen Drug ProductsContent and Format of Data Submissions To Support a GRASE Determination Under the Sunscreen Innovation 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 th 10001 New Hampshire Ave., Hillandale Bldg., 4 Floor Silver Spring, MD 20993 Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) November 2015 OTC Contains Nonbinding Recommendations Draft — Not for Implementation TABLE OF CONTENTS INTRODUCTION............................................................................................................. 1 BACKGROUND ............................................................................................................... 3 Regulation of Sunscreen Products................................................................................... 3 FDA’S Filing Determinations and Refusal To File a Request ...................................... 4 Scope of This Draft Guidance .......................................................................................... 5 Related Draft Guidance.................................................................................................... 6 CHARACTERISTICS OF A COMPLETE GRASE DATA SUBMISSION .............. 6 General Recommendations .............................................................................................. 6 Recommended Organization and Contents .................................................................... 9 Characteristics of an Incomplete Request and GRASE Data Submission ................ 12 How and Where To Submit GRASE Data Submissions ............................................. 13 1 2 3 Contains Nonbinding Recommendations Draft — Not for Implementation Nonprescription Sunscreen Drug ProductsContent and Format of Data Submissions To Support a GRASE Determination Under the Sunscreen Innovation Act 41 56 Guidance for Industry 7 8 9 10 11 12 13 14 15 16 17 I. INTRODUCTION 18 19 This draft guidance addresses the current thinking of the Food and Drug Administration (FDA or 20 Agency) on the format and content of information provided to support a request submitted under 21 section 586A (586A request) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 22 U.S.C. 360fff-1), as amended by the Sunscreen Innovation Act (SIA),2 or in support of a pending 23 request as defined under section 586(6) of the FD&C Act (21 U.S.C. 360fff(6)).3 A 586A 24 request seeks a determination from FDA of whether an over-the-counter (OTC or 25 nonprescription) sunscreen active ingredient,4 or a combination of nonprescription sunscreen 26 active ingredients,5 is generally recognized as safe and effective (GRASE) for use under 27 specified conditions and should be included in the OTC sunscreen drug monograph (GRASE 28 determination). The GRASE determination is primarily based on FDA’s review of safety and 29 effectiveness data and other information submitted by the request’s sponsor6 (GRASE data 1 This guidance has been prepared by the Division of Nonprescription Drug Products and the Office of Regulatory Policy in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration. 2 21 U.S.C. Ch. 9 Sub. 5 Part I, enacted November 26, 2014. 3 The SIA defines a “pending request” to mean a request for a nonprescription sunscreen active ingredient to be included in the over-the-counter monograph that was originally submitted as a time and extent application under section 330.14 of FDA’s regulations (21 CFR § 330.14) and was determined to be eligible for review and for which safety and effectiveness data were submitted prior to the enactment of the SIA (section 586(6) of the FD&C Act). 4 A “sunscreen,” as defined in the SIA, means a drug containing one or more sunscreen active ingredients (section 586(9) of the FD&C Act (21 U.S.C. 360fff(9))), and the term “sunscreen active ingredient,” as also defined in the SIA, means an active ingredient that is intended for application to the skin of humans for purposes of absorbing, reflecting, or scattering ultraviolet radiation (section 586(10) of the FD&C Act (21 U.S.C. 360fff(10))). 5 For convenience, references in this guidance to an “active ingredient” also apply to combinations of active ingredients. 6 An SIA “sponsor” is a person who has submitted a 586A request, a pending request, or any other application subject to the SIA (section 586(8) of the FD&C Act (21 U.S.C. 360fff(8))). This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance listed on the title page. 1 Contains Nonbinding Recommendations Draft — Not for Implementation 30 submission) as well as information and views submitted to the public docket by other interested 31 parties.7 Before that review may begin, however, FDA must review the GRASE data submission 32 for completeness and determine accordingly whether to file or refuse to file it for substantive 33 review (filing determination). If the submission is not sufficiently complete to enable us to 34 conduct a substantive GRASE review, including being formatted in a manner that will enable us 35 to evaluate its completeness, we will refuse to file the submission.8 36 37 We are issuing this draft guidance as directed by the SIA, which calls for FDA to publish a draft 38 and final guidance on the format and content of information submitted by a sponsor in support of 39 a 586A request or a pending request. When final, the recommendations in this draft guidance 40 will help sponsors prepare GRASE data submissions for 586A requests9 that are sufficiently 41 complete to be filed for substantive review, as well as helping guide FDA’s filing 42 determinations. Only data submissions provided by or on behalf of a sponsor are subject to a 43 filing determination as described in this draft guidance, and we anticipate that information 44 provided by other interested parties will supplement the sponsor’s data submission rather than 45 duplicating the full extent of a complete data submission as described in this draft guidance. 46 However, we encourage other interested parties to follow the recommendations in this guidance 47 to the extent that they are applicable to a given submission. We also anticipate that the advice in 48 this draft guidance will also be useful to persons who are preparing safety and efficacy data 49 submissions for review by FDA in other regulatory proceedings whose intent is to determine 50 whether particular nonprescription drug active ingredients or other OTC conditions are GRASE 51 and therefore may be included in an applicable OTC monograph (such as a future non-sunscreen 52 TEA (Time and Extent Application) or a request for additional data in an ongoing SIA 53 proceeding). 54 55 Section II of this draft guidance provides background information on the sunscreen OTC 56 monograph process and the new procedures governing GRASE determinations under the SIA 57 (the SIA process). Section II also summarizes the filing determination process for GRASE data 58 submissions and describes what sponsors can do if FDA refuses to file a GRASE data 59 submission. Section III describes FDA’s current thinking on the recommended format and 60 content of a GRASE data submission that will be considered complete and therefore fileable for 61 substantive review. 62 63 64 7 Section 586B(b)(1) of the FD&C Act (21 U.S.C. 360fff-2(b)(1)). 8 Section 586B(b)(2) of the FD&C Act (21 U.S.C. 360fff-2(b)(2)). 9 We note that although the SIA directs FDA to issue a draft guidance on the format and content of information submitted by a sponsor in support of 586A and pending requests, pending requests were submitted prior to enactment of the SIA and thus not required to meet the filing requirements in the SIA at the time of their submission. The SIA exempts pending requests from the filing determination stage and provides that the FDA will issue a proposed sunscreen order based on the safety and effectiveness data submitted soon after enactment of the SIA (see section 586C(b)(2), (3), (4), and (5) (21 U.S.C. 360fff-3(b)(2), (3), (4), and (5))). There are eight pending requests, and, as required by the SIA, all of them have received proposed sunscreen orders. We recommend that any future data submissions regarding the eight pending requests follow the content and format recommendations outlined in this draft guidance. 2 Contains Nonbinding Recommendations Draft — Not for Implementation 65 In general, FDA’s guidance documents do not establish legally enforceable responsibilities. 66 Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only 67 as recommendations, unless specific regulatory or statutory requirements are cited. The use of 68 the word should in Agency guidances means that something is suggested or recommended, but 69 not required. 70 71 72 II. BACKGROUND 73 10 74 A. Regulation of Sunscreen Products 75 76 All sunscreens are regulated as drugs in the United States under one of two processes: 77 78 • 79 80 • 81 82 83 Products regulated under the new drug approval process may not be marketed without FDA’s 84 prior review and approval of a new drug application (NDA) or abbreviated new drug application 85 (ANDA) for each product. Products marketed under the OTC drug monograph process are not 86 individually reviewed and approved prior to marketing. Instead, OTC drug monographs 87 categorize drugs by therapeutic categories, such as sunscreens. For each category, the 88 monograph establishes conditions under which any drug that satisfies those conditions and 89 FDA’s general regulations for OTC drugs is considered to be GRASE and not misbranded when 90 used under the conditions prescribed, recommended, or suggested in labeling.11 91 92 Initially, active ingredients that were not used in sunscreens in the United States prior to the 93 inception of the OTC Drug Review were not eligible for the OTC Drug Review. FDA 94 considered a drug that was ineligible for inclusion in the OTC monograph system to be subject to 95 the new drug approval process. 96 97 In 2002, before the SIA was enacted, FDA published the “time and extent application” (TEA) 98 regulation in 21 CFR 330.14. The TEA regulation (§ 330.14(c)) established a process through 99 which any person could request that an active ingredient or other OTC drug condition, including 100 one not previously marketed in the United States before the inception of the OTC Drug Review, 101 be added to an existing OTC drug monograph. 102 10 We have previously published Federal Register notices about rulemaking actions for OTC sunscreen monograph products and about actions taken under the SIA. This information can be found on our “Status of OTC Rulemakings” Web site (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over- the-CounterOTCDrugs/StatusofOTCRulemakings/default.htm) and “Sunscreens” Web site (http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingOver-the- CounterMedicines/ucm239463.htm). 11 Part 330. The new drug approval process described in 21 CFR part 314 The OTC drug monograph process (also known as the OTC Drug Review) described in part 330 (21 CFR part 330), as supplemented by the SIA 3 Contains Nonbinding Recommendations Draft — Not for Implementation 103 For OTC sunscreens, the SIA process supplements the TEA regulation. The SIA amended the 104 FD&C Act in part by providing new procedures for establishing that nonprescription sunscreen 105 active ingredients or combinations of nonprescription sunscreen active ingredients are GRASE 106 and not misbranded when used under the conditions specified in a final sunscreen order.12 107 Active ingredients that are determined to be GRASE in a final sunscreen order may be used in 108 U.S.-marketed sunscreens without first obtaining an approved NDA or ANDA. Because the 109 monograph and SIA processes are public, anyone, not just the sponsor who originated the 110 request, may submit data during public comment periods. 111 112 As with the TEA process, the SIA process calls for an initial eligibility determination, 113 by submissions of safety and efficacy data, and a GRASE determination phase. However, the 114 SIA process also requires FDA to make a filing determination as described in this draft guidance, 115 and to make proposed and final GRASE determinations in the form of administrative orders 116 rather than the rulemaking required by the TEA regulation. The SIA process also establishes 117 strict timelines for the necessary administrative actions. 118 119 B. FDA’S Filing Determinations and Refusal To File a Request 120 121 The SIA requires FDA to conduct an initial filing review to determine whether a sponsor’s 122 submission of safety and efficacy data and other relevant information to support a 586A request 123 for a sunscreen active ingredient is sufficiently complete to enable us to conduct a substantive 124 GRASE review (including being organized so that we can determine its completeness).14 The 125 initial filing review will help conserve FDA resources and streamline the GRASE review for 126 nonprescription sunscreen active ingredients by making the start of the GRASE review 127 contingent on a determination that the submission is sufficiently complete to support a GRASE 128 substantive review. As a result, it is the date of filing by FDA, and not the date when the 129 submission was submitted to or received by FDA, that triggers FDA’s statutory time frame for 130 completing the GRASE determination and issuing a proposed sunscreen order (which in turn 131 triggers various other action dates under the SIA).15 132 133 No later than 60 days after receiving a sponsor’s GRASE data submission, FDA must take one of 134 the following sets of actions: 135 136 • 137 138 12 Section 586C of the FD&C Act (21 U.S.C. 360fff-3). 13 Section 586B(a) of the FD&C Act (21 U.S.C. 360fff-2(a)). 14 We note that section 586F(a)(1)(B) of the FD&C Act (21 U.S.C. 360fff-6) provides the possibility that sponsors of non-sunscreen TEAs submitted prior to enactment of the SIA may choose a review framework that would incorporate “an initial filing review under the processes and procedures described in section 586B(b).” FDA expects to conduct initial filing reviews for such applications in the same manner as 586A requests for sunscreen active ingredients. 15 Section 586C(a)(1) of the FD&C Act (21 U.S.C. 360 fff-3(a)(1)). 16 Section 586B(b)(2)(A) of the FD&C Act (21 U.S.C. 360fff-2(b)(2)(A)). If FDA determines that the submission is sufficiently complete, FDA will file the sponsor’s 586A request, notify the sponsor in writing that the request has been filed, and make the notification publicly available.16 13 followed 4 Contains Nonbinding Recommendations Draft — Not for Implementation 139 140 • 141 142 143 144 145 146 If FDA refuses to file the sponsor’s request, the sponsor may, within 30 days of receipt of the 147 notification, request in writing a meeting with FDA to discuss the refusal to file.18 The sponsor 148 may also submit additional data or other information to FDA. If the sponsor requests a meeting, 149 FDA will convene that meeting within 30 days of the request.19 Following such a meeting, FDA 150 may file the request within 60 days, the sponsor may submit additional data or other information, 151 or the sponsor may, within 120 days, direct FDA to file the request over protest, with or without 152 amendments to correct any deficiencies in the request.20 If the sponsor submits additional data 153 or other information (whether before, after, or in the absence of a meeting), FDA must reconsider 154 its initial refusal to file, along with any additional information provided by the sponsor, and 155 make a new filing determination within 60 days.21 If, after a meeting, the sponsor elects to have 156 FDA file the request, FDA will file the request over protest within 30 days of the sponsor’s 157 election, notify the sponsor in writing that the request has been filed, and make such notification 158 public.22 159 160 C. Scope of This Draft Guidance 161 162 This draft guidance describes our current thinking on the content and format of a complete and 163 fileable request under the SIA. When final, the recommendations in this draft guidance will 164 provide advice to sponsors on how to prepare a successful GRASE submission, as well as guide 165 FDA’s filing determinations. 166 167 As noted in section II.B above, the “refusal to file” provision in the SIA applies only to GRASE 168 data submissions made by sponsors to support 586A requests.23 However, we anticipate that the 169 advice in this draft guidance will also be useful to persons who are preparing safety and efficacy 170 data submissions for review by FDA in other regulatory proceedings whose intent is to determine 171 whether particular nonprescription drug active ingredients or other OTC conditions are GRASE 17 Section 586B(b)(2)(B) of the FD&C Act (21 U.S.C. 360fff-2(b)(2)(B)). 18 Section 586B(b)(3) of the FD&C Act (21 U.S.C. 360fff-2(B)(b)(3)). 19 Section 586B(b)(3)(B) of the FD&C Act (21 U.S.C. 360fff-2(B)(b)(3)(B)). 20 Section 586B(b)(3). 21 Section 586B(b)(3)(C) of the FD&C Act (21 U.S.C. 360fff-2(b)(3)(C)). 22 Section 586B(b)(3)(B)(ii)((III) of the FD&C Act (21 U.S.C. 360fff-2(b)(3)(B)(ii)(III)). 23 As previously noted, non-sponsors also may submit partial or supplemental information and views to the applicable public docket (such as scientific articles, professional opinions, or statements from public advocacy groups). While such submissions are not subject to filing review, we recommend that interested parties consult the recommendations in this draft guidance to the extent that they are applicable to a given submission. If FDA determines that the submission is not sufficiently complete, FDA will refuse to file the sponsor’s 586A request and GRASE data submission, notify the sponsor in writing of the determination to refuse to file the request, and make the notification publicly available. The notification will explain the reasons for the refusal, including why the GRASE submission was not sufficiently complete.17 5 Contains Nonbinding Recommendations Draft — Not for Implementation 172 and therefore may be included in an applicable OTC monograph (such as a future non-sunscreen 173 TEA request or a request for additional data in an ongoing SIA proceeding). 174 175 This draft guidance does not detail the specific clinical and nonclinical data that should be 176 submitted to support a GRASE determination for a nonprescription sunscreen active ingredient. 177 Instead, it broadly identifies the key structural elements, topics to be addressed, and 178 recommended organization of a complete and fileable GRASE data submission. For the 179 Agency’s current thinking on the specific scientific testing and data recommended to support a 180 GRASE determination for sunscreen active ingredients, see the guidance Over-the-Counter 181 Sunscreens: Safety and Effectiveness Data (Safety and Effectiveness Draft Guidance). Sponsors 182 are encouraged to read that draft guidance document and meet with FDA before preparing and 183 submitting a GRASE data submission. 184 185 D. Related Draft Guidance 186 187 In addition to this draft guidance, the SIA directs FDA to issue three additional draft guidance 188 documents on other topics.24 These topics include: 189 190 • 191 192 193 194 • 195 196 • 197 198 199 200 201 202 As they become available, FDA will make these draft guidances available on the FDA Drugs 203 guidance Web page.25 204 205 206 III. 207 208 209 24 Section 586D(a)(1)(A) of the FD&C Act (21 U.S.C. 360fff-4(a)(1)(A)); see also “Guidance Agenda: New & Revised Draft Guidances CDER is Planning to Publish During Calendar Year 2015,” available online at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm417290.pdf. 25 When available, FDA will post each draft guidance on the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. When final, these guidances will represent the FDA’s current thinking on these topics. The data required to meet the safety and efficacy standard for determining whether a nonprescription sunscreen active ingredient is GRASE and not misbranded (the Safety and Efficacy Draft Guidance) The process for withdrawing a 586A request or a pending request The process by which FDA will carry out section 586C(c) of the FD&C Act as amended by the SIA, including the process for requesting an advisory committee meeting, the circumstances that limit the number and frequency of advisory committee meetings FDA is required to convene, and the number of requests to be considered per advisory committee meeting. CHARACTERISTICS OF A COMPLETE GRASE DATA SUBMISSION A. General Recommendations 6 Contains Nonbinding Recommendations Draft — Not for Implementation 210 FDA will refuse to file 586A requests for which the data and other information submitted are not 211 sufficiently complete. GRASE data submissions that are materially incomplete or inadequately 212 formatted do not permit FDA to conduct a substantive review. A complete submission by the 213 sponsor should generally have the following characteristics: 214 215 1. 216 217 218 2. 219 220 221 222 3. 223 224 225 226 227 228 4. 229 230 231 232 233 234 235 236 237 238 239 240 241 5. 242 243 244 6. 245 A separate submission should be provided for each active ingredient that is the subject of a 586A request. All data and information relevant to the requested GRASE determination should be provided in a single submission. A complete GRASE submission should include all of the data on which the sponsor intends to rely.26 If the sponsor wants FDA to consider data or information previously provided to FDA (such as data submitted to an NDA or ANDA, to the OTC sunscreen monograph proceeding, to another SIA docket, or in a citizen petition, the submission should identify the prior submission, submission date, and docket number and provide a complete copy of the previously submitted information. If the submission refers to a literature search or searches, the submission should identify the databases included in each search and the search terms used. The submission should include complete copies of scientific articles or other published materials that the sponsor wishes FDA to consider as part of its review. Each literature search should be placed (by subject) in the appropriate section of the submission, as described in section III.B of this draft guidance. Copies of scientific articles and other published materials should also be placed in the relevant sections by subject. For electronic submissions, all items in reference lists and all in-text references citing scientific articles or other published materials should include a hyperlink to a full copy of the referenced article or other published material. If the submission is not electronic, each item in the reference list and all in-text references should provide specific location data for the full copy of the referenced material. The submission should be in the English language. If any portion of a submission is in a foreign language, the sponsor should provide a complete and accurate English translation. The SIA requires that any information included in a GRASE data submission that the sponsor considers to be confidential must be identified by the sponsor at the time of the 26 The recommendations in this draft guidance are primarily directed to sponsors who are preparing a complete safety and efficacy data submission. Once such a submission has been made, sponsors should limit any further (supplemental) submissions to important, newly acquired data (such as safety data or results of newly completed or newly published studies). A supplemental submission should identify the original submission and the original submission date and should be labeled as a supplement. Depending on the volume and complexity of a supplemental submission and when it is submitted, it may be difficult or impossible for FDA to conduct a thorough scientific review within the stringent timelines prescribed by the SIA. Nonetheless, FDA encourages the submission of important new adverse safety information at any time during the review process. 7 246 247 248 249 250 251 252 253 254 255 256 257 7. 258 259
Contains Nonbinding Recommendations Draft — Not for Implementation submission.27 The sponsor might also consider redacting information that is not relevant to a GRASE determination, such as: Contractual relationships that are not public (e.g., names of contract testing laboratories or raw material suppliers) and names of contractors’ employees. The names of employees of the sponsor or its contractors, such as technicians, nurses, or sub-investigators. Product formulation information that is not public and is not relevant to a GRASE determination (e.g., quantity of an inactive ingredient). Safety and efficacy data that are not available to the public cannot be relied on to support a conclusion that an active ingredient is generally recognized as safe and effective. Accordingly, sponsors should not submit, and FDA generally does not intend to rely on, evidence of safety and efficacy that the sponsor has marked as confidential unless the sponsor also includes a statement that the information may be released to the public. Similarly, if the submission includes data or information marked as confidential by a third party (such as a contract research organization or consultant), the sponsor should include a statement that the sponsor is authorized to make the information publicly available or include an authorization from the third party permitting the information to be publicly disclosed. If a data submission includes studies or other information that were previously submitted to an NDA or ANDA submission without marking them as confidential, FDA intends to presume that the sponsor intends to make such data publicly available. 270 The principle that data to support a GRASE determination must be publicly available is most 271 pertinent to studies or detailed study findings that are critical to FDA’s evaluation of safety 272 and efficacy, such as information needed to confirm that the study was appropriately 273 designed and conducted or detailed study findings needed to substantiate the reported study 274 results. This principle does not apply to information that has no bearing on FDA’s scientific 275 review of safety and efficacy data, such as that described in item 6, because such information 276 is not relevant to a GRASE determination. 277 To enable a timely filing review, Module 128 should include the following, under the heading 278 “Confidential Information”: 279 • 280 281 282 • 283 A statement that all information considered by the sponsor to be confidential has been identified in the data submission, with a description of the method used to designate the information as confidential A statement identifying any confidential study or report, or a significant portion of it, that may not be released to the public or that lacks required third-party permission for public 27 Section 586B(b)(4) of the FD&C Act (21 U.S.C. 360fff-2(b)(4)). 28 For more information on Module 1, see section III.B. 8 284 285 286 287 8. 288 289 9. 290 291 292 Contains Nonbinding Recommendations Draft — Not for Implementation release. For purposes of this statement, FDA considers a portion to be significant if it is important to permit a full evaluation of study methods and conclusions All pages should be numbered. FDA encourages electronic submissions. B. Recommended Organization and Contents 293 FDA recommends that the GRASE data submission be organized using the general structure and 294 table of contents (TOC) described in the Common Technical Document (CTD) in effect at the 295 time of the submission.29 The CTD is an internationally harmonized set of specifications for 296 preparing applications relating to new drugs that is maintained by the International Conference 297 on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human 298 Use and has been recommended by the FDA in multiple guidance documents. Using this 299 organized approach will streamline FDA’s GRASE review because the CTD format is familiar to 300 and routinely used by FDA’s subject matter reviewers. 301 302 A submission using the eCTD TOC should be organized into five modules: 303 304 1. 305 2. 306 3. 307 4. 308 5. 309 310 The TOC in a GRASE data submission should be detailed, including both major section 311 headings and subheadings. However, it is neither necessary nor recommended that GRASE 312 data submissions meet the full technical specifications of an eCTD or include all of the 313 information identified in the CTD TOC headings. Because the eCTD TOC is designed to 314 accommodate multiple types of regulatory applications, it contains many headings and 315 subheadings that are not pertinent to the safety and efficacy of these ingredients. We therefore 316 do not recommend that such information be included in a GRASE data submission. However, 317 we do recommend that your TOC include all of the major headings from the CTD TOC (using 318 the appropriate heading numbers) and indicate, when appropriate, that no information is being 319 submitted for a given heading. 320 321 If the submission is electronic, the TOC should include hyperlinks to each section. If a 322 submission is not electronic, the submission should still be organized using the eCTD TOC. 323 324 A complete GRASE data submission based on the eCTD TOC should generally have the 325 following characteristics: 29 Current ICH and FDA guidances use the term “eCTD” (or electronic CTD) rather than “CTD” to reflect the transition to mandatory electronic submissions for regulatory submissions other than the GRASE data submissions addressed in this draft guidance. Administrative Information Overview and Summary of Modules 3 to 5 Relevant Quality Information Preclinical Data (Pharmacology/Toxicology) Clinical Safety and Efficacy 9 326 327 328 329 • 330 331 • 332 333 334 • 335 336 337 338 • 339 340 341 342 • 343 344 345 346 347 348 349 350 351 352 353 354 • 355 356 357 • 358 359 360 361 • 362 363 364 365 366 367 • 368 369 370 Contains Nonbinding Recommendations Draft — Not for Implementation MODULE 1: ADMINISTRATIVE INFORMATION Include any administrative and labeling information. Include statements about confidential information recommended in item 7 of section III.A. Include a cover letter that identifies the type of submission, the sponsor, the full contact information for the sponsor, the submission date, the active ingredient that is the subject of the submission, and the applicable docket number. Include any financial disclosure information, if applicable. MODULE 2: SUMMARIES Overall Summary: Include a concise narrative summary of (1) the evidence supporting a conclusion that the active ingredient is GRASE for the intended nonprescription use and (2) the data that are not supportive of a determination that the active ingredient is GRASE. The summary should clearly identify and address each of the major topics addressed in the submission. Also include a summary table listing all studies relied upon in the submission with their corresponding titles (as they appear in the study reports), study numbers, and location in the submission (with hyperlinks to each study if the submission is submitted electronically). There should be one clearly identified study number for each study submitted. Overall Quality Summary: Include a summary of all chemistry, manufacturing, and controls data included in the submission. Nonclinical Summary: Include a narrative summary of all nonclinical data included in the submission. This summary should address data that are both supportive and non-supportive of a determination that the ingredient is GRASE. Clinical Summary: Include a narrative summary of all clinical data included in the submission. This summary should address data that are both supportive and non- supportive of a determination that the active ingredient is GRASE. MODULE 3: QUALITY DATA Compendial Status: Include the compendial status of the active ingredient(s), including the current status of the United States Pharmacopeia (USP) listing(s) application. 10 Contains Nonbinding Recommendations Draft — Not for Implementation Chemical and/or Manufacturing Characteristics: Include any known chemical and/or manufacturing characteristics of the active ingredient that may be relevant to FDA’s GRASE evaluation. For example, include known interactions with other sunscreen active ingredients or commonly used sunscreen vehicle components; specific requirements for formulation that enhance photostability, efficacy or safety; or information on particle size for micronized or nanoscale active ingredients. 371 • 372 373 374 382 literature searches, scientific articles, or other published materials). Full copies of all 383 published materials should be provided. The specific ingredient and formulation(s) used in 384 each study should be described in detail. 385 386 Each individual study in the submission should include its own TOC and summary. 387 Complete data sets (not selected or summary data) should be included in the submission. We 388 expect that data from studies provided only in summary form will generally not be 389 considered sufficient evidence that an active ingredient is GRASE. 390 391 Examples of nonclinical studies to be provided in this module include dermal and systemic 392 carcinogenicity studies, developmental and reproductive toxicity studies, and animal 393 toxicokinetic data. 394 395 MODULE 5: CLINICAL STUDY REPORTS 396 397 Module 5 should include separate comprehensive integrated summaries of effectiveness and 398 clinical safety. The summary of effectiveness should include the active ingredient’s 399 mechanism of action and the specific doses, concentrations, and formulations proposed for 400 use. The summary of safety should include exposure data, and, if available, address safety in 401 specific populations such as children, the elderly, and pregnant or lactating women. The 402 summary of safety should also address specific safety issues expected with either the 403 ingredient or its application. For sunscreens, examples of such safety issues could include 404 dermal safety, hypersensitivity, accidental ocular exposure, or inhalational safety. All 405 available efficacy and safety data, including both supportive data and any data demonstrating 406 potential safety signals, should be submitted. 407 408 This module should also include full reports of (1) all clinical effectiveness and safety studies 409 and other clinical data and (2) all clinical pharmacology and human toxicokinetic data. In 410 addition to actual study reports, all other types of clinical data (e.g., from literature searches, 411 scientific articles, or other published materials) should be included in this module. Full copies of 412 all published materials should be provided. Each study report should contain a description of the 413 specific ingredient and formulation(s) used. For literature reports, this information may be 414 included in the relevant summary document. 415 375
380 This module should include data and reports from nonclinical studies discussed in the Safety 381 and Efficacy Draft Guidance, as well as any other types of nonclinical information (e.g., MODULE 4: NONCLINICAL STUDY REPORTS 11 Contains Nonbinding Recommendations Draft — Not for Implementation 416 Human studies to be included in Module 5 are discussed in the Safety and Effectiveness Data 417 Draft Guidance. These include sun protection factor studies and other effectiveness studies (such 418 as in vitro broad spectrum studies, if performed), human irritation and sensitization studies, 419 human photosafety studies, human absorption studies, and human maximal usage trials. 420 421 Module 5 should also include reports of in vitro testing performed by the sponsor in connection 422 with human maximal usage trials to support final formulation safety testing if the active 423 ingredient is determined to be GRASE, as discussed in Safety and Effectiveness Data Draft 424 Guidance. 425 426 Each individual study in the submission should include its own TOC and summary. Complete 427 data sets (not selected or summary data) should be included in the submission. Generally, we 428 intend not to consider study data provided only in summary form to be sufficient evidence that 429 an active ingredient is GRASE. 430 431 Further, postmarketing safety data as discussed in the Safety and Effectiveness Data Draft 432 Guidance,30 should be included in Module 5. For adverse event reports, there should be a TOC 433 with a separate link to each adverse event report. The section on adverse event reports should be 434 organized according to the Medical Dictionary for Regulatory Activities System Organ Class 435 categories. 436 437 C. Characteristics of an Incomplete Request and GRASE Data Submission 438 439 Some examples of incomplete information or inadequate organization that may render the 440 GRASE data submission insufficiently complete31 for review are listed below.32 These 441 characteristics could cause FDA to refuse to file a GRASE data submission. 442 443 1. 444 445 446 447 2. 448 449 450 3. 451 452 453 4. 454 455 30 Id. 31 See section 586B(b)(2) of the FD&C Act. 32 Please note that this list is not exhaustive. The submission is unreasonably disorganizedthat is, its structure does not permit ready review for completeness by lacking a recommended TOC that itemizes the submission’s elements and data. Electronic submissions cannot be opened or readily navigated (e.g., hyperlinks do not operate). Data tabulations or graphic displays are not interpretable, are inadequately labeled, or do not indicate data sources. Summaries or tables of contents do not indicate or link to the location of specific discussions, studies, or other referenced information elsewhere in the submission. 12 Contains Nonbinding Recommendations Draft — Not for Implementation The submission is materially incomplete on its face (e.g., it does not include sufficient information for FDA to make a GRASE determination because it completely fails to include some or all of the information identified in Section III.B of this draft guidance, unless the sponsor explains the reasons why the missing information is not included and why the active ingredient or other condition should be found to be GRASE in its absence). All or essential portions of the submission are marked as confidential. 456 5. 457 458 459 460 461 462 463 6. 464 465 466 467 GRASE data submissions can be sent (1) in hard copy to the Division of Dockets Management 468 (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852 469 or (2) electronically to http://www.regulations.gov using the previously established docket 470 number. In addition, a copy of the cover letter should be sent to the Division of Nonprescription 471 Drug Products, Food and Drug Administration, Bldg. 22, Mail Stop 5411, 10903 New 472 Hampshire Avenue, Silver Spring, MD 20993. 473 474
D. How and Where To Submit GRASE Data Submissions 13 Joomla SEO by MijoSEF