Warning: Creating default object from empty value in /home4/sspccco/public_html/pharmafacts.com/plugins/system/J2top.php on line 78
FDA Guidances - PharmaFacts
gototopgototop
If you don't find what you're looking for, please let us know.

FDA Guidances

FDA Guidances

All Information was adapted from the Food and Drug Administration website as a service to our readers. The most current versions can be found on the FDA Website.

Sunscreen Innovation Act: Withdrawal of a 586A Request or Pending Request Guidance for Industry DRAFT GUIDANCE

Sunscreen Innovation Act: Withdrawal of a 586A Request or Pending Request

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DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.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be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.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

page1image8912 page1image9072

Sunscreen Innovation Act: Withdrawal of a 586A Request or Pending Request

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 20993-0002
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

page2image5632

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

November 2015 OTC

I. II.

A. B. C.

III. A.

B.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 BACKGROUND ............................................................................................................... 2 Regulation of Sunscreen Products ................................................................................................2 Section 586D(a) Draft Guidance on Withdrawal Process...........................................................4 Related Draft Guidance .................................................................................................................4 GENERAL WITHDRAWAL PROCEDURES.............................................................. 5 Request for Withdrawal ................................................................................................................5 Withdrawal Due to Sponsor’s Failure to Take Action................................................................6

EFFECT OF WITHDRAWAL OF 586A REQUESTS AND PENDING
586A Request — Withdrawal........................................................................................................7

1. Withdrawal Prior to an Eligibility Determination or After a Determination That a
Request Is Ineligible..............................................................................................................................7 2. Withdrawal After an Eligibility Determination but Prior to a Filing Determination ......................8 3. Withdrawal After Filing Determination ...........................................................................................8 4. Withdrawal After a Proposed Sunscreen Order Under Section 586(7)(C)......................................9

Pending Requests — Withdrawal .................................................................................................9 New Requests ................................................................................................................................10

IV.
REQUESTS ................................................................................................................................... 7

A.

B. C.

1 2 3 4

Contains Nonbinding Recommendations

Draft — Not for Implementation

Sunscreen Innovation Act: Withdrawal of a 586A Request or Pending Request

51 67 Guidance for Industry

8

 9
10
11
12
13
14
15

16
17
18
I. INTRODUCTION 19

  1. 20  This draft guidance addresses the process for (1) withdrawal of a request submitted under section

  2. 21  586A (586A request)2 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended by

  3. 22  Public Law 113-195 (also referred to as the Sunscreen Innovation Act or SIA)3 and (2)

  4. 23  withdrawal of a pending request, as defined under section 586(6) of the FD&C Act.4 When

  5. 24  final, the recommendations in this guidance will apply to 586A requests and pending requests5

  6. 25  that seek a determination from FDA of whether a nonprescription sunscreen active ingredient or

  7. 26  a combination of nonprescription sunscreen active ingredients is generally recognized as safe and

    1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.

    2 A 586A request is a request submitted to FDA for a determination of whether a nonprescription sunscreen active ingredient or a combination of nonprescription sunscreen active ingredients, for use under specified conditions, is generally recognized as safe and effective (GRASE) and should be included in the sunscreen OTC monograph (section 586A of the FD&C Act (21 U.S.C. 360fff-1)).

    3 21 U.S.C. Ch. 9 Sub. 5 Part 1, enacted November 26, 2014.

    4 Section 586(6) of the FD&C Act defines a pending request to mean a request for a nonprescription sunscreen active ingredient submitted under § 330.14 (21 CFR 330.14) for consideration for inclusion in the OTC monograph that was determined to be eligible for review and for which safety and effectiveness data was submitted prior to the enactment of the SIA (section 586(6) of the FD&C Act (21 U.S.C 360fff(6)). These pending requests were submitted as time and extent applications (TEAs) under § 330.14 of FDA’s regulations.

    5 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 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))).

page4image25368

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 as listed on the title page.

page4image38784
page4image40200

1

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 27  effective (GRASE) for use under specified conditions and should be included in the over-the-

  2. 28  counter (OTC) sunscreen drug monograph.

  3. 29  The SIA, enacted on November 26, 2014, added new section 586D(a)(1) to the FD&C Act,

  4. 30  which directs FDA to issue draft and final guidance on the process by which a request under

  5. 31  section 586A or a pending request is withdrawn.6 This draft guidance is organized as follows:

32 33
34

35 36
37
38

39 40

  1. 41  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 42  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

  3. 43  as recommendations, unless specific regulatory or statutory requirements are cited. The use of

  4. 44  the word should in Agency guidances means that something is suggested or recommended, but

  5. 45  not required.

46
47
48
II. BACKGROUND
49
50
A. Regulation of Sunscreen Products
51
52 All sunscreens are regulated as drugs in the United States under one of two processes: 53
54

55 56

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

Section II provides background information on the sunscreen OTC monograph process and the new procedures under the SIA (the SIA process) for reviewing 586A requests and pending requests for nonprescription sunscreen active ingredients.7

Section III addresses the general withdrawal process for a 586A request or pending request. At certain stages of the SIA process, the sponsor8 who submitted a 586A request or pending request might seek to have it withdrawn, or the request may be withdrawn due to the sponsor’s failure to act on the request and failure to respond to communications from FDA.

Section IV addresses the effect of this withdrawal process on key phases of the SIA process.

The new drug approval process described in part 314 (21 CFR part 314)

57

  1. 58  Products regulated under the new drug approval process may not be marketed without FDA’s

  2. 59  prior review and approval of a new drug application (NDA) or abbreviated new drug application

6 Section 586D(a)(1) of the FD&C Act (21 U.S.C. 360fff-4(a)(1)).

7 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” and “Sunscreens” Web sites respectively. See http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the- CounterOTCDrugs/StatusofOTCRulemakings/default.htm and http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingOver-the- CounterMedicines/ucm239463.htm.

8 A sponsor under the SIA is a person that 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))).

page5image29104 page5image29264 page5image29424 page5image29584 page5image29744

2

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 60  (ANDA) for each product.9 Products marketed under the OTC drug monograph process are not

  2. 61  individually reviewed and approved prior to marketing. Instead, OTC drug monographs

  3. 62  categorize drugs by therapeutic categories, such as sunscreens. For each category, a monograph

  4. 63  establishes conditions under which any drug that satisfies those conditions and FDA’s general

  5. 64  regulations for OTC drugs is considered to be GRASE and not misbranded when used under the

  6. 65  conditions prescribed, recommended, or suggested in the drug’s labeling.10

66

  1. 67  Only active ingredients that were used in U.S.-marketed sunscreens before the OTC Drug

  2. 68  Review began were eligible to be included in the OTC sunscreen monograph. An active

  3. 69  ingredient or other condition that is ineligible for inclusion in the OTC monograph system is

  4. 70  subject to the new drug approval process.

71

  1. 72  In 2002, before the SIA was enacted, FDA published the “time and extent application” (TEA)

  2. 73  regulation in 21 CFR 330.14. The TEA regulation (§ 330.14(c)) has provided a process through

  3. 74  which any person may request that FDA amend an existing OTC drug monograph to include an

  4. 75  active ingredient or other OTC drug condition, including one not previously marketed in the

  5. 76  United States before the OTC Drug Review began.

77

  1. 78  For OTC sunscreens, the SIA process supplements FDA’s TEA regulation (§ 330.14). The SIA

  2. 79  amended the FD&C Act in part by providing new procedures for establishing that

  3. 80  nonprescription sunscreen active ingredients or combinations of nonprescription sunscreen active

  4. 81  ingredients are GRASE and not misbranded when used under the conditions specified in a final

  5. 82  sunscreen order (GRASE determination).11 Active ingredients that are determined to be GRASE

  6. 83  under specified conditions of use in a final sunscreen order may be used in U.S.-marketed

  7. 84  sunscreens without first obtaining an approved NDA or ANDA. Because the monograph and

  8. 85  SIA processes are public, anyone, not just the sponsor who originated the request, may submit

  9. 86  data during public comment periods.

87

  1. 88  As with the TEA process, the SIA process calls for an initial eligibility determination, followed

  2. 89  by submissions of safety and efficacy data, and a GRASE determination phase. However, the

  3. 90  SIA process also requires FDA to make a filing determination12 and to make proposed and final

  4. 91  GRASE determinations in the form of orders rather than the rulemaking required by the TEA

  5. 92  regulation. The SIA process also establishes strict timelines for the necessary administrative

  6. 93  actions.

94 95 96

9 See sections 505(a) and 301(d) of the FD&C Act.
10 21 CFR part 330.
11 Section 586C of the FD&C Act (21 U.S.C. 360fff-3).

12 The filing determination requires FDA to determine whether the safety and efficacy data submitted to support a GRASE determination are appropriately formatted and sufficiently complete to support a substantive GRASE review (section 586B(b)(2) of the FD&C Act (21 U.S.C. 360fff-2(b)(2))).

page6image29184

3

Contains Nonbinding Recommendations

Draft — Not for Implementation

97 B. Section 586D(a) Draft Guidance on Withdrawal Process 98

  1. 99  Section 586D(a)(1)(A)(iii) of the FD&C Act requires the Agency to issue guidance on “the

  2. 100  process by which a request under section 586A or a pending request is withdrawn.”13 The

  3. 101  statute does not address the process by which a sponsor or FDA could withdraw a 586A request

  4. 102  or pending request under the SIA. In addition, FDA’s current regulations governing TEA

  5. 103  requests do not include a withdrawal process (§ 330.14). As directed by the SIA, FDA is issuing

  6. 104  this draft guidance to explain how, at different stages of the SIA process, a 586A request or

  7. 105  pending request may be withdrawn.

106

  1. 107  Although neither the SIA nor the current TEA regulation otherwise discuss the process of

  2. 108  withdrawal, we note, that in the preamble of the final rule promulgating the TEA regulation,

  3. 109  FDA discussed the effect of a withdrawal of a TEA request when a non-GRASE determination

  4. 110  for that condition is expected. We explained that although a sponsor can withdraw its request,

  5. 111  we would still consider the submission to be a part of the public docket and FDA would still

  6. 112  have the discretion to publish the Agency’s non-GRASE decision, notwithstanding the

  7. 113  withdrawal.14 It is the Agency’s view that consideration for OTC drug monograph status is a

  8. 114  public process and all information provided should be part of the public record if the condition is

  9. 115  determined to be eligible.15 Thus, after the data and information has been submitted in response

  10. 116  to a notice of eligibility (NOE), the Agency will have the information upon which to base its

  11. 117  GRASE determination.

118

  1. 119  Based on the requirements of the SIA and the Agency’s prior consideration of a similar issue in

  2. 120  implementing the TEA regulation,16 this draft guidance describes our recommendations for

  3. 121  addressing the process for withdrawal of a 586A request or pending request and the effect of a

  4. 122  withdrawal on the GRASE review process.

123
124
C. Related Draft Guidance 125

  1. 126  In addition to this draft guidance, the SIA directs FDA to issue three additional draft guidance

  2. 127  documents on other topics.17 These topics include:

128
129
The format and content of information submitted by a sponsor in support of a 586A

130 131

request or a pending request;

13 Section 586C(a)(1)(A)(iii) of the FD&C Act (21 U.S.C. 360fff-3(a)(1)(A)(iii)). 14 See 2002 TEA Final Rule, 67 FR 3060 at 3066 and 3067.

15 Id. There may be limited situations in which certain information submitted may be considered confidential. Id.; see also section 586B(a)(3) of the FD&C Act (21 U.S.C. 360fff-4(a)(3)).

16 See 2002 TEA Final Rule, 67 FR 3060 at 3067.
17 Section 586D(a)(1)(A) of the FD&C Act (21 U.S.C. 360fff-4(a)(1)(A)).

page7image28440

4

Contains Nonbinding Recommendations

Draft — Not for Implementation

The data required to meet the safety and efficacy standard for determining whether a nonprescription sunscreen active ingredient or combination of nonprescription sunscreen active ingredients is GRASE and not misbranded; and

132 133
134
135

136 137
138
139

140 141

  1. 142  As they become available, FDA will make these draft guidances available on the FDA Drugs

  2. 143  guidance Web page.18

144
145
146
III. 147
148
149

  1. 150  A sponsor seeking to withdraw its 586A request or pending request should submit its written or

  2. 151  electronic request for withdrawal to the docket for that proceeding with a copy to the Division of

  3. 152  Nonprescription Drug Products in the Office of Drug Evaluation IV.19 Written requests should

  4. 153  be submitted to:

154

  1. 155  Division of Dockets Management (HFA-305)

  2. 156  Food and Drug Administration

  3. 157  5630 Fishers Lane, Rm. 1061

  4. 158  Rockville, MD 20852

  5. 159  and

  6. 160  Food and Drug Administration

  7. 161  Division of Nonprescription Drug Products

  8. 162  Bldg. 22, Mail Stop 5411

  9. 163  10903 New Hampshire Avenue

  10. 164  Silver Spring, MD 20993

165

  1. 166  Electronic requests, and electronic copies of written requests, should be submitted to

  2. 167 http://www.regulations.gov in the applicable docket. The withdrawal request should include the

  3. 168  following information:

  4. 169 submitter

    18 When available, FDA will post each draft guidance available on the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
    When final, the guidance will represent the FDA’s current thinking on this topic.

    19 If the Agency has not opened a docket for the proceeding, the sponsor should submit its written request for withdrawal to the Division of Nonprescription Drug Products in the Office of Drug Evaluation IV as described above.

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.

GENERAL WITHDRAWAL PROCEDURES A. Request for Withdrawal

page8image24632 page8image24792 page8image24952

5

  1. 170

  2. 171

  3. 172

173

Contains Nonbinding Recommendations

Draft — Not for Implementation

submission date
active ingredient or other condition that is the subject of the submission applicable docket number

  1. 174  A request to withdraw informs FDA of the sponsor’s intent to discontinue its request for a

  2. 175  determination from the Agency of whether the sunscreen active ingredient, or combination of

  3. 176  active ingredients, is GRASE and should be included in the sunscreen OTC monograph. FDA

  4. 177  intends to respond to a request for withdrawal from the sponsor by sending a letter to the sponsor

  5. 178  acknowledging the withdrawal of the request. If the withdrawal is made after a docket has been

  6. 179  opened for that proceeding, FDA will place a copy of the acknowledgement letter in that docket.

180

  1. 181  As explained in more detail below, generally, if a sponsor submits a request to withdraw its

  2. 182  586A or pending request at any time prior to FDA’s issuance of a final sunscreen order, FDA

  3. 183  intends to consider the request withdrawn. If a proposed sunscreen order has not been issued,

  4. 184  FDA intends to stop its review of that request. However, similar to FDA’s approach under the

  5. 185  TEA regulation, if a proposed sunscreen order has already been issued prior to the withdrawal,

  6. 186  FDA intends to proceed with issuing a final sunscreen order consistent with the SIA and as

  7. 187  priorities and resources permit. In addition, FDA intends that the original submission and the

  8. 188  data and information submitted in support of the 586A request will remain a part of the public

  9. 189  docket for that proceeding, and FDA may continue to rely on such data and information.20

190
191
192
B. Withdrawal Due to Sponsor’s Failure to Take Action 193

  1. 194  We note that there are several stages in the review process for 586A requests and pending

  2. 195  requests at which the Agency will be waiting for the sponsor or other interested parties to submit

  3. 196  necessary information or data. With the exception of designated comment periods, the SIA does

  4. 197  not require the sponsor or others to submit such information or data within an established

  5. 198  deadline. Based on our past experience with the OTC monograph process, this may create a

  6. 199  situation in which the necessary information or data are never submitted.

200

  1. 201  Accordingly, we recommend that sponsors keep us apprised of the anticipated timing of their

  2. 202  data submissions if those submissions are expected to occur more than 1 year from the date of

  3. 203  the notice of eligibility (NOE) or the sponsor’s most recent submission. To facilitate the review

  4. 204  process and better utilize the Agency’s time and resources, FDA may also request periodic

  5. 205  updates from the sponsor on the status of the information or data to be submitted if nothing has

  6. 206  been submitted by the sponsor for more than 1 year. If an update is not provided or no

  7. 207  information or data are submitted to FDA within 90 days of FDA’s request for an update, the

  8. 208  Agency intends to consider the sponsor’s failure to respond to be a request by the sponsor to

  9. 209  withdraw the 586A or pending request. By failing to take action, the sponsor will have

  10. 210  indicated that it is no longer interested in pursuing a GRASE determination for a particular

  11. 211  request. FDA intends to send a letter notifying the sponsor that the request is withdrawn, and

  12. 212  FDA intends to place a copy of the letter in the public docket for that proceeding. It is the

    20 See 2002 TEA Final Rule, 67 FR 3060 at 3067. Generally, the Agency will open a docket when the notice of eligibility (NOE) is issued.

page9image35920

6

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 213  Agency’s view that this withdrawal process will provide notice to the public of the status of the

  2. 214  proceeding and of our intent to stop review of the request due to the sponsor’s failure to take

  3. 215  action. As discussed in section IV.C, if a 586A request or pending request is withdrawn, a

  4. 216  sponsor can submit a new request for the same sunscreen active ingredient or combination of

  5. 217  sunscreen active ingredients.

218
219
220
IV. EFFECT OF WITHDRAWAL OF 586A REQUESTS AND PENDING REQUESTS 221

  1. 222  As explained above, the SIA process calls for an initial eligibility determination phase followed

  2. 223  by the submission of safety and efficacy data, a filing determination by FDA, and a GRASE

  3. 224  determination phase, which includes a proposed sunscreen order and final sunscreen order.

225

  1. 226  If a 586A request is determined to be eligible for review, the Agency opens a docket for the

  2. 227  proceeding, publicly posts the NOE and the 586A request,21 and provides interested parties 45

  3. 228  days to submit comments relating to a GRASE determination on the request, including data and

  4. 229  other information related to the safety and efficacy of the request.22

230

  1. 231  A key step in the SIA process requires FDA to determine whether the information and data

  2. 232  submitted to support a GRASE determination are appropriately formatted and sufficiently

  3. 233  complete to support a substantive GRASE review (filing determination).23 Based on that

  4. 234  determination, FDA will either file or refuse to file the request (thus triggering various action

  5. 235  timelines).24

236

  1. 237  The following sections address the effect that a withdrawal of a 586A request or pending request

  2. 238  may have on these and other key phases of the SIA process.

239
240
241
A. 242
243
1. 244
245

  1. 246  If a sponsor withdraws its 586A request before FDA issues an eligibility determination, we

  2. 247  intend to stop our review of the request because we no longer have a 586A request upon which to

  3. 248  make a determination of eligibility. Similarly, if FDA has made a determination that the 586A

  4. 249  request is not eligible for review under the SIA process, the matter may be considered closed

  5. 250  without the need for a withdrawal because there is no longer an open matter from which to

    21 For information on the treatment of confidential data in 586A requests, see section 586B(a)(3) of the FD&C Act (21 U.S.C. 360fff-2(a)(3)).

    22 Section 586B(b)(1) of the FD&C Act (21 U.S.C. 360fff-2(b)(1)). 23 Section 586B(b)(2) of the FD&C Act (21 U.S.C. 360fff-2(b)(2)). 24 Section 586B(b)(3) of the FD&C Act (21 U.S.C. 360fff-2(b)(3)).

586A Request — Withdrawal

Withdrawal Prior to an Eligibility Determination or After a Determination That a Request Is Ineligible

page10image28568

7

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 251  withdraw. For requests withdrawn prior to an eligibility determination, FDA does not intend to

  2. 252  publicly post the withdrawal notification.

253
254
2. 255
256
257
258

  1. 259  If a sponsor withdraws its 586A request after FDA has determined that the request is eligible for

  2. 260  review and has issued an NOE, but before the data package described in section 586B(b)(1) of

  3. 261  the FD&C Act has been submitted, FDA intends to stop its review of the withdrawn request.

  4. 262  Upon the sponsor’s withdrawal, there will be no 586A request which may be filed. If a new

  5. 263  586A request is submitted for the same sunscreen active ingredient or combination of sunscreen

  6. 264  active ingredients after the withdrawal of the original request, we intend to follow the process for

  7. 265  the new request as explained in section IV.C.

266
267 b. Postsubmission of Data Package 268

  1. 269  If a sponsor withdraws its 586A request after FDA has determined that the request is eligible for

  2. 270  review and has issued an NOE determination, and after the data package described in section

  3. 271  586B(b)(1) of the FD&C Act has been submitted, but prior to FDA’s filing determination, the

  4. 272  Agency intends to stop its review of the 586A request. Upon the sponsor’s withdrawal, there

  5. 273  will be no 586A request. If a new 586A request is submitted for the same sunscreen active

  6. 274  ingredient or combination of sunscreen active ingredients after the withdrawal of the original

  7. 275  request, we intend to follow the process for the new request as explained in section IV.C.

276
277
3. Withdrawal After Filing Determination

Withdrawal After an Eligibility Determination but Prior to a Filing Determination

a. Presubmission of Data Package

278 279 280

  1. 281  If FDA determines that the data and information are sufficiently complete to conduct a GRASE

  2. 282  review, the Agency will file the 586A request. If a sponsor withdraws its 586A request after the

  3. 283  Agency has filed the request and before the Agency has issued the proposed sunscreen order, the

  4. 284  Agency intends to stop its review of the withdrawn request. If a new 586A request is submitted

  5. 285  for the same sunscreen active ingredient or combination of sunscreen active ingredients after the

  6. 286  withdrawal of the original request, we intend to follow the process for the new request as

  7. 287  explained in section IV.C.

288
289 b. Refuse to File 290

  1. 291  If a sponsor withdraws its 586A request after FDA refuses to file the request, the Agency intends

  2. 292  to stop its review of the withdrawn request. A sponsor can submit additional data or other

  3. 293  information in response to a refuse to file. If a sponsor withdraws its 586A request after it has

  4. 294  submitted additional data or information, but before FDA has made a new filing determination,

a. Filed 586A Request

8

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 295  the Agency intends to stop its review of the withdrawn request.25 If a new 586A request is

  2. 296  submitted for the same sunscreen active ingredient or combination of sunscreen active

  3. 297  ingredients after FDA refuses to file the original 586A request, we intend to follow the process

  4. 298  for the new request as explained in section IV.C.

299
300
4. Withdrawal After a Proposed Sunscreen Order Under Section 586(7)(C) 301

  1. 302  If a sponsor withdraws the 586A request after the Agency has made a tentative determination of

  2. 303  GRASE status of an active ingredient under certain conditions of use in a proposed sunscreen

  3. 304  order, 26 FDA intends to deem the 586A request withdrawn, but may continue to rely on the

  4. 305  information submitted to the docket and may proceed to issuing a final sunscreen order. As

  5. 306  explained in section II.B, we consider all data and information submitted (e.g., in response to the

  6. 307  NOE, a feedback letter, or tentative GRASE determination) to be part of the public record. Upon

  7. 308  submission of such information, the Agency has the data upon which to base its final sunscreen

  8. 309  order notwithstanding the withdrawal. If a new 586A request is submitted for the same

  9. 310  sunscreen active ingredient or combination of sunscreen active ingredients after the withdrawal

  10. 311  of the original request, we intend to follow the process for the new request as explained in

  11. 312  section IV.C.

313
314
315
B. Pending Requests — Withdrawal 316

  1. 317  As explained above, a pending request under the SIA is defined to mean a request for a

  2. 318  nonprescription sunscreen active ingredient submitted under § 330.14 for consideration for

  3. 319  inclusion in the OTC monograph that was determined to be eligible for review and for which

  4. 320  safety and effectiveness data were submitted prior to the enactment of the SIA (section 586(6) of

  5. 321  the FD&C Act). There are eight pending requests as defined under section 586(6) of the FD&C

  6. 322  Act. FDA has issued proposed sunscreen orders for all eight pending requests.27 As of the date

  7. 323  of this draft guidance, all of the proposed sunscreen orders for these pending requests tentatively

  8. 324  determined that the active ingredients are not GRASE and more data are necessary to allow FDA

  9. 325  to determine otherwise. 28

    25 Section 586B(b)(3) of the FD&C Act provides sponsors with a process to submit additional information and request meetings if FDA refuses to file the request. If FDA makes a new filing determination based on the additional information and accepts the request for filing, then any withdrawal of the request sought thereafter will fall under the approach described in section IV.A.3.a.

    26 Section 586C(a)(5)(A) of the FD&C Act (21 U.S.C. 360fff-3(a)(5)(A)). Under the SIA, FDA has 300 days to evaluate the information and data submitted to the docket and to issue a proposed sunscreen order on its GRASE determination (section 586C(a)(1) of the FD&C Act (21 U.S.C. 360fff-3(a)(1))). In the proposed sunscreen order, FDA can find that the active ingredient under consideration is GRASE, not GRASE, or not GRASE and more information and data are necessary to allow FDA to determine otherwise (section 586(7) of the FD&C Act (21 U.S.C. 360fff(7))). The sponsor and interested parties will have 45 days to submit comments on the proposed order (section 586C(a)(3) of the FD&C Act (21 U.S.C. 360fff-3(a)(3))).

    27 Section 586C(b)(3) of the FD&C Act (21 U.S.C. 360fff-3(b)(3)).

    28 http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingOver-the- CounterMedicines/ucm239463.htm.

page12image32264 page12image32424 page12image32584

9

 

Contains Nonbinding Recommendations

Draft — Not for Implementation

326

  1. 327  Accordingly, FDA intends for the same withdrawal process described in section IV.A.4 to apply

  2. 328  if a sponsor of a pending request withdraws the pending request prior to the issuance of the final

  3. 329  sunscreen order. If a new 586A request is submitted for the same sunscreen active ingredient

  4. 330  after the withdrawal of the pending request, we intend to follow the process for the new request

  5. 331  as explained in section IV .C.

332 333 334

  1. 335  The same or a different sponsor can submit a new 586A request for the same sunscreen active

  2. 336  ingredient or combination of sunscreen active ingredients after the original request has been

  3. 337  withdrawn. If FDA has already made a determination that the active ingredient is eligible for

  4. 338  further review under the SIA process, FDA intends for the existing NOE to remain in effect and

  5. 339  the sunscreen active ingredient or combination of active ingredients to remain eligible for

  6. 340  consideration under the SIA. The sponsor of the new 586A request may rely on the existing

  7. 341  NOE for that active ingredient; but, thereafter, we intend to treat the new submission as a new

  8. 342  586A request under the SIA process, and the sponsor should submit a new and complete data

  9. 343  submission package for its request. The data package may include data and other information

  10. 344  that were submitted as part of a prior 586A or pending request for that ingredient under the SIA.

  11. 345  If there is no existing NOE or the active ingredient has been found ineligible, then we intend to

  12. 346  treat the submission of another 586A request for this ingredient as a new 586A request subject to

  13. 347  the full SIA process, including an eligibility determination.

348 349

C. New Requests

10

 

Over-the-Counter Sunscreens: Safety and Effectiveness Data Guidance for Industry DRAFT GUIDANCE

page1image408

Over-the-Counter

Sunscreens: Safety

and Effectiveness Data 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

page1image9032 page1image9192

31736dft.doc 10/29/15

Over-the-Counter

Sunscreens: Safety

and Effectiveness Data 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
Tel: 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

I. II. III.

A.

B.

C. IV.

V.

1.

2. 3.

1. 2. 3.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 PHARMACEUTICAL QUALITY/MANUFACTURING DATA................................ 3

SAFETY DATA NEEDED TO ESTABLISH THAT AN OTC SUNSCREEN ACTIVE INGREDIENT IS GRASE............................................................................... 3

Clinical Safety Testing...................................................................................................................5

Human Dermal Safety Studies ......................................................................................................... 5

  1. Human irritation and sensitization studies ................................................................................ 5

  2. Human photosafety studies ....................................................................................................... 6

Human Absorption Studies/Maximal Usage Trial ........................................................................... 7 Pediatric Considerations ................................................................................................................. 8 Nonclinical Safety Testing.............................................................................................................9

Carcinogenicity Studies: Dermal and Systemic..............................................................................9 Developmental and Reproductive Toxicity Studies.......................................................................... 9 Toxicokinetics ................................................................................................................................ 10 Postmarketing Safety Data.......................................................................................................... 10

EFFECTIVENESS TESTING....................................................................................... 11 ANTICIPATED FINAL FORMULATION TESTING .............................................. 12

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 1 Over-the-Counter Sunscreens:

  2. 2 Safety and Effectiveness Data

  3. 3 Guidance for Industry1

4 5 6

7 8 9

10 11 12 13

14
15
16
17
I. INTRODUCTION 18

  1. 19  This guidance addresses the Food and Drug Administration’s (FDA’s or Agency’s) current

  2. 20  thinking about the safety and effectiveness data needed to determine whether a nonprescription

  3. 21  (also referred to as over-the-counter (OTC)) sunscreen active ingredient or combination of active

  4. 22  ingredients evaluated under the Sunscreen Innovation Act (SIA) is generally recognized as safe

  5. 23  and effective (GRASE) and not misbranded when used under specified conditions.2 For brevity,

  6. 24  references to sunscreen active ingredients3 in this guidance also include combinations of active

  7. 25  ingredients unless otherwise specified.

26

  1. 27  FDA is issuing this guidance in partial implementation of the SIA. Among other things, the SIA

  2. 28  supplemented FDA’s existing regulation for adding a new active ingredient or other condition to

  3. 29  an OTC drug monograph4 with new procedures and review time lines for establishing that a

  4. 30  nonprescription sunscreen active ingredient is GRASE and not misbranded when used under the

  5. 31  conditions specified in a final sunscreen order.5 A critical step in that process is FDA’s review

    1 This guidance has been prepared by the Center for Drug Evaluation and Research at the Food and Drug Administration.

    2 21 U.S.C. ch. 9, sub. 5, part I, enacted November 26, 2014

    3 For purposes of this guidance, the term sunscreen active ingredient refers to an active ingredient that is intended for application to the skin of humans for purposes of absorbing, reflecting, or scattering ultraviolet radiation (see section 586(10) of the Federal Food, Drug, and Cosmetic Act (FD&C Act)).

    4 See 21 CFR 330.14. This regulation sets out the time and extent application procedure by which a new active ingredient or other condition (e.g., dosage form, dosage strength, or route of administration) can be considered for inclusion in the OTC drug monograph system.

    5 See sections 586A (submission of a new request for GRASE determination), 586B (preliminary filing review, eligibility determination, and request for submission of safety and effectiveness data), and 586C (GRASE determination and issuance of proposed and final orders) of the FD&C Act.

page4image24952

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 as listed on the title page.

page4image38048
page4image39624

1

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 32  of safety and efficacy data submitted by the person requesting the GRASE determination

  2. 33  (sponsor).6 If FDA determines that the active ingredient in question is GRASE and not

  3. 34  misbranded for use in nonprescription sunscreens, it will issue a final sunscreen order setting out

  4. 35  the conditions that sunscreen products containing the active ingredient must satisfy to be

  5. 36  marketed without an approved new drug application (NDA).7 Sunscreen products that satisfy

  6. 37  those conditions and other requirements for nonprescription drugs may be marketed immediately

  7. 38  upon issuance of the final sunscreen order and for as long as that order remains in effect. Any

  8. 39  future rulemaking to amend the OTC sunscreen drug monograph will include the active

  9. 40  ingredient found GRASE in the final order.8

41

  1. 42  The SIA also directed FDA to issue draft guidance on the data a nonprescription sunscreen active

  2. 43  ingredient would need to meet the safety and efficacy standard for a GRASE determination.9

  3. 44  The recommendations in this guidance will help sponsors identify and obtain the safety and

  4. 45  effectiveness data needed to show that sunscreen active ingredients are GRASE for use in

  5. 46  nonprescription sunscreens. Unlike the review of sunscreen products under the new drug

  6. 47  approval process,10 for which premarketing testing focuses on individual product formulations,

  7. 48  the GRASE review for active ingredients takes into account the fact that the ingredient, if found

  8. 49  GRASE, may be included in a variety of formulations that will be marketed without product-

  9. 50  specific review and approval.

51

  1. 52  The recommendations in this guidance are designed to ensure that FDA’s GRASE

  2. 53  determinations for OTC sunscreen active ingredients under the SIA are consistent, up to date,

  3. 54  and appropriately reflect current scientific knowledge and patterns of nonprescription sunscreen

  4. 55  use by consumers. The recommendations reflect FDA’s scientific expertise, existing technical

  5. 56  guidance, experience from reviewing safety and efficacy data submitted for GRASE review of

  6. 57  sunscreen active ingredients under current OTC drug regulations, and input from and

  7. 58  concurrence by outside scientific experts. This guidance also addresses FDA’s current thinking

  8. 59  about an approach to safety-related final formulation testing that it anticipates adopting in the

  9. 60  future.

61

6 See section 586C of the FD&C Act. FDA will also consider other relevant public data submitted by other parties or otherwise available.

7 See section 586C of the FD&C Act generally for detailed procedures.

8 See sections 586C(e)(1)(A) (effect of final sunscreen order for sunscreen active ingredient(s) found to be GRASE) and 586C(e)(3) (future amendments of OTC sunscreen monograph to include any nonprescription sunscreen active ingredient(s) subject to an effective final sunscreen order determining it to be GRASE, and to set forth the conditions of use) of the FD&C Act.

9 See section 586D(a)(1)(A)(ii) of the FD&C Act. The SIA also requires FDA to issue three other draft guidances on procedural matters relating to nonprescription sunscreen active ingredients: (1) format and content of data submissions (section 586D(a)(1)(A)(i)); (2) process for withdrawing requests for a GRASE determination (section 586D(a)(1)(A)(iii)); and (3) process by which FDA will carry out section 586C(c), regarding advisory committee meetings (section 586D(a)(1)(A)(iv)).

10 This process is described in 21 CFR part 314.

page5image30880

2

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 62  FDA’s specific recommendations on the data needed to support a positive GRASE determination

  2. 63  under the SIA are detailed in sections II (pharmaceutical quality/manufacturing data), III (safety

  3. 64  data), and IV (effectiveness data). Section V presents FDA’s current thinking on an approach to

  4. 65  safety testing of final sunscreen formulations that it anticipates adopting in the future.

66

  1. 67  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 68  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

  3. 69  as recommendations, unless specific regulatory or statutory requirements are cited. The use of

  4. 70  the word should in Agency guidances means that something is suggested or recommended, but

  5. 71  not required.

72
73
74
II. PHARMACEUTICAL QUALITY/MANUFACTURING DATA 75

  1. 76  FDA needs information that characterizes the identity of each sunscreen active ingredient

  2. 77  sufficiently for FDA reviewers to determine how, if at all, the safety and efficacy studies

  3. 78  submitted for review are relevant to the ingredient for which GRASE determination is sought.11

  4. 79  This information is also necessary to appropriately characterize the active ingredient in the final

  5. 80  sunscreen order. Sponsors should provide the compendial status of the ingredient, including

  6. 81  reference to a United States Pharmacopeia — National Formulary monograph. Sponsors should

  7. 82  also provide any known chemical and/or manufacturing characteristics of the active ingredient

  8. 83  that may be relevant to FDA’s GRASE evaluation and to the establishment of the conditions of

  9. 84  any resulting final order.12 Such information should include known interactions with other

  10. 85  sunscreen active ingredients or commonly used sunscreen vehicle components, and particle size

  11. 86  information for micronized or nanoscale active ingredients. In addition, sponsors should

  12. 87  describe aspects of formulation, if any, needed to enhance photostability, efficacy, or safety of

  13. 88  the active ingredient to establish its GRASE status.

89
90
91
III. SAFETY DATA NEEDED TO ESTABLISH THAT AN OTC SUNSCREEN

92 93

  1. 94  FDA’s OTC drug regulations identify the general types of safety information that sponsors

  2. 95  should submit as evidence that an OTC drug is GRASE for use as labeled (21 CFR 330.10(a)(2))

  3. 96  and the standard by which safety is to be judged (21 CFR 330.10(a)(4)(i)). When applying these

  4. 97  regulations to each potential active ingredient, FDA uses its scientific expertise to determine

    11 For example, if key studies were conducted using a related but different compound, or using a combination of active ingredients whose individual contributions to the observed results were not examined, those studies may have little relevance to a GRASE determination for the sunscreen active ingredient identified by the requested quality/manufacturing data.

    12 The determination of whether a sunscreen active ingredient is GRASE and not misbranded also requires the Agency to describe the conditions under which any future product incorporating that sunscreen active ingredient will be GRASE and not misbranded. See, for example, section 586C(e) of the FD&C Act. For further discussion see section V.

ACTIVE INGREDIENT IS GRASE

page6image29744

3

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 98  what constitutes “adequate tests by methods reasonably applicable to show the drug is safe under

  2. 99  the prescribed, recommended, or suggested conditions of use.”13

100

  1. 101  In the case of OTC sunscreen active ingredients, FDA balances the important role that broad

  2. 102  spectrum sunscreens with a sun protection factor (SPF) value of 15 or higher play in decreasing

  3. 103  the risk of skin cancer and early skin aging caused by the sun, if used as directed with other sun

  4. 104  protection measures; the benefits, with the public health importance of providing an adequate

  5. 105  safety margin14 for OTC sunscreen active ingredients and finished sunscreen products, versus the

  6. 106  risks. When determining the specific testing and other data needed to adequately demonstrate

  7. 107  that an OTC sunscreen active ingredient is safe, FDA considers both the circumstances under

  8. 108  which OTC sunscreen products are intended to be used by consumers and current scientific

  9. 109  knowledge and assessment technology.

110

  1. 111  To ensure full discussion of the kinds of data needed to address sunscreen safety, FDA held a 2-

  2. 112  day meeting of the Nonprescription Drugs Advisory Committee on September 4-5, 2014, at

  3. 113  which FDA presented much of the same approach that is recommended in this guidance. There

  4. 114  was consensus among the independent scientific experts on the committee that FDA’s

  5. 115  framework was a good starting point.15 This guidance takes into consideration the

  6. 116  recommendations FDA received from this committee.

117

  1. 118  FDA’s current approach to clinical safety evaluation of potential OTC sunscreen active

  2. 119  ingredients is based on current scientific understanding regarding safety evaluation of topical

  3. 120  products for chronic use, and thus is generally consistent with the safety data requirements that

  4. 121  would apply to an NDA for a chronic-use cutaneous drug product (i.e., topical safety studies

  5. 122  (irritation, sensitization, and photosafety), bioavailability (absorption), and evaluation of adverse

  6. 123  events observed in clinical studies).16 In addition, the evaluation of adverse events reported

  7. 124  during the commercial marketing of sunscreen products containing the ingredient and other

  8. 125  postmarketing safety information is also relevant to safety.

126

  1. 127  FDA’s current approach to the nonclinical safety evaluation of these active ingredients takes into

  2. 128  account that only active ingredients that have been marketed to a material extent and for a

  3. 129  material time in OTC sunscreen products are eligible under the SIA for a GRASE determination

  4. 130  and inclusion in the OTC sunscreen drug monograph.17 In contrast to nonclinical data

  5. 131  requirements for a chronic-use cutaneous drug product NDA, which include comprehensive

    13 21 CFR 330.10(a)(4)(i)

    14 A safety margin is an estimated exposure level in humans that is calculated based on toxic effects seen in animal studies; the safety margin is used to predict a safe exposure level in humans well below where toxicities were seen in animals.

    15 See the minutes of the FDA September 4-5, 2014, meeting of the Nonprescription Drugs Advisory Committee (2014 NDAC Minutes) at http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/NonprescriptionDrugsAdvisoryCom mittee/ucm380890.htm (accessed October 8, 2015).

    16 Chronic use is defined as continuous or intermittent use for at least 6 months during the course of a lifetime. 17 See section 586B(a)(2) of the FD&C Act.

page7image31120

4

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 132  nonclinical pharmacology and toxicology safety testing, the approach to nonclinical safety

  2. 133  testing in this guidance is largely focused on potential long-term adverse effects or effects not

  3. 134  otherwise readily detected from human use (i.e., carcinogenicity and reproductive toxicity).

  4. 135  Additional testing beyond what is recommended in this guidance may be needed for active

  5. 136  ingredients for which data suggest a concern about other long-term effects, such as hormonal

  6. 137  disruption.

138

  1. 139  The following sections describe the specific safety data that FDA needs to determine whether an

  2. 140  active ingredient is GRASE for use in sunscreens. However, FDA will consider alternative

  3. 141  scientifically based approaches for addressing a particular data need. Sponsors are encouraged to

  4. 142  discuss alternative proposals with FDA before initiating studies.

143
144
A. Clinical Safety Testing
145
146
1. Human Dermal Safety Studies 147

  1. 148  Human dermal safety studies for topical products in which exposure to light after application is

  2. 149  anticipated generally consist of two sets of studies — those conducted without specific exposure

  3. 150  to light and those conducted to assess reactions after ultraviolet exposure (photosafety studies).18

  4. 151  The studies usually consist of dermal irritation patch testing, dermal sensitization patch testing,

  5. 152  dermal phototoxicity testing, and dermal photoallergenicity testing.

153

  1. 154  Because marketed sunscreen products typically contain a combination of active ingredients, and

  2. 155  brand name product formulations frequently change, it is difficult to determine causal links

  3. 156  between individual active ingredients and reported irritation and hypersensitivity adverse events

  4. 157  associated with a particular product. Therefore, FDA generally expects to use data from human

  5. 158  irritation studies, human skin sensitization studies, and human photosafety studies, in

  6. 159  conjunction with postmarketing adverse event data, to inform GRASE determinations and

  7. 160  labeling. Nonetheless, in some cases, it may be reasonable to omit human irritation studies,

  8. 161  human skin sensitization studies, and/or human photosafety studies, depending on the rigor of

  9. 162  available postmarketing safety information. For example, if FDA concludes that there is a

  10. 163  positive risk-benefit for a sunscreen active ingredient but that it is known to be a sensitizer, it

  11. 164  may be possible to develop safety labeling to address this risk without data generated in the

  12. 165  human dermal safety studies described below. Sponsors who believe there is a scientific

  13. 166  rationale that may preclude the need for some or all of the described studies are urged to contact

  14. 167  FDA before initiating studies.

168
169 a. Human irritation and sensitization studies 170

  1. 171  Studies of skin irritation and sensitization, using the repeat insult patch test or other relevant

  2. 172  tests, are recommended elements in the safety evaluation of topical drug products that, like

  3. 173  sunscreens, are applied to the skin repeatedly over long periods of time. Designed to detect the

  4. 174  potential for local dermatologic events with fewer subjects than might be observed in larger

    18 See the ICH guidance for industry S10 Photosafety Evaluation of Pharmaceuticals. We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

page8image30808

5

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 175  clinical trials, these tests often employ product application that can be more frequent and/or for

  2. 176  longer duration than proposed clinical dosing. In dermal irritation studies, a test substance is

  3. 177  applied to a small pad (patch) and affixed to the test subject’s skin, usually on the back, to

  4. 178  determine whether the ingredient causes direct skin toxicity. Dermal sensitization studies are

  5. 179  conducted similarly, but are designed to detect immunologically mediated reactions, which

  6. 180  require prior exposure to the allergen.

181

  1. 182  Nonprescription sunscreen active ingredients, when found GRASE, may be used in numerous, as

  2. 183  yet unknown, product formulations. Therefore, FDA recommends that cumulative irritation

  3. 184  studies evaluate the proposed sunscreen active ingredient at the highest concentration for which a

  4. 185  GRASE determination is sought, in an appropriate vehicle, the vehicle alone, and with both

  5. 186  negative and positive controls. The evaluation should include scoring of erythema, edema, and a

  6. 187  papular response or skin erosion.

188

  1. 189  Skin sensitization studies, conducted to detect immunologically mediated reactions, should be

  2. 190  conducted in three phases:

191

  1. 192  (1) The induction phase (three weekly applications for 3 weeks)

  2. 193  (2) The rest phase (no product application for 10 to 14 days)

  3. 194  (3) The challenge phase (patch applications to new sites for 48 hours with a confirmatory

  4. 195  rechallenge to exclude false positives)

196

  1. 197  Although FDA recommends separate dermal irritation and sensitization studies, irritation and

  2. 198  sensitization studies can be combined in the same study as long as a sufficient number of

  3. 199  subjects are included for sensitization evaluation.

200
201 b. Human photosafety studies 202

  1. 203  Topically applied dermatologic drug products should be tested for photosafety if they absorb

  2. 204  light in the ultraviolet A (UVA), ultraviolet B (UVB), or visible spectra. FDA recommends that

  3. 205  photosafety evaluations of sunscreen active ingredients that absorb light consist of skin

  4. 206  photoallergenicity and skin phototoxicity testing. Photoallergy is an immunologically mediated

  5. 207  reaction to a chemical, initiated by the formation of photoproducts (e.g., protein adducts)

  6. 208  following a photochemical reaction. As does dermal sensitivity testing described above, these

  7. 209  tests use an induction/rest/challenge/rechallenge multiphase design to assess erythema, edema,

  8. 210  and vesiculation. Phototoxicity (photoirritation) is an acute light-induced tissue response to a

  9. 211  photoreactive chemical. Testing typically includes a test patch, a vehicle patch, and a sham

  10. 212  patch application for 24 hours, followed by ultraviolet light exposure of the test area. A second

  11. 213  set of patch application areas not irradiated with light serves as a control. FDA recommends that

  12. 214  photosafety studies of sunscreen active ingredients that absorb light be conducted using the

  13. 215  active ingredient at the highest concentration for which a GRASE determination is sought in an

  14. 216  appropriate vehicle, the vehicle alone, and a negative control.

217

6

Contains Nonbinding Recommendations

Draft — Not for Implementation

218 2. Human Absorption Studies/Maximal Usage Trial 219

  1. 220  Because nonprescription sunscreens are topically applied, a critical safety consideration is

  2. 221  whether dermal application results in skin penetration and systemic exposure to the active

  3. 222  ingredient and, if so, to what extent. This information helps identify potential safety concerns

  4. 223  and helps determine whether an adequate safety margin exists for an active sunscreen ingredient

  5. 224  to be included in the OTC sunscreen monograph.

225

  1. 226  The principal barrier to cutaneous drug product penetration is the multilayered, lipid-rich stratum

  2. 227  corneum. The passage of any drug product through this layer is influenced by many factors,

  3. 228  including the drug product’s physicochemical features, molecular weight, and

  4. 229  vehicle/formulation properties. Vehicle/formulation properties are particularly important

  5. 230  because the choice of vehicle can markedly affect the permeation potential of a drug product.

  6. 231  Effects can range from simple hydration of the stratum corneum by occlusive

  7. 232  vehicles/formulations to direct permeation enhancement by solvent effects on the lipids in the

  8. 233  stratum corneum. Products absorbed through the skin have the potential to cause systemic

  9. 234  adverse effects, affecting the safety assessment. Because sunscreens are intended to work at the

  10. 235  skin’s surface, systemic absorption may also lower efficacy, affecting the efficacy assessment.

236

  1. 237  Since the mid-1990s, topical product NDAs have included a Maximal Usage Trial (MUsT) as

  2. 238  part of the clinical pharmacology/bioavailability assessment. A MUsT is designed to capture the

  3. 239  effect of maximal use on absorption into the blood with standard pharmacokinetic assessments

  4. 240  (e.g., Cmax, Tmax, area under the curve, half-life, clearance, and volume of distribution). For an

  5. 241  NDA, the MUsT is conducted in subjects with the disease of interest and with the specific

  6. 242  product formulation for which approval is sought applied at the upper limit of surface area

  7. 243  involvement that is studied in the phase 3 clinical trials and is proposed for labeling. That is to

  8. 244  say, if the proposed labeling permits the product to be used on up to 30 percent of body surface

  9. 245  area, that would be the coverage evaluated in the MUsT.19,20

246

  1. 247  FDA recommends that sponsors of sunscreen active ingredients provide data from a MUsT to

  2. 248  support an adequate assessment of safety.21 Because a determination that an active sunscreen

  3. 249  product is GRASE would permit its use in a variety of finished sunscreen products, FDA

  4. 250  recommends that the MUsT be conducted under maximal use conditions employing a minimum

  5. 251  of four formulations containing the new sunscreen active ingredient as the only active ingredient

  6. 252  to support the GRASE determination. These formulations should be prepared using

  7. 253  vehicle/formulation systems that are appropriate for sunscreen topical products (e.g.,

  8. 254  deployability, spreadability) and that are expected to produce the highest in vivo absorption.

  9. 255  Justification for the formulations chosen, including results of in vitro testing using a human

    19 Bashaw ED, Tran DC, Shukla CG, et al., 2014, Maximal Usage Trial: An Overview of the Design of Systemic Bioavailability Trial for Topical Dermatological Products, Therapeutic Innovation & Regulatory Science, published online 27 June 2014, DOI:10.1177/2168479014539157.

    20 See the draft guidance for industry Acne Vulgaris: Developing Drugs for Treatment. When final, this guidance will represent the FDA’s current thinking on this topic.

    21 See 2014 NDAC Minutes, supra note 15 at 6 (response to Discussion Question 1) (expressing need for human maximal use studies in all cases).

page10image33088

7

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 256  cadaver skin permeation system (e.g., static or flow-through cells),22 should be included in the

  2. 257  study protocol. The protocol should contain sufficient detail for others to reproduce the

  3. 258  formulations and manufacturing process.

259

  1. 260  FDA anticipates that the use of multiple formulations will help identify the overall absorption

  2. 261  potential of the sunscreen active ingredient of interest. The MUsT should be conducted in

  3. 262  subjects with normal (nondiseased) skin at the highest concentration of the ingredient for which a

  4. 263  GRASE determination is sought and eligibility under the SIA has been established. Based on

  5. 264  recommended sunscreen use on all exposed skin, the exposed area should include nearly all of

  6. 265  the body surface area. Data from the formulation that produces the highest in vivo absorption

  7. 266  would then be used to determine the safety margin.

267

  1. 268  The assay used in the MUsT should be properly validated according to current good laboratory

  2. 269  practices (21 CFR part 58) and should be consistent with the guidance for industry Bioanalytical

  3. 270 Method Validation. The assay’s limit of quantitation-limit of detection should be sufficiently

  4. 271  low to allow a signal:noise ratio that ensures confidence in detection of a derived concentration

  5. 272  of 0.5 nanogram (ng)/milliliter (mL).

273

  1. 274  An important consideration for designing a MUsT is that it includes testing for a duration that

  2. 275  allows for the attainment of steady state levels to ensure that maximum penetration of the

  3. 276  ingredient has taken place and to optimize its chances of being detected. Thus, for sunscreen

  4. 277  ingredients, FDA expects that single application studies would be inadequate. Because the

  5. 278  subjects in a MUsT represent an enriched dataset in the upper range of exposures, FDA currently

  6. 279  recommends collection of safety-related data (such as vital signs, adverse skin events) from the

  7. 280  study’s regularly scheduled physical examinations. Sponsors are strongly encouraged to discuss

  8. 281  their MUsT protocol with FDA before beginning the trial. As discussed further in section V, if

  9. 282  the sunscreen active ingredient is determined to be GRASE, FDA believes that it would be

  10. 283  appropriate to designate the formulation that produces the highest in vivo absorption in the

  11. 284  MUsT as a standard control formulation for future in vitro human cadaver skin permeation

  12. 285  system testing (e.g., static or flow-through cells) of each final sunscreen formulation that

  13. 286  includes that active ingredient.

287

  1. 288  If in vitro permeation of the sunscreen active ingredient in the final product formulation is equal

  2. 289  to or less than the value from in vitro testing of the standard control formulation (that was shown

  3. 290  by the MUsT to have the highest degree of systemic absorption), FDA anticipates that the safety

  4. 291  margin calculated would be considered adequate to support the finished formulation.

292
293
3. Pediatric Considerations 294

  1. 295  Young children have a larger ratio of skin surface to body volume compared to adults, which can

  2. 296  increase a child’s systemic exposure to topically applied drug products. In addition, growing

  3. 297  children have greater potential to experience deleterious developmental effects from drug

  4. 298  exposure. If the calculated safety margin for a proposed monograph active ingredient (based on

  5. 299  nonclinical results and human MUsT) supports a GRASE determination but the safety margin is

    22 Bronaugh R and Stewart F, 1985, Methods for In Vitro Percutaneous Absorption Studies IV: The Flow-Through Diffusion Cell, J. Pharm. Sci, 74(1), 64-67.

page11image33528

8

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 300  relatively small, FDA will exercise its scientific judgment to determine if a sunscreen active

  2. 301  ingredient MUsT in young children or other studies are warranted to ensure that the safety

  3. 302  margin for marketed products containing the ingredient is within an acceptable range for this

  4. 303  population.

304
305
B. 306
307
1. 308

  1. 309  FDA generally recommends carcinogenicity studies for any pharmaceutical with an expected

  2. 310  continuous clinical use of at least 6 months or when used for a minimum of 6 months in an

  3. 311  intermittent manner.23 The animal carcinogenicity studies help characterize the potential tumor

  4. 312  risks associated with a sunscreen active ingredient by identifying any observed tumors by type,

  5. 313  the level of exposure at which tumors occur, and the highest level of exposure at which no

  6. 314  adverse effects occur, referred to as the no observed adverse effect level (NOAEL). The NOAEL

  7. 315  would be used in determining the safety margin for human exposure to sunscreens containing the

  8. 316  active ingredient. In addition to detecting carcinogenic potential, carcinogenicity studies in

  9. 317  animals can also help to identify other systemic or organ toxicities that may be associated with

  10. 318  the proposed ingredient.

319

  1. 320  A dermal carcinogenicity study that involves applying the product to the skin of mice or rats for

  2. 321  2 years is thus recommended to support OTC sunscreen active ingredients. FDA also considers

  3. 322  it important to study the effects of systemic exposure if human bioavailability data show that

  4. 323  dermal application of a particular formulation could potentially result in skin penetration and

  5. 324  systemic exposure. After the active ingredient is marketed in nonprescription sunscreens, that

  6. 325  active ingredient is likely to be used in a wide variety of product formulations that might alter its

  7. 326  skin penetration. Therefore, a second carcinogenicity study by a route that produces systemic

  8. 327  exposure is also generally recommended. This can be a 2-year study or a shorter (usually 6

  9. 328  months) alternative carcinogenicity model and should be conducted in a species different from

  10. 329  that used in the dermal carcinogenicity study. All carcinogenicity studies regardless of route

  11. 330  should assess a full panel of tissues.24

331
332
2. Developmental and Reproductive Toxicity Studies 333

  1. 334  Developmental and reproductive toxicity (DART) studies are recommended to evaluate the

  2. 335  potential effects that exposure to the sunscreen active ingredient may have on developing

  3. 336  offspring throughout gestation and postnatally until sexual maturation, as well as on the

    23 See the ICH guidance for industry S1A The Need for Long-Term Rodent Carcinogenicity Studies of Pharmaceuticals.

    24 FDA expects that a systemic carcinogenicity study would not be needed to support a GRASE determination for a sunscreen active ingredient if an adequately conducted human pharmacokinetic MUsT results in a steady state blood level less than 0.5 ng/mL and an adequately conducted toxicology program does not reveal any other safety signals for the ingredient or any known structurally similar compound indicating the potential for adverse effects at lower levels. The threshold value of 0.5 ng/mL is based on the principle that the level would approximate the highest plasma level below which the carcinogenic risk of any unknown compound would be less than 1 in 100,000 after a single dose.

Nonclinical Safety Testing

Carcinogenicity Studies: Dermal and Systemic

page12image32240

9

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 337  reproductive competence of sexually mature male and female animals.25 Gestational and

  2. 338  neonatal stages of development may be particularly sensitive to active ingredients with hormonal

  3. 339  activity (endocrine disruption). For this reason, FDA recommends that these studies include

  4. 340  assessments of endpoints such as vaginal patency, preputial separation, anogenital distance, and

  5. 341  nipple retention, which can be incorporated into traditional DART study designs to assess

  6. 342  potential hormonal effects on the developing offspring. FDA also recommends performing

  7. 343  behavioral assessments (e.g., mating behavior) of offspring, which may detect neuroendocrine

  8. 344  effects.26

345
346
3. Toxicokinetics27 347

  1. 348  FDA recommends collecting animal toxicokinetic data for sunscreen active ingredients because

  2. 349  these data provide an important bridge between toxic levels seen in animal studies and any

  3. 350  potential human adverse events associated with systemic exposure to the sunscreen’s active

  4. 351  ingredient (see section III.A.2). Toxicokinetic measurements usually are obtained during the

  5. 352  course of ongoing nonclinical toxicity studies, such as carcinogenicity or DART studies, rather

  6. 353  than through separate studies.

354
355
C. Postmarketing Safety Data 356

  1. 357  In addition to the active ingredient safety data already described, FDA’s GRASE evaluation also

  2. 358  takes into consideration available information about serious adverse drug experiences and known

  3. 359  or expected adverse effects associated with commercially marketed products that contain the

  4. 360  active ingredient(s) under consideration. FDA specifically requests the following information:

361
362
363
364
365
366
367
368
369
370
371
372

25 See the ICH guidance for industry S5A Detection of Toxicity to Reproduction for Medicinal Products. FDA expects that studies to assess fertility and pre- or postnatal toxicity may not be needed if an adequately conducted human MUsT shows absorption that results in a steady state blood level less than 0.5 ng/mL, and there are no signals in an adequately conducted toxicology program indicating the ingredient or any known structurally similar compound interacts with related pathways, such as endocrine function or signaling pathways related to growth and development.

26 See the guidance for industry Nonclinical Evaluation of Endocrine-Related Drug Toxicity.
27 See the ICH guidance for industry S3A Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies.

A summary of all potentially associated serious adverse drug experiences.
A summary of all available potentially associated nonserious adverse drug experiences.

A summary of expected or frequently reported side effects, whether serious or nonserious.

Copies of all available reports of potentially associated serious adverse drug experiences, in the form of individual case safety reports as described in 21 CFR 314.80. Each report submitted should refer only to an individual consumer or a single attached publication.

page13image27784

10

373 374
375
376

Contains Nonbinding Recommendations

Draft — Not for Implementation

Any available safety information from studies of safety and effectiveness in humans.

Relevant medical literature describing associated adverse events.

377 English translations should be provided for all foreign language materials. 378

  1. 379  For products marketed outside the United States, submissions should also state whether each

  2. 380  country’s system allows for adverse event reporting and, if so, how each country’s system

  3. 381  identifies and collects the adverse events.28 If adverse event information is not available from all

  4. 382  countries where the active ingredient has been marketed in OTC sunscreen products, the sponsor

  5. 383  should provide an explanation for the missing data. It is important to note, however, that even

  6. 384  when countries have an adverse event reporting system that includes sunscreen products,

  7. 385  underreporting is a significant limitation of any system that depends on spontaneous reports.

386

  1. 387  Many factors can influence whether an adverse event is reported, including whether a possible

  2. 388  relationship between the event and an ingredient or product is recognized by consumers or health

  3. 389  care providers. For example, adverse events that occur many years after a causal drug exposure

  4. 390  may not be recognized as such, especially if the background rate of the event is high (e.g., a

  5. 391  common cancer or developmental problem). Thus, absence of reports does not necessarily

  6. 392  equate to absence of adverse events. Despite the limitations of adverse event reporting, FDA

  7. 393  considers postmarketing data to be relevant both to the overall GRASE assessment of OTC

  8. 394  sunscreen active ingredients and to labeling considerations because these data may reveal safety

  9. 395  signals not otherwise observed in clinical or nonclinical testing.

396
397
398
IV . EFFECTIVENESS TESTING 399

  1. 400  FDA’s OTC drug regulations generally identify the types of effectiveness information that

  2. 401  sponsors should submit as evidence that a drug product containing an active ingredient or other

  3. 402  OTC drug condition could be GRASE for use as labeled (21 CFR 330.10(a)(2)) and the standard

  4. 403  by which effectiveness is to be judged, which requires controlled clinical investigations to

  5. 404  support effectiveness (21 CFR 330.10(a)(4)(ii)).

405

  1. 406  When applying these regulations to each potential sunscreen active ingredient, FDA requests

  2. 407  evidence from at least two adequate and well-controlled SPF studies showing that the active

  3. 408  ingredient effectively prevents sunburn, because sunburn prevention is the minimum indication

  4. 409  for an OTC sunscreen product. Two adequate and well-controlled SPF studies of the active

  5. 410  ingredient at a lower concentration than the maximum requested should be conducted according

  6. 411  to established standards.29 These SPF studies should demonstrate that the selected concentration

  7. 412  provides an SPF value of 2 or higher.

413

28 See, for example, 21 CFR 330.14(c)(2)(v).

29 FDA expects that the upper bound of any concentration of the active ingredient ultimately established would be governed by the safety data, as well as by efficacy.

page14image29744

11

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 414  The current standard procedure for SPF testing is described in 21 CFR 201.327(i).30 Any new

  2. 415  SPF tests for a particular ingredient should be performed as described in these regulations, using

  3. 416  a test formulation containing the ingredient as the only active ingredient to identify its

  4. 417  contribution to the overall SPF test results. The study should also include a vehicle control arm

  5. 418  to rule out any contribution the vehicle may have on the SPF test results. Finally, as described in

  6. 419  21 CFR 201.327(i), an SPF standard formulation comparator arm should be another component

  7. 420  of the study design.

421

  1. 422  Current sunscreen testing and labeling regulations in 21 CFR 201.327(j) also specify a broad

  2. 423  spectrum testing procedure, which provides an in vitro measurement of a sunscreen product’s

  3. 424  ability to protect against both UVA and UVB radiation. Although this test can be used to

  4. 425  support related labeling claims for sunscreen products marketed under the stayed final

  5. 426  monograph, those additional claims are permitted, but not required.31 Broad spectrum protection

  6. 427  is often the result of the combined contribution of multiple active ingredients in a final sunscreen

  7. 428  formulation. Thus, FDA does not expect that a sunscreen active ingredient would undergo broad

  8. 429  spectrum effectiveness testing to establish its effectiveness for a GRASE determination for use in

  9. 430  OTC sunscreen products.

431

  1. 432  Under 21 CFR 201.327, the determination of whether an individual sunscreen product subject to

  2. 433  that rule may be labeled as broad spectrum and bear the related additional claims is made on a

  3. 434  product-specific basis, applying the standard testing methods set forth in those regulations.

  4. 435  These test procedures are also described in the guidance for industry Labeling and Effectiveness

  5. 436 Testing: Sunscreen Drug Products for Over-The-Counter Human Use — Small Entity

  6. 437 Compliance Guide. If a sunscreen active ingredient evaluated under the SIA is established to be

  7. 438  GRASE for use in nonprescription sunscreens, the final sunscreen order can likewise address

  8. 439  broad spectrum testing and related labeling conditions for final sunscreen formulations

  9. 440  containing that ingredient.

441
442
443
V. ANTICIPATED FINAL FORMULATION TESTING 444

  1. 445  Preceding sections of this guidance concentrate on recommendations for safety and effectiveness

  2. 446  data needed to support FDA’s determination that a sunscreen active ingredient is GRASE for use

  3. 447  in sunscreens. FDA’s determination that an active ingredient is GRASE will be made in the

  4. 448  form of a final sunscreen order that will set out the conditions under which any future product

  5. 449  incorporating that sunscreen active ingredient will be GRASE and not misbranded (see section

    30 Although the SPF testing procedure is used primarily for final formulation testing of finished products marketed without approved NDAs, it is equally applicable for determining whether or not a sunscreen active ingredient is generally recognized as effective as part of the overall GRASE determination.

    31 FDA strongly encourages manufacturers to develop OTC sunscreen products that provide broad spectrum protection and have an SPF value of 15 or higher because of the deleterious health effects that may result if consumers increase their overall sun exposure through use of sunscreen products that help prevent sunburn, but do not provide sufficient protection to help reduce the risk of skin cancer and early skin aging caused by the sun. FDA requires these sunburn only products to bear a prominent warning stating: “Skin Cancer/Skin Aging Alert: Spending time in the sun increases your risk of skin cancer and early skin aging. This product has been shown only to help prevent sunburn, not skin cancer or early skin aging” (21 CFR 201.327(d)(2)).

page15image34032

12

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 450  I).32 As noted in section III.A.2, variations among individual sunscreen products — and in

  2. 451  particular, aspects of the lotion or other vehicle in which active ingredients are delivered — can

  3. 452  affect absorption and thus safety and effectiveness.

453

  1. 454  To address this variability among sunscreen formulations containing the same active

  2. 455  ingredient(s), FDA requires final formulation testing of nonprescription sunscreen products to

  3. 456  ensure their effectiveness — namely testing for SPF value as well as broad spectrum protection

  4. 457  and water resistance, where those attributes are claimed in product labels.33 Likewise, FDA

  5. 458  anticipates that final sunscreen orders issued for sunscreen active ingredients determined to be

  6. 459  GRASE under the SIA would include conditions requiring final formulation testing to ensure the

  7. 460 safety of all sunscreen formulations permitted by the order.

461

  1. 462  The discussion that follows provides FDA’s current thinking about such final formulation safety

  2. 463  testing, to be conducted in the future. The public is encouraged to comment on this general

  3. 464  approach when commenting on this draft guidance. Note that FDA has not yet determined

  4. 465  whether final formulation testing as described in this draft guidance will be a necessary condition

  5. 466  for determining whether each of the individual sunscreen active ingredients is GRASE for use

  6. 467  alone or in combination in a sunscreen product. Making that determination for a specific

  7. 468  ingredient requires consideration of the data recommended to be supplied under other parts of

  8. 469  this guidance to support a GRASE determination (e.g., whether any safety signals are detected in

  9. 470  well-conducted nonclinical carcinogenicity and DART studies). Interested parties also can

  10. 471  provide relevant information and comment for an individual sunscreen active ingredient as part

  11. 472  of the process for GRASE determination for that ingredient. FDA is particularly interested in

  12. 473  comments that include a scientifically persuasive rationale as to why it is not necessary to

  13. 474  conduct the anticipated final formulation safety testing for a particular sunscreen active

  14. 475  ingredient, or that provide an alternative, scientifically supported approach to ensure that

  15. 476  formulated sunscreen products containing that ingredient will have an acceptable safety margin.

477

  1. 478  Specifically, FDA’s current thinking is that final formulation safety testing of nonprescription

  2. 479  sunscreens would not generally call for in vivo study. Instead, FDA expects that the conditions

  3. 480  of marketing for sunscreen active ingredients would require manufacturers to perform in vitro

  4. 481  permeation testing before marketing each new formulation as described in the following

  5. 482  paragraphs.34 Consistent with the approach for final formulation efficacy testing required by

  6. 483  21 CFR 201.327, FDA would not review the results of the in vitro final formulation safety

  7. 484  testing before product marketing. Rather, FDA expects that the conditions of marketing for

  8. 485  sunscreen active ingredients described in final sunscreen orders would require manufacturers to

  9. 486  maintain records of this testing. These records would be available to FDA.

487

32 See section 586D(e) of the FD&C Act.

33 See 21 CFR 201.327 for the current requirements for OTC sunscreens containing the active ingredients already evaluated under the monograph system. OTC sunscreens marketed under NDAs provide similar information in their product-specific applications to substantiate their labeling.

34 FDA recommends this approach as an alternative to final in vivo (MUsT) testing of final product formulations, which was recommended by the Nonprescription Drugs Advisory Committee. See 2014 NDAC Minutes, supra note 15 at 7 (Discussion Question 2).

page16image33240

13

 

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 488  First, as mentioned in section III.A.2, FDA anticipates establishing a standard control

  2. 489  formulation for each sunscreen active ingredient, to be used in this final formulation testing of

  3. 490  products containing that ingredient. The standard control formulation would be the formulation

  4. 491  that produces the highest in vivo absorption in the MUsT. The results of in vitro human cadaver

  5. 492  skin testing using this control formulation can then be used to bridge to a corresponding level of

  6. 493  in vivo absorption from the MUsT used to establish the safety margin for the GRASE ingredient.

494

  1. 495  Then, FDA anticipates that final formulation testing would be conducted for each formulation

  2. 496  intended to be marketed, by testing both the new formulation and the standard control

  3. 497  formulation, using the same type of human cadaver skin diffusion cell: Franz (static) or

  4. 498  Bronaugh (flow-through). The results of the in vitro permeation testing of the new formulation

  5. 499  would then be compared to the values determined for the standard control formulation for the

  6. 500  active ingredient it contains. If a final sunscreen formulation contains multiple sunscreen active

  7. 501  ingredients, FDA anticipates that the final formulation would be tested against the standard

  8. 502  control formulations for each of the sunscreen active ingredients it contains.

503

  1. 504  If in vitro permeation of each sunscreen active ingredient in the final formulated product is equal

  2. 505  to or less than the value obtained from in vitro testing of the standard control formulation for that

  3. 506  active ingredient, FDA anticipates that the product’s safety margin would be considered to fall

  4. 507  within the parameters judged to be GRASE and thus to support marketing of the new

  5. 508  formulation. However, if the in vitro permeation of the active ingredient from the specific final

  6. 509  formulation is greater than the value obtained from in vitro permeation testing of the standard

  7. 510  control formulation for that active ingredient, the formulation would not be considered GRASE.

511

  1. 512  If the results of the testing show that in vitro permeation of the sunscreen active ingredient in the

  2. 513  final formulated product is greater than the value obtained from testing of the standard control

  3. 514  formulation for that active ingredient, manufacturers would have the following options:

515
516
517
518
519
520
521
522
523
524
525
526

Reformulate the product and repeat the in vitro testing

In particular cases where the difference in permeation is small, consult with FDA as to whether the new formulation’s safety margin may be considered acceptable

Conduct a MUsT evaluation of the final formulation itself using the recommendations described in section III.A.2 to establish an acceptable safety margin for the final formulation

Seek NDA approval for the new formulation

14

 

Sunscreen Innovation Act: Section 586C(c) Advisory Committee Process Guidance for Industry DRAFT GUIDANCE

Sunscreen Innovation Act: Section 586C(c) Advisory Committee Process

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

page1image8624 page1image8784

Sunscreen Innovation Act: Section 586C(c) Advisory Committee Process

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 20993-0002
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

page2image7088

I. II.

A. B. C.

III.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 BACKGROUND ............................................................................................................... 2 Advisory Committees and the Nonprescription Drugs Advisory Committee...........................2 Regulation of OTC Sunscreen Products.......................................................................................4 Related Draft Guidance .................................................................................................................5 SECTION 586C(c) OF THE FD&C ACT ...................................................................... 6

IV. PREPARATION AND PUBLIC AVAILABILITY OF INFORMATION GIVEN
TO ADVISORY COMMITTEE MEMBERS ............................................................................ 8

Contains Nonbinding Recommendations

Draft — Not for Implementation

1
2
Sunscreen Innovation Act:
3 Section 586C(c) Advisory Committee Process

41 56 Guidance for Industry

7 8 9

10 11 12 13

14
15
16
I. INTRODUCTION 17

  1. 18  This draft guidance addresses the process by which the Food and Drug Administration (FDA or

  2. 19  Agency) intends to carry out section 586C(c) of the Federal Food, Drug, and Cosmetic Act

  3. 20  (FD&C Act) (21 U.S.C. 360fff-3(c)), as amended by Public Law 113-195 (also referred to as the

  4. 21  Sunscreen Innovation Act (SIA)).2 Under the SIA, the Agency may convene the Advisory

  5. 22  Committee (also referred to in this draft guidance as the Nonprescription Drugs Advisory

  6. 23  Committee or NDAC)3 to provide recommendations on requests submitted to FDA for a

  7. 24  determination of whether a sunscreen active ingredient or combination of sunscreen active

  8. 25  ingredients, for use under specified conditions, is generally recognized as safe and effective

  9. 26  (GRASE) and should be added to the over-the-counter (OTC) sunscreen drug monograph

  10. 27  system. However, section 586C(c) of the FD&C Act provides specific circumstances under

  11. 28  which FDA is not required to convene or submit requests to the NDAC. The SIA also added

  12. 29  section 586D(a)(1) to the FD&C Act (21 U.S.C. 360fff-4(a)(1)), which directs FDA to issue a

  13. 30  draft guidance and a final guidance on the process by which FDA will carry out section 586C(c)

  14. 31  of the FD&C Act, including with respect to how FDA will address the total number of requests

  15. 32  received under section 586A and pending requests, as defined by the SIA.

33

  1. 34  The recommendations in this draft guidance apply to section 586A requests and to pending

  2. 35  requests. A 586A request seeks a determination from FDA on whether a nonprescription

    1 This draft guidance has been prepared by the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.

    2 21 USC Ch. 9 Sub. 5 Part 1, enacted November 26, 2014.

    3 The SIA defines “Advisory Committee” to mean the Nonprescription Drugs Advisory Committee of the Food and Drug Administration or any successor to such Committee (section 586(1) of the FD&C Act (21 U.S.C. 360fff(1))).

page4image24288

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.

page4image37344
page4image38920

1

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 36  sunscreen active ingredient,4 or a combination of nonprescription sunscreen active ingredients, is

  2. 37  GRASE for use under specified conditions and should be included in the OTC sunscreen drug

  3. 38  monograph (section 586A of the FD&C Act). FD&C Act § 586(6), as amended by the SIA,

  4. 39  defines a “pending request” to mean a request for a nonprescription sunscreen active ingredient

  5. 40  submitted under section 330.14 for consideration for inclusion in the OTC monograph that was

  6. 41  determined to be eligible for review and for which safety and effectiveness data were submitted

  7. 42  prior to the enactment of the SIA. FD&C Act § 586(6) (21 USC § 360fff(6)).5

43

  1. 44  We have published a number of Federal Register notices about rulemaking actions for OTC

  2. 45  sunscreen monograph products and about actions taken under the SIA. Information on these

  3. 46  notices can be found on our “Status of OTC Rulemakings” 6 and “Sunscreen”7 Web sites.

47

  1. 48  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 49  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

  3. 50  as recommendations, unless specific regulatory or statutory requirements are cited. The use of

  4. 51  the word should in Agency guidances means that something is suggested or recommended, but

  5. 52  not required.

53
54
55
II. BACKGROUND
56
57
A. Advisory Committees and the Nonprescription Drugs Advisory Committee 58

  1. 59  FDA has established advisory committees “to secure independent professional expertise in

  2. 60  accomplishing its mission and maintaining the public trust.”8 FDA's advisory committees

  3. 61  provide independent expert advice to the Agency on a range of complex scientific, technical, and

  4. 62  policy issues. An advisory committee meeting also provides a forum for a public hearing on

  5. 63  important matters. Although advisory committees provide important advice and

    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” 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 These pending requests were submitted as time and extent applications (TEAs) under section 21 CFR 330.14 of FDA’s regulations. 21 CFR 330.14

    6 The “Status of OTC Rulemakings” Web site is available at

    http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the- CounterOTCDrugs/StatusofOTCRulemakings/default.htm.

    7 The “Sunscreen” Web site is available at

    http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingOver-the- CounterMedicines/ucm239463.htm.

    8 See guidance for industry, Advisory Committees: Implementing Section 120 of the Food and Drug Administration Modernization Act of 1997 (Advisory Committee Guidance), at 1, available at http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm079765.pdf.

page5image26680 page5image26840 page5image27000 page5image27160 page5image27320 page5image27480

2

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 64  recommendations to FDA, the Agency has sole discretion concerning action to be taken and

  2. 65  policy to be expressed on any matter considered by an advisory committee.9

66

  1. 67  The NDAC was established under the Federal Advisory Committee Act

  2. 68  statutory and regulatory provisions), which sets forth requirements for the formation and

  3. 69  utilization of advisory committees. 21 CFR part 14 describes the procedures and rules that

  4. 70  govern the Agency’s use of advisory committees (such as the NDAC).

71

  1. 72  The NDAC reviews and evaluates available data concerning the safety and effectiveness of OTC

  2. 73  drug products for use in the treatment of a broad spectrum of human symptoms and diseases and

  3. 74  advises the Agency on the requirements for monographs establishing conditions under which

  4. 75  these drugs are GRASE and not misbranded.11 The NDAC consists of approximately 10 voting

  5. 76  members selected from among specialists knowledgeable in the fields of internal medicine,

  6. 77  family practice, pediatrics, clinical toxicology, clinical pharmacology, pharmacy, and related

  7. 78  specialties.12 The Agency may call upon individuals to supplement the core membership on an

  8. 79  ad hoc basis so that the group considering an issue presented to an advisory committee may also

  9. 80  include members who are specialists with expertise in the particular disease or condition for

  10. 81  which the drug product under consideration is proposed to be indicated.13 For example, NDAC

  11. 82  committees considering matters related to sunscreens may be supplemented with dermatologists.

83

  1. 84  FDA recognizes that advisory committee meetings impose significant resource commitments on

  2. 85  advisory committee members, sponsors, and other public participants, as well as on the Agency

  3. 86  itself, and therefore FDA seeks to limit use of such meetings to important matters. In general,

  4. 87  FDA has discretion to decide whether to present a matter to an advisory committeehere, to the

  5. 88  NDACfor consideration. In making this decision, FDA generally considers several factors,

  6. 89  including the following:

90
91
92
93
94
95
96
97
98

9 Id.
10 Public Law 92-463 (5 U.S.C. Appendix).

11 See the NDAC Charter, available at

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/NonprescriptionDrugsAdvisoryCom mittee/ucm105992.htm.

12 Id.
13 Advisory Committee Guidance, supra note 8, at 2.

(a) (b)

Is the matter at issue of such significant public health importance that it would be highly beneficial to obtain the advice of an advisory committee as part of the Agency’s regulatory decision-making process?

Is the matter at issue so controversial that it would be highly beneficial to obtain the advice of an advisory committee as part of the Agency’s regulatory decision-making process?

10

(in addition to other

page6image28656 page6image28816 page6image28976

3

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 99  (c) Is there a special type of expertise that an advisory committee could provide that is

  2. 100  needed for the Agency to fully consider a matter?

101

  1. 102  If one or more of these factors are met, FDA generally refers the matter at issue to an advisory

  2. 103  committee. Conversely, FDA generally refrains from referring a matter to an advisory

  3. 104  committee if none of the factors are met. By prioritizing matters according to these factors, FDA

  4. 105  helps ensure that the finite resources of the advisory committee program are devoted to

  5. 106  consideration of the most important matters, including those matters in which the Agency would

  6. 107  most benefit from the advice of outside experts.

108

  1. 109  Specifically for the NDAC, if FDA determines that it would be useful to convene a meeting to

  2. 110  discuss sunscreen active ingredients being considered through the SIA process, the Agency

  3. 111  would generally make the following preparations, including, but not limited to: (1) identifying

  4. 112  additional members, if necessary, for each NDAC meeting who are specialists on the issue(s) to

  5. 113  be considered, as well as determining their availability; (2) preparing FDA briefing information

  6. 114  and presentations; (3) publishing notice of the NDAC meeting in the Federal Register; and (4)

  7. 115  organizing the logistics of setting up and holding the NDAC meeting. Based on the Agency’s

  8. 116  experience with past NDAC meetings, it may take 4 to 6 months to prepare for an NDAC

  9. 117  meeting.

118
119
B. RegulationofOTCSunscreenProducts
120
121 All sunscreen products are regulated as drugs in the United States under one of two processes: 122
123

124
125

126
127

  1. 128  Products regulated under the new drug approval process may not be marketed without FDA’s

  2. 129  prior review and approval of a new drug application (NDA) or abbreviated new drug application

  3. 130  (ANDA) for each product.14 Products marketed under the OTC drug monograph process are not

  4. 131  individually reviewed and approved prior to marketing. Instead, OTC drug monographs

  5. 132  categorize drugs by therapeutic categories, such as sunscreens. For each category, a monograph

  6. 133  establishes conditions under which any drug that satisfies those conditions and FDA’s general

  7. 134  regulations for OTC drugs is considered to be GRASE and not misbranded when used under the

  8. 135  conditions prescribed, recommended, or suggested in the drug’s labeling.15

136

  1. 137  Only active ingredients that were used in U.S.-marketed sunscreens before the OTC Drug

  2. 138  Review began were eligible to be included in the OTC sunscreen monograph. An active

  3. 139  ingredient or other condition that is ineligible for inclusion in the OTC monograph system is

  4. 140  subject to the new drug approval process.

    14 See sections 505(a) and 301(d) of the FD&C Act. 15 21 CFR 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

page7image30568

4

Contains Nonbinding Recommendations

Draft — Not for Implementation

141

  1. 142  In 2002, before the SIA was enacted, FDA published the “time and extent application” (TEA)

  2. 143  regulation in 21 CFR 330.14. The TEA regulation (§ 330.14(c)) has provided a process through

  3. 144  which any person may request that FDA amend an existing OTC drug monograph to include an

  4. 145  active ingredient or other OTC drug condition, including one not previously marketed in the

  5. 146  United States before the OTC Drug Review began.

147

  1. 148  For OTC sunscreens, the SIA process supplements FDA’s TEA regulation (§ 330.14). The SIA

  2. 149  amended the FD&C Act in part by providing new procedures for establishing that

  3. 150  nonprescription sunscreen active ingredients or combinations of nonprescription sunscreen active

  4. 151  ingredients are GRASE and not misbranded when used under the conditions specified in a final

  5. 152  sunscreen order (GRASE determination).16 Active ingredients that are determined to be GRASE

  6. 153  under specified conditions of use in a final sunscreen order may be used in U.S.-marketed

  7. 154  sunscreens without first obtaining an approved NDA or ANDA. Because the monograph and

  8. 155  SIA processes are public, anyone, not just the sponsor who originated the request, may submit

  9. 156  data during public comment periods.

157

  1. 158  As with the TEA process, the SIA process calls for an initial eligibility determination, followed

  2. 159  by submissions of safety and efficacy data, and a GRASE determination phase. However, the

  3. 160  SIA process also requires FDA to make a filing determination17 and to make proposed and final

  4. 161  GRASE determinations in the form of orders rather than the rulemaking required by the TEA

  5. 162  regulation. The SIA process also establishes strict timelines for the necessary administrative

  6. 163  actions. At certain stages in the SIA process, FDA has the discretion to convene the NDAC for

  7. 164  the purpose of reviewing and providing recommendations on a 586A request or on a pending

  8. 165  request.

166
167
C. Related Draft Guidance 168

  1. 169  In addition to this draft guidance, the SIA directs FDA to issue three additional draft guidance

  2. 170  documents on other topics.18 These topics include:

171
172
173
174
175
176
177
178

16 Section 586C of the FD&C Act (21 U.S.C. 360fff-3).

17 The filing determination requires FDA to determine whether the safety and efficacy data submitted to support a GRASE determination are appropriately formatted and sufficiently complete to support a substantive GRASE review (section 586B(b)(2) of the FD&C Act (21 U.S.C. 360fff-2(b)(2))).

18 Section 586D(a)(1)(A) of the FD&C Act (21 U.S.C. 360fff-4(a)(1)(A)). 5

The format and content of information submitted by a sponsor in support of a 586A request or a pending request;

The data required to meet the safety and efficacy standard for determining whether a nonprescription sunscreen active ingredient or combination of nonprescription sunscreen active ingredients is GRASE and not misbranded; and

page8image29424

Contains Nonbinding Recommendations

Draft — Not for Implementation

179 The process for withdrawing a 586A request or a pending request. 180

  1. 181  As they become available, FDA will make these draft guidances available on the FDA Drugs

  2. 182  guidance Web page.19

183
184
185
III. SECTION 586C(c) OF THE FD&C ACT 186

  1. 187  Section 586D(a)(1)(A)(iv) of the FD&C Act (21 U.S.C. 360fff-4(a)(1)(A)(iv)) requires FDA to

  2. 188  issue guidance on the process it will use to carry out section 586C(c) of the FD&C Act, including

  3. 189  with respect to how FDA will address the total number of requests received under section 586A

  4. 190  and pending requests.20 Section 586C(c) of the FD&C Act states that:

191
192
193
194
195
196
197
198
199
200

  1. 201  Below, we describe how we intend to carry out section 586C(c), including how we intend to

  2. 202  handle the total number of 586A requests and pending requests.

203

  1. 204  As an initial matter, a sponsor can request that FDA convene the NDAC to consider certain

  2. 205  issues related to the sponsor’s 586A request or pending request. (An NDAC meeting is not

  3. 206  meant to take the place of the public feedback meetings with CDER provided for elsewhere in

  4. 207  the SIA.22) Sponsors of 586A requests and pending requests that are interested in seeking an

  5. 208  NDAC meeting should submit their request for such meeting as early as possible in the process

  6. 209  to provide adequate time for the parties to prepare for the NDAC meeting.

210

  1. 211  The request for an NDAC meeting should be sent as a letter (either by hard copy or

  2. 212  electronically) to the Division of Nonprescription Drug Products (DNDP). If there is an

  3. 213  applicable docket, 23 a duplicate letter should be sent (either by hard copy or electronically) to the

  4. 214  Division of Dockets Management as well. Both addresses are as follows:

    19 When available, FDA will post each draft guidance available on the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
    When final, the guidance will represent the FDA’s current thinking on this topic.

    20 Section 586D of the FD&C Act (21 U.S.C. 360fff-4).
    21 Section 586C(c) of the FD&C Act.
    22 See, e.g., section 586B(b)(3)(A), 586C(a)(4), and 586C(b)(7) of the FD&C Act (21 U.S.C. 360fff-2, 360fff-3). 23 If no docket has been opened for the matter, the request should be sent only to the DNDP.

FDA is not required to convene the NDAC “more than once with respect to any request under section 586A or any pending request.”

FDA is not required to convene the NDAC “more than twice in any calendar year with respect to the review under this section.”

FDA is not required to “submit more than a total of 3 requests under section 586A or pending requests to the Advisory Committee per meeting.”21

page9image28888 page9image29048

6

Contains Nonbinding Recommendations

Draft — Not for Implementation

215

  1. 216  Food and Drug Administration

  2. 217  Division of Nonprescription Drug Products

  3. 218  Bldg. 22, Mail Stop 5411

  4. 219  10903 New Hampshire Avenue

  5. 220  Silver Spring, MD 20993

221

  1. 222  Food and Drug Administration

  2. 223  Division of Dockets Management (HFA-305)

  3. 224  5630 Fishers Lane, Rm. 1061

  4. 225  Rockville, MD 20852

  5. 226  Electronic letters should be submitted at http://www.regulations.gov in the applicable

  6. 227  docket.

228

  1. 229  We recommend the sponsor submit the following information as part of a request for an NDAC

  2. 230  meeting:

231
232 1. 233
234
235 2. 236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256 3. 257
258

page10image12632

The subject line should be prominently labeled: “SIA (586A Request/Pending Request) - Request that FDA Convene the Nonprescription Drugs Advisory Committee.”

The body of the letter should contain the following:

-

-

- - -

-

A statement that the sponsor requests FDA to convene the NDAC for review and recommendations regarding a 586A request or a pending request for a sunscreen active ingredient or combination of sunscreen active ingredients under specified conditions of use.

Information about the specific sunscreen active ingredient or combination of sunscreen active ingredients and specified conditions of use to be the subject of the requested NDAC meeting.

The name of the specific sponsor that will present information to the NDAC.
A statement of the specific matter proposed for discussion at the NDAC meeting.

A statement explaining why the specific matter warrants NDAC discussion and why it should be considered at the particular time of the request.

As applicable, the statement should refer to the factors discussed above in Section II.A in support of the request for an NDAC meeting.

The name, title, address, telephone number, and e-mail address of the sponsor’s contact person should be included.

7

 

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 259  Upon receipt of the NDAC request,24 DNDP intends to review the letter. FDA intends to

  2. 260  consider an NDAC request to have been made when the Agency acknowledges receipt of the

  3. 261  request letter. DNDP intends to provide an acknowledgment letter to the sponsor within 30 days

  4. 262  of receipt. Acknowledgment of the receipt of the request does not constitute an agreement by

  5. 263  FDA to convene the NDAC. If FDA decides that the NDAC will be convened, FDA will notify

  6. 264  the sponsor.

265

  1. 266  Under the SIA, FDA may decide whether to convene an NDAC for any particular 586A request

  2. 267  or pending request regardless of whether the sponsor has made an NDAC request. FDA intends

  3. 268  to address and prioritize the total number of 586A requests and pending requests received by

  4. 269  using the factors described in Section II.A above to determine whether and when to refer such a

  5. 270  request to the NDAC. For example, FDA would be more likely to convene a meeting for matters

  6. 271  that are dissimilar to those discussed at a previous NDAC and for which a clear path forward had

  7. 272  not already been determined. In addition, FDA may convene an NDAC on its own initiative,

  8. 273  using similar criteria as those factors used to determine whether to present sponsor requests to an

  9. 274  NDAC.

275

  1. 276  As explained above, referring a matter to the NDAC involves a substantial expenditure of the

  2. 277  Agency’s limited resources and time. Accordingly, depending on the total number of 586A

  3. 278  requests and pending requests to be considered by the NDAC, FDA intends to limit the number

  4. 279  of NDAC meetings per year and the number of requests to be considered per meeting as

  5. 280  discussed in section 586C(c) of the FD&C Act.

281

282

  1. 283 IV. PREPARATION AND PUBLIC AVAILABILITY OF INFORMATION GIVEN TO

  2. 284 ADVISORY COMMITTEE MEMBERS

285

  1. 286  For each advisory committee meeting, the sponsor should provide briefing materials to be

  2. 287  considered by the members of the NDAC. For most meetings, these materials should consist of

  3. 288  the sponsor’s briefing document that addresses the issues to be considered by the NDAC, and the

  4. 289  sponsor’s slides to be presented. The briefing document should include all information relevant

  5. 290  to the matters to be discussed at the NDAC meeting, presented in a concise summary.

  6. 291  Information on briefing materials preparation, timelines and public availability of briefing

  7. 292  material information is included in the guidance for industry Advisory Committee Meetings –

  8. 293 Preparation and Public Availability of Information Given to Advisory Committee Members.25

294 295

24 The official date of receipt of the letter may be assigned by FDA and may not necessarily be the date of mailing or of delivery by a delivery service.

25 See guidance for industry, Advisory Committee Meetings – Preparation and Public Availability of Information Given to Advisory Committee Members (Advisory Committee Meetings Guidance), available at, http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-afda-gen/documents/document/ucm125650.pdf.

page11image29560 page11image29720

8

 

Nonprescription Sunscreen Drug ProductsContent and Format of Data Submissions To Support a GRASE Determination Under the Sunscreen Innovation Act Guidance for Industry

Nonprescription Sunscreen Drug

ProductsContent 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

page1image9376

Nonprescription Sunscreen Drug

ProductsContent 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

page2image7736

Contains Nonbinding Recommendations

Draft — Not for Implementation

TABLE OF CONTENTS

  1. INTRODUCTION............................................................................................................. 1

  2. BACKGROUND ............................................................................................................... 3

    1. Regulation of Sunscreen Products................................................................................... 3

    2. FDA’S Filing Determinations and Refusal To File a Request ...................................... 4

    3. Scope of This Draft Guidance .......................................................................................... 5

    4. Related Draft Guidance.................................................................................................... 6

  3. CHARACTERISTICS OF A COMPLETE GRASE DATA SUBMISSION .............. 6

    1. General Recommendations .............................................................................................. 6

    2. Recommended Organization and Contents .................................................................... 9

    3. Characteristics of an Incomplete Request and GRASE Data Submission ................ 12

    4. How and Where To Submit GRASE Data Submissions ............................................. 13

1 2 3

Contains Nonbinding Recommendations

Draft — Not for Implementation

Nonprescription Sunscreen Drug ProductsContent 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

  1. 19  This draft guidance addresses the current thinking of the Food and Drug Administration (FDA or

  2. 20  Agency) on the format and content of information provided to support a request submitted under

  3. 21  section 586A (586A request) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21

  4. 22  U.S.C. 360fff-1), as amended by the Sunscreen Innovation Act (SIA),2 or in support of a pending

  5. 23  request as defined under section 586(6) of the FD&C Act (21 U.S.C. 360fff(6)).3 A 586A

  6. 24  request seeks a determination from FDA of whether an over-the-counter (OTC or

  7. 25  nonprescription) sunscreen active ingredient,4 or a combination of nonprescription sunscreen

  8. 26  active ingredients,5 is generally recognized as safe and effective (GRASE) for use under

  9. 27  specified conditions and should be included in the OTC sunscreen drug monograph (GRASE

  10. 28  determination). The GRASE determination is primarily based on FDA’s review of safety and

  11. 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))).

page4image28688

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.

page4image42064
page4image43480

1

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 30  submission) as well as information and views submitted to the public docket by other interested

  2. 31  parties.7 Before that review may begin, however, FDA must review the GRASE data submission

  3. 32  for completeness and determine accordingly whether to file or refuse to file it for substantive

  4. 33  review (filing determination). If the submission is not sufficiently complete to enable us to

  5. 34  conduct a substantive GRASE review, including being formatted in a manner that will enable us

  6. 35  to evaluate its completeness, we will refuse to file the submission.8

36

  1. 37  We are issuing this draft guidance as directed by the SIA, which calls for FDA to publish a draft

  2. 38  and final guidance on the format and content of information submitted by a sponsor in support of

  3. 39  a 586A request or a pending request. When final, the recommendations in this draft guidance

  4. 40  will help sponsors prepare GRASE data submissions for 586A requests9 that are sufficiently

  5. 41  complete to be filed for substantive review, as well as helping guide FDA’s filing

  6. 42  determinations. Only data submissions provided by or on behalf of a sponsor are subject to a

  7. 43  filing determination as described in this draft guidance, and we anticipate that information

  8. 44  provided by other interested parties will supplement the sponsor’s data submission rather than

  9. 45  duplicating the full extent of a complete data submission as described in this draft guidance.

  10. 46  However, we encourage other interested parties to follow the recommendations in this guidance

  11. 47  to the extent that they are applicable to a given submission. We also anticipate that the advice in

  12. 48  this draft guidance will also be useful to persons who are preparing safety and efficacy data

  13. 49  submissions for review by FDA in other regulatory proceedings whose intent is to determine

  14. 50  whether particular nonprescription drug active ingredients or other OTC conditions are GRASE

  15. 51  and therefore may be included in an applicable OTC monograph (such as a future non-sunscreen

  16. 52  TEA (Time and Extent Application) or a request for additional data in an ongoing SIA

  17. 53  proceeding).

54

  1. 55  Section II of this draft guidance provides background information on the sunscreen OTC

  2. 56  monograph process and the new procedures governing GRASE determinations under the SIA

  3. 57  (the SIA process). Section II also summarizes the filing determination process for GRASE data

  4. 58  submissions and describes what sponsors can do if FDA refuses to file a GRASE data

  5. 59  submission. Section III describes FDA’s current thinking on the recommended format and

  6. 60  content of a GRASE data submission that will be considered complete and therefore fileable for

  7. 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.

page5image34512

2

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 65  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 66  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

  3. 67  as recommendations, unless specific regulatory or statutory requirements are cited. The use of

  4. 68  the word should in Agency guidances means that something is suggested or recommended, but

  5. 69  not required.

70 71

  1. 72 II. BACKGROUND

  2. 73 10

  3. 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

  1. 83  Products regulated under the new drug approval process may not be marketed without FDA’s

  2. 84  prior review and approval of a new drug application (NDA) or abbreviated new drug application

  3. 85  (ANDA) for each product. Products marketed under the OTC drug monograph process are not

  4. 86  individually reviewed and approved prior to marketing. Instead, OTC drug monographs

  5. 87  categorize drugs by therapeutic categories, such as sunscreens. For each category, the

  6. 88  monograph establishes conditions under which any drug that satisfies those conditions and

  7. 89  FDA’s general regulations for OTC drugs is considered to be GRASE and not misbranded when

  8. 90  used under the conditions prescribed, recommended, or suggested in labeling.11

91

  1. 92  Initially, active ingredients that were not used in sunscreens in the United States prior to the

  2. 93  inception of the OTC Drug Review were not eligible for the OTC Drug Review. FDA

  3. 94  considered a drug that was ineligible for inclusion in the OTC monograph system to be subject to

  4. 95  the new drug approval process.

96

  1. 97  In 2002, before the SIA was enacted, FDA published the “time and extent application” (TEA)

  2. 98  regulation in 21 CFR 330.14. The TEA regulation (§ 330.14(c)) established a process through

  3. 99  which any person could request that an active ingredient or other OTC drug condition, including

  4. 100  one not previously marketed in the United States before the inception of the OTC Drug Review,

  5. 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

page6image27872 page6image28032 page6image28192 page6image28352 page6image28512

3

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 103  For OTC sunscreens, the SIA process supplements the TEA regulation. The SIA amended the

  2. 104  FD&C Act in part by providing new procedures for establishing that nonprescription sunscreen

  3. 105  active ingredients or combinations of nonprescription sunscreen active ingredients are GRASE

  4. 106  and not misbranded when used under the conditions specified in a final sunscreen order.12

  5. 107  Active ingredients that are determined to be GRASE in a final sunscreen order may be used in

  6. 108  U.S.-marketed sunscreens without first obtaining an approved NDA or ANDA. Because the

  7. 109  monograph and SIA processes are public, anyone, not just the sponsor who originated the

  8. 110  request, may submit data during public comment periods.

111

  1. 112  As with the TEA process, the SIA process calls for an initial eligibility determination,

  2. 113  by submissions of safety and efficacy data, and a GRASE determination phase. However, the

  3. 114  SIA process also requires FDA to make a filing determination as described in this draft guidance,

  4. 115  and to make proposed and final GRASE determinations in the form of administrative orders

  5. 116  rather than the rulemaking required by the TEA regulation. The SIA process also establishes

  6. 117  strict timelines for the necessary administrative actions.

118
119
B. FDA’S Filing Determinations and Refusal To File a Request 120

  1. 121  The SIA requires FDA to conduct an initial filing review to determine whether a sponsor’s

  2. 122  submission of safety and efficacy data and other relevant information to support a 586A request

  3. 123  for a sunscreen active ingredient is sufficiently complete to enable us to conduct a substantive

  4. 124  GRASE review (including being organized so that we can determine its completeness).14 The

  5. 125  initial filing review will help conserve FDA resources and streamline the GRASE review for

  6. 126  nonprescription sunscreen active ingredients by making the start of the GRASE review

  7. 127  contingent on a determination that the submission is sufficiently complete to support a GRASE

  8. 128  substantive review. As a result, it is the date of filing by FDA, and not the date when the

  9. 129  submission was submitted to or received by FDA, that triggers FDA’s statutory time frame for

  10. 130  completing the GRASE determination and issuing a proposed sunscreen order (which in turn

  11. 131  triggers various other action dates under the SIA).15

132

  1. 133  No later than 60 days after receiving a sponsor’s GRASE data submission, FDA must take one of

  2. 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

page7image33368

4

Contains Nonbinding Recommendations

Draft — Not for Implementation

139
140
141
142
143
144
145

  1. 146  If FDA refuses to file the sponsor’s request, the sponsor may, within 30 days of receipt of the

  2. 147  notification, request in writing a meeting with FDA to discuss the refusal to file.18 The sponsor

  3. 148  may also submit additional data or other information to FDA. If the sponsor requests a meeting,

  4. 149  FDA will convene that meeting within 30 days of the request.19 Following such a meeting, FDA

  5. 150  may file the request within 60 days, the sponsor may submit additional data or other information,

  6. 151  or the sponsor may, within 120 days, direct FDA to file the request over protest, with or without

  7. 152  amendments to correct any deficiencies in the request.20 If the sponsor submits additional data

  8. 153  or other information (whether before, after, or in the absence of a meeting), FDA must reconsider

  9. 154  its initial refusal to file, along with any additional information provided by the sponsor, and

  10. 155  make a new filing determination within 60 days.21 If, after a meeting, the sponsor elects to have

  11. 156  FDA file the request, FDA will file the request over protest within 30 days of the sponsor’s

  12. 157  election, notify the sponsor in writing that the request has been filed, and make such notification

  13. 158  public.22

159
160
C. Scope of This Draft Guidance 161

  1. 162  This draft guidance describes our current thinking on the content and format of a complete and

  2. 163  fileable request under the SIA. When final, the recommendations in this draft guidance will

  3. 164  provide advice to sponsors on how to prepare a successful GRASE submission, as well as guide

  4. 165  FDA’s filing determinations.

166

  1. 167  As noted in section II.B above, the “refusal to file” provision in the SIA applies only to GRASE

  2. 168  data submissions made by sponsors to support 586A requests.23 However, we anticipate that the

  3. 169  advice in this draft guidance will also be useful to persons who are preparing safety and efficacy

  4. 170  data submissions for review by FDA in other regulatory proceedings whose intent is to determine

  5. 171  whether particular nonprescription drug active ingredients or other OTC conditions are GRASE

    1. 17 Section 586B(b)(2)(B) of the FD&C Act (21 U.S.C. 360fff-2(b)(2)(B)).

    2. 18 Section 586B(b)(3) of the FD&C Act (21 U.S.C. 360fff-2(B)(b)(3)).

    3. 19 Section 586B(b)(3)(B) of the FD&C Act (21 U.S.C. 360fff-2(B)(b)(3)(B)).

    4. 20 Section 586B(b)(3).

    5. 21 Section 586B(b)(3)(C) of the FD&C Act (21 U.S.C. 360fff-2(b)(3)(C)).

    6. 22 Section 586B(b)(3)(B)(ii)((III) of the FD&C Act (21 U.S.C. 360fff-2(b)(3)(B)(ii)(III)).

    7. 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

page8image32048

5

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 172  and therefore may be included in an applicable OTC monograph (such as a future non-sunscreen

  2. 173  TEA request or a request for additional data in an ongoing SIA proceeding).

174

  1. 175  This draft guidance does not detail the specific clinical and nonclinical data that should be

  2. 176  submitted to support a GRASE determination for a nonprescription sunscreen active ingredient.

  3. 177  Instead, it broadly identifies the key structural elements, topics to be addressed, and

  4. 178  recommended organization of a complete and fileable GRASE data submission. For the

  5. 179  Agency’s current thinking on the specific scientific testing and data recommended to support a

  6. 180  GRASE determination for sunscreen active ingredients, see the guidance Over-the-Counter

  7. 181 Sunscreens: Safety and Effectiveness Data (Safety and Effectiveness Draft Guidance). Sponsors

  8. 182  are encouraged to read that draft guidance document and meet with FDA before preparing and

  9. 183  submitting a GRASE data submission.

184
185
D. Related Draft Guidance 186

  1. 187  In addition to this draft guidance, the SIA directs FDA to issue three additional draft guidance

  2. 188  documents on other topics.24 These topics include:

189
190
191
192
193
194
195
196
197
198
199
200
201

  1. 202  As they become available, FDA will make these draft guidances available on the FDA Drugs

  2. 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

page9image26544 page9image26704 page9image26864

6

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 210  FDA will refuse to file 586A requests for which the data and other information submitted are not

  2. 211  sufficiently complete. GRASE data submissions that are materially incomplete or inadequately

  3. 212  formatted do not permit FDA to conduct a substantive review. A complete submission by the

  4. 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

page10image26072

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
260
261
262
263
264
265
266
267
268
269

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.

  1. 270  The principle that data to support a GRASE determination must be publicly available is most

  2. 271  pertinent to studies or detailed study findings that are critical to FDA’s evaluation of safety

  3. 272  and efficacy, such as information needed to confirm that the study was appropriately

  4. 273  designed and conducted or detailed study findings needed to substantiate the reported study

  5. 274  results. This principle does not apply to information that has no bearing on FDA’s scientific

  6. 275  review of safety and efficacy data, such as that described in item 6, because such information

  7. 276  is not relevant to a GRASE determination.

  8. 277  To enable a timely filing review, Module 128 should include the following, under the heading

  9. 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

page11image29256

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

  1. 293  FDA recommends that the GRASE data submission be organized using the general structure and

  2. 294  table of contents (TOC) described in the Common Technical Document (CTD) in effect at the

  3. 295  time of the submission.29 The CTD is an internationally harmonized set of specifications for

  4. 296  preparing applications relating to new drugs that is maintained by the International Conference

  5. 297  on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human

  6. 298  Use and has been recommended by the FDA in multiple guidance documents. Using this

  7. 299  organized approach will streamline FDA’s GRASE review because the CTD format is familiar to

  8. 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

  1. 304  1.

  2. 305  2.

  3. 306  3.

  4. 307  4.

  5. 308  5.

309

  1. 310  The TOC in a GRASE data submission should be detailed, including both major section

  2. 311  headings and subheadings. However, it is neither necessary nor recommended that GRASE

  3. 312 data submissions meet the full technical specifications of an eCTD or include all of the

  4. 313 information identified in the CTD TOC headings. Because the eCTD TOC is designed to

  5. 314  accommodate multiple types of regulatory applications, it contains many headings and

  6. 315  subheadings that are not pertinent to the safety and efficacy of these ingredients. We therefore

  7. 316  do not recommend that such information be included in a GRASE data submission. However,

  8. 317  we do recommend that your TOC include all of the major headings from the CTD TOC (using

  9. 318  the appropriate heading numbers) and indicate, when appropriate, that no information is being

  10. 319  submitted for a given heading.

320

  1. 321  If the submission is electronic, the TOC should include hyperlinks to each section. If a

  2. 322  submission is not electronic, the submission should still be organized using the eCTD TOC.

323

  1. 324  A complete GRASE data submission based on the eCTD TOC should generally have the

  2. 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

page12image29560

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.

page13image24768 page13image24928 page13image25088 page13image25248 page13image25408

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

  1. 382  literature searches, scientific articles, or other published materials). Full copies of all

  2. 383  published materials should be provided. The specific ingredient and formulation(s) used in

  3. 384  each study should be described in detail.

385

  1. 386  Each individual study in the submission should include its own TOC and summary.

  2. 387  Complete data sets (not selected or summary data) should be included in the submission. We

  3. 388  expect that data from studies provided only in summary form will generally not be

  4. 389  considered sufficient evidence that an active ingredient is GRASE.

390

  1. 391  Examples of nonclinical studies to be provided in this module include dermal and systemic

  2. 392  carcinogenicity studies, developmental and reproductive toxicity studies, and animal

  3. 393  toxicokinetic data.

394
395 M
ODULE 5: CLINICAL STUDY REPORTS 396

  1. 397  Module 5 should include separate comprehensive integrated summaries of effectiveness and

  2. 398  clinical safety. The summary of effectiveness should include the active ingredient’s

  3. 399  mechanism of action and the specific doses, concentrations, and formulations proposed for

  4. 400  use. The summary of safety should include exposure data, and, if available, address safety in

  5. 401  specific populations such as children, the elderly, and pregnant or lactating women. The

  6. 402  summary of safety should also address specific safety issues expected with either the

  7. 403  ingredient or its application. For sunscreens, examples of such safety issues could include

  8. 404  dermal safety, hypersensitivity, accidental ocular exposure, or inhalational safety. All

  9. 405  available efficacy and safety data, including both supportive data and any data demonstrating

  10. 406  potential safety signals, should be submitted.

407

  1. 408  This module should also include full reports of (1) all clinical effectiveness and safety studies

  2. 409  and other clinical data and (2) all clinical pharmacology and human toxicokinetic data. In

  3. 410  addition to actual study reports, all other types of clinical data (e.g., from literature searches,

  4. 411  scientific articles, or other published materials) should be included in this module. Full copies of

  5. 412  all published materials should be provided. Each study report should contain a description of the

  6. 413  specific ingredient and formulation(s) used. For literature reports, this information may be

  7. 414  included in the relevant summary document.

415

page14image26728
375
376
377
378
379
  1. 380  This module should include data and reports from nonclinical studies discussed in the Safety

  2. 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

  1. 416  Human studies to be included in Module 5 are discussed in the Safety and Effectiveness Data

  2. 417  Draft Guidance. These include sun protection factor studies and other effectiveness studies (such

  3. 418  as in vitro broad spectrum studies, if performed), human irritation and sensitization studies,

  4. 419  human photosafety studies, human absorption studies, and human maximal usage trials.

420

  1. 421  Module 5 should also include reports of in vitro testing performed by the sponsor in connection

  2. 422  with human maximal usage trials to support final formulation safety testing if the active

  3. 423  ingredient is determined to be GRASE, as discussed in Safety and Effectiveness Data Draft

  4. 424  Guidance.

425

  1. 426  Each individual study in the submission should include its own TOC and summary. Complete

  2. 427  data sets (not selected or summary data) should be included in the submission. Generally, we

  3. 428  intend not to consider study data provided only in summary form to be sufficient evidence that

  4. 429  an active ingredient is GRASE.

430

  1. 431  Further, postmarketing safety data as discussed in the Safety and Effectiveness Data Draft

  2. 432  Guidance,30 should be included in Module 5. For adverse event reports, there should be a TOC

  3. 433  with a separate link to each adverse event report. The section on adverse event reports should be

  4. 434  organized according to the Medical Dictionary for Regulatory Activities System Organ Class

  5. 435  categories.

436
437
C. Characteristics of an Incomplete Request and GRASE Data Submission 438

  1. 439  Some examples of incomplete information or inadequate organization that may render the

  2. 440  GRASE data submission insufficiently complete31 for review are listed below.32 These

  3. 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 disorganizedthat 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.

page15image26976

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

  1. 467  GRASE data submissions can be sent (1) in hard copy to the Division of Dockets Management

  2. 468  (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852

  3. 469  or (2) electronically to http://www.regulations.gov using the previously established docket

  4. 470  number. In addition, a copy of the cover letter should be sent to the Division of Nonprescription

  5. 471  Drug Products, Food and Drug Administration, Bldg. 22, Mail Stop 5411, 10903 New

  6. 472  Hampshire Avenue, Silver Spring, MD 20993.

473

474
475
476
477
478

D. How and Where To Submit GRASE Data Submissions

page16image14200

13

 

Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants Guidance for Industry

page1image392

Formal Meetings Between the

FDA and Biosimilar

Biological Product Sponsors

or Applicants Guidance for Industry

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)

November 2015 Procedural

OMB Control No. 0910-0802
Expiration Date 9/30/2018
See additional PRA statement in section XV of this guidance.

page1image5576

Formal Meetings Between the

FDA and Biosimilar

Biological Product Sponsors

or Applicants 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
Tel: 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

or

Office of Communication, Outreach, and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, rm. 3128
Silver Spring, MD 20993-0002
Tel: 800-835-4709 or 240-402-8010; Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www .fda.gov/BiologicsBloodV accines/GuidanceComplianceRegulatoryInformation/Guidances/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)

November 2015 Procedural

I. II. III. IV.

V. A.

B. C. D. E.

VI. VII. A.

B. VIII.

IX. X.

A. B. C.

XI.

XII. XIII. XIV . XV.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1

BACKGROUND ............................................................................................................... 2

MEETING TYPES ........................................................................................................... 3

PARTICIPATION IN THE FDA’S BIOSIMILAR BIOLOGICAL PRODUCT DEVELOPMENT PROGRAM ....................................................................................... 5

MEETING PROCEDURES............................................................................................. 6

Biosimilar Initial Advisory Meeting ............................................................................................. 6

BPD Type 1 Meeting ...................................................................................................................... 6

BPD Type 2 Meeting ...................................................................................................................... 6

BPD Type 3 Meeting ...................................................................................................................... 6

BPD Type 4 Meeting ...................................................................................................................... 7

MEETING REQUESTS BY SPONSORS OR APPLICANTS..................................... 7

ASSESSING MEETING REQUESTS............................................................................ 9

Meeting Denied .............................................................................................................................. 9

Meeting Granted .......................................................................................................................... 10

RESCHEDULING MEETINGS ................................................................................... 10

CANCELLING MEETINGS......................................................................................... 11

MEETING PACKAGE CONTENT AND SUBMISSION.......................................... 12

Timing of Submission .................................................................................................................. 12

Where and How Many Copies of Meeting Packages to Send .................................................. 12

Meeting Package Content............................................................................................................ 13

PREMEETINGS AND COMMUNICATIONS WITH SPONSORS OR APPLICANTS ................................................................................................................. 14

PROCEDURES FOR THE CONDUCT OF MEETINGS.......................................... 15 DOCUMENTATION OF MEETINGS......................................................................... 15 RESOLUTION OF DISPUTE ABOUT MEETING MINUTES................................ 15 PAPERWORK REDUCTION ACT OF 1995.............................................................. 16

Contains Nonbinding Recommendations

Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants Guidance for Industry1

page4image3936

This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not create 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 as listed on the title page.

page4image16872

I. INTRODUCTION

This guidance provides recommendations to industry on formal meetings between the Food and Drug Administration (FDA) and biosimilar biological product sponsors or applicants. The Biosimilar User Fee Act of 2012 (BsUFA), enacted as part of the Food and Drug Administration Safety and Innovation Act (FDASIA), amended the Federal Food, Drug, and Cosmetic Act (the FD&C Act) to authorize a new user fee program for biosimilar biological products.2,3 The FDA has committed to meeting certain performance goals set forth in a letter from the Secretary of Health and Human Services to the Chairman of the Committee on Health, Education, Labor, and Pensions of the Senate and the Chairman of the Committee on Energy and Commerce of the House of Representatives.4 The performance goals include meeting management goals for formal meetings that occur between the FDA and sponsors or applicants during the development phase of a biosimilar biological product. The FDA encourages sponsors and applicants to use

1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.

2 For the statutory definition of biosimilar and biological product and definitions of selected terms used in this guidance, see the Glossary of the guidance for industry Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. (We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.) For the statutory definition of biosimilar biological product application, see section 744G(4) of the FD&C Act.

3 Sections 401-408 of FDASIA, adding sections 744G, 744H, and 744I to the FD&C Act.

4 The BsUFA goals letter, which is titled “Biosimilar Biological Product Authorization Performance Goals and Procedures Fiscal Years 2013 Through 2017,” is available on the FDA’s Web site at http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/Approv alApplications/TherapeuticBiologicApplications/Biosimilars/UCM281991.pdf.

page4image34392

1

Contains Nonbinding Recommendations

the meetings described in this guidance to optimize product development and facilitate submission of marketing applications.

For the purposes of this guidance, formal meeting includes any meeting that is requested by a sponsor or applicant following the request procedures provided in this guidance and includes meetings conducted in any format (i.e., face-to-face meeting, teleconference, or videoconference).

This guidance reflects a unified approach to all formal meetings between sponsors or applicants and the FDA for biosimilar biological products. This guidance is intended to assist sponsors or applicants in generating and submitting a meeting request and the associated meeting package to the FDA for biosimilar biological products intended to be submitted under 351(k) of the Public Health Service Act (PHS Act). This guidance does not apply to meetings associated with new drug applications or abbreviated new drug applications under section 505 of the FD&C Act or to biologics license applications (BLAs) under section 351(a) of the PHS Act.5

This guidance discusses the principles of good meeting management practices (GMMPs) and describes standardized procedures for requesting, preparing, scheduling, conducting, and documenting such formal meetings.

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

II. BACKGROUND

Each year, FDA review staff participate in many meetings with biosimilar biological product sponsors or applicants who seek advice relating to the development and review of biosimilar biological products. Because these meetings often represent critical points in the regulatory and development process, it is important that there are efficient, consistent procedures for the timely and effective conduct of such meetings. The GMMPs in this guidance are intended to provide consistent procedures that will promote well-managed meetings, and ensure that such meetings are scheduled within a reasonable time, conducted efficiently, and documented appropriately.

page5image18120

5 For information on meetings for new drug applications and 351(a) BLAs, see the guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants.

2

Contains Nonbinding Recommendations

III. MEETING TYPES6

There are five types of formal meetings that can occur between sponsors or applicants and FDA staff to discuss development of a biosimilar biological product:

1. Biosimilar Initial Advisory meeting: A Biosimilar Initial Advisory meeting is an initial assessment limited to a general discussion regarding whether licensure under section 351(k) of the PHS Act may be feasible for a particular product, and, if so, general advice on the expected content of the development program. This meeting type does not include any meeting that involves substantive review of summary data or full study reports. However, preliminary comparative analytical similarity data from at least one lot of the proposed biosimilar biological product compared to the U.S.-licensed reference product should be provided in the meeting package. The analytical similarity data should be sufficient to enable the FDA to make a preliminary determination as to whether licensure under section 351(k) of the PHS Act may be feasible for a particular product, and to provide meaningful advice. A general overview of the development program, including synopses of results and findings from all completed studies and information about planned studies, also should be provided.

Extensive analytical, nonclinical, and/or clinical data are not expected to be provided based on the expected stage of development of the proposed biosimilar biological product. If the sponsor or applicant is seeking targeted advice on the adequacy of any comparative data or extensive advice for any aspect of an ongoing biosimilar development program, a different meeting type should be requested.

2. BPD Type 1 meeting: A Biosimilar Biological Product Development (BPD) Type 1 meeting is a meeting that is necessary for an otherwise stalled BPD program to proceed. Examples of a BPD Type 1 meeting include:

  • Meetings to discuss clinical holds: (1) in which the sponsor or applicant seeks input on how to address the hold issues; or (2) in which a response to hold issues has been submitted, and reviewed by the FDA, but the FDA and the sponsor or applicant agree that the development is stalled and a new path forward should be discussed

  • Special protocol assessment meetings that are requested after receipt of an FDA letter in response to protocols submitted under the special protocol assessment procedures as described in section VI of the BsUFA goals letter

  • Meetings to discuss an important safety issue, when such an issue is identified and the FDA and the sponsor or applicant agree that the issue should be discussed

    6 The meeting types and goal dates for BPD meetings were developed by the FDA in consultation with public and industry stakeholders as directed by the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). For more information about BsUFA and the fee criteria for BPD meetings, refer to the BsUFA Web page at http://www.fda.gov/ForIndustry/UserFees/BiosimilarUserFeeActBsUFA/default.htm.

page6image24688

3

Contains Nonbinding Recommendations

Dispute resolution meetings as described in 21 CFR 10.75 and 312.48, and in section IV of the BsUFA goals letter, and the draft guidance for industry and review staff Formal Dispute Resolution: Appeals Above the Division Level7

3. BPD Type 2 meeting: A BPD Type 2 meeting is a meeting to discuss a specific issue (e.g., proposed study design or endpoints) or questions where the FDA will provide targeted advice regarding an ongoing BPD program. This meeting type can include substantive review of summary data, but does not include review of full study reports.

4. BPD Type 3 meeting: A BPD Type 3 meeting is an in-depth data review and advice meeting regarding an ongoing BPD program. This meeting type includes substantive review of full study reports or an extensive data package (e.g., detailed and robust analytical similarity data), FDA advice regarding the similarity between the proposed biosimilar biological product and the reference product based on a comprehensive data package, and FDA advice regarding the need for additional studies, including design and analysis, based on a comprehensive data package.

  • Examples of a BPD Type 3 meeting submission include:

    • Comprehensive analytical similarity data that permit the FDA to make a preliminary evaluation of analytical similarity during development. The level of analytical data provided should be similar to what the sponsor or applicant intends to submit in a 351(k) BLA (e.g., full study reports and/or datasets that support the full study reports).

    • Full study report(s) for a clinical study(ies).

  • Based on the data and/or datasets and results reported in the full study reports, the FDA encourages the sponsor or applicant to provide an update on the development plan of the proposed biosimilar biological product. Examples of topics the sponsor or applicant can address as part of a BPD Type 3 meeting in addition to the in-depth data submitted include the following:

    • Proposal for any planned additional studies

    • Proposal for extrapolation

      5. BPD Type 4 meeting: A BPD Type 4 meeting is a meeting to discuss the format and content of a biosimilar biological product application or supplement to be submitted under section 351(k) of the PHS Act. Although the proposed content of the application will be discussed, this meeting type does not include substantive review of summary data or full study reports.

      7 When final, this guidance will represent the FDA’s current thinking on this topic. 4

page7image22056

Contains Nonbinding Recommendations

Sponsors or applicants are not required to request meetings in sequential order (i.e., Biosimilar Initial Advisory meeting, BPD Type 2, BPD Type 3, then BPD Type 4). The meeting type requested depends on the stage of the development program and/or the advice being sought. Although the FDA would most likely grant one Biosimilar Initial Advisory meeting and BPD Type 4 meeting for a particular biosimilar biological product, sponsors or applicants can request, as appropriate, as many BPD Type 2 and Type 3 meetings as needed to support ongoing development of a biosimilar biological product.

IV. PARTICIPATION IN THE FDA’S BIOSIMILAR BIOLOGICAL PRODUCT DEVELOPMENT PROGRAM

As stipulated by statute, a sponsor or applicant must pay a biosimilar biological product development fee (BPD fee) to participate in the FDA’s BPD program to receive a BPD Type 1, 2, 3, or 4 meeting for a product.8 There is no fee for a Biosimilar Initial Advisory meeting. The BPD fee is an annual per-product fee, not a per-meeting or per-review activity fee. There are three types of BPD fees: the initial BPD fee, the annual BPD fee, and the reactivation fee. The initial BPD fee is due on the date a sponsor or applicant submits an investigational new drug application (IND) for an investigation that the FDA determines is intended to support a biosimilar biological product application for a product, or within 5 calendar days after the FDA grants the sponsor’s or applicant’s request for a BPD Type 1, 2, 3, or 4 meeting for that product, whichever occurs first.9

After a sponsor or applicant has paid the initial BPD fee, beginning in the next fiscal year, an annual BPD fee will be assessed for the product until the sponsor or applicant submits a marketing application that is accepted for filing, or discontinues participation in the BPD program for that product.10 If a sponsor or applicant has discontinued participation in the BPD program for a product and wants to again engage with the FDA on development of the product as a biosimilar biological product, the sponsor must pay a reactivation fee to resume participation in the BPD program for that product.11 The reactivation fee is due on the date the sponsor submits an IND for an investigation that the FDA determines is intended to support a biosimilar biological product application for the product, or within 5 calendar days after the FDA grants the sponsor’s or applicant’s request for a BPD Type 1, 2, 3, or 4 meeting for the product, whichever occurs first.12

Section 744H(a)(1)(E) of the FD&C Act establishes the consequences of failure to pay BPD fees. With respect to meetings, if the FDA grants a request for a BPD Type 1, 2, 3, or 4 meeting for a product, and the granting of the meeting request triggers an obligation to pay an initial BPD

8 See section 744H(a)(1)(E) of the FD&C Act. 9 See section 744H(a)(1)(A) of the FD&C Act. 10 See section 744H(a)(1)(B) of the FD&C Act. 11 See section 744H(a)(1)(D) of the FD&C Act. 12 Id.

page8image25976

5

Contains Nonbinding Recommendations

fee or a reactivation fee for the product, the meeting will be cancelled if the sponsor or applicant fails to pay the fee within 5 calendar days after the meeting is officially granted.13 Additionally, if a sponsor or applicant is in arrears with respect to an annual BPD fee for a product, the FDA will deny the sponsor’s or applicant’s request for a BPD Type 1, 2, 3, or 4 meeting for that product, and cancel any scheduled BPD meetings for that product.14

V. MEETING PROCEDURES

Each meeting type is subject to different procedures, as described below.

A. Biosimilar Initial Advisory Meeting

Biosimilar Initial Advisory meetings should be scheduled to occur within 90 calendar days of FDA receipt of a written meeting request and meeting package. If a sponsor or applicant requests a meeting date that is beyond 90 days from the date of the request receipt, the FDA will work with the sponsor or applicant to determine the earliest agreeable date.

B. BPD Type 1 Meeting

If sponsors or applicants are considering submission of a request for a BPD Type 1 meeting, they should first contact the relevant division in either the Center for Biologics Evaluation and Research (CBER) or the Center for Drug Evaluation and Research (CDER) to discuss the suitability of the request. BPD Type 1 meetings should be scheduled to occur within 30 calendar days of FDA receipt of a written meeting request and meeting package. If a sponsor or applicant requests a meeting date that is beyond 30 days from the date of the request receipt, the FDA will work with the sponsor or applicant to determine the earliest agreeable date.

C. BPD Type 2 Meeting

BPD Type 2 meetings should be scheduled to occur within 75 calendar days of FDA receipt of a written meeting request and meeting package. If a sponsor or applicant requests a meeting date that is beyond 75 days from the date of request receipt, the FDA will work with the sponsor or applicant to determine the earliest agreeable date.

D. BPD Type 3 Meeting

BPD Type 3 meetings should be scheduled to occur within 120 calendar days of FDA receipt of a written meeting request and meeting package. If a sponsor or applicant requests a meeting date that is beyond 120 days from the date of the request receipt, the FDA will work with the sponsor or applicant to determine the earliest agreeable date.

13 See section 744H(a)(1)(E) of the FD&C Act. 14 Id.

page9image22384

6

Contains Nonbinding Recommendations

E. BPD Type 4 Meeting

BPD Type 4 meetings should be scheduled to occur within 60 calendar days of FDA receipt of a written meeting request and meeting package. If a sponsor or applicant requests a meeting date that is beyond 60 days from the date of the request receipt, the FDA will work with the sponsor or applicant to determine the earliest agreeable date.

VI. MEETING REQUESTS BY SPONSORS OR APPLICANTS

To make the most efficient use of FDA resources, before seeking a meeting with CBER or CDER, sponsors or applicants should consider other sources of information applicable to their product development program, such as FDA and International Conference on Harmonisation guidances. Written correspondence to request such a meeting should be submitted to the sponsor’s or applicant’s application (e.g., IND, BLA) through the controlled document system.15

If there is no application, the request should be submitted to either the appropriate CDER division director with a copy sent to the division’s chief of project management staff or to the office director/division director of the appropriate product office within CBER. Before submitting any meeting request by fax or email when there is no application, the sponsor or applicant should contact the appropriate product office within CBER, or the appropriate division or the Biosimilars Program staff within CDER, Office of New Drugs, to determine to whom the request should be directed, how the request should be submitted, and the appropriate format for the request, and to arrange for confirmation of receipt of the request. This contact reduces the possibility that faxed or emailed requests will be overlooked because of the volume of faxes and emails received daily by FDA staff. Faxed or emailed requests should be sent during official business hours (8:00 a.m. to 4:30 p.m. EST/EDT) Monday through Friday (except Federal government holidays).

A meeting request for the development of a proposed biosimilar biological product with multiple indications that span multiple review divisions should be submitted to the division that has regulatory oversight of the reference product.

The meeting request, regardless of the submission method, should include adequate information for the FDA to assess the potential utility of the meeting and to identify FDA staff necessary to discuss proposed agenda items. The meeting request should include the following information:

  1. The product name.

  2. The application number (if applicable).

  3. The proposed proper name (or proper name if post-licensure).

15 See http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/de fault.htm#Addresses.

page10image22064

7

Contains Nonbinding Recommendations

  1. The structure (if applicable).

  2. The reference product name.

  3. The proposed indication(s) or context of product development.

  4. The meeting type being requested (i.e., Biosimilar Initial Advisory meeting, BPD Type 1, 2, 3, or 4 meeting). The rationale for requesting the meeting type should be included.

  5. A brief statement of the purpose of the meeting. This statement should include a brief background of the issues underlying the agenda. It also can include a brief summary of completed or planned studies or data that the sponsor or applicant intends to discuss at the meeting, the general nature of the critical questions to be asked, and where the meeting fits in overall development plans. Although the statement need not provide detailed documentation of trial designs or completed studies and clinical trials, it should provide enough information to facilitate understanding of the issues, such as a small table that summarizes major results.

  6. A list of the specific objectives/outcomes the requester expects from the meeting.

  7. A proposed agenda, including estimated times needed for discussion of each agenda item not to exceed the total allotted meeting time.

  8. A list of questions, grouped by discipline. Each question should be precise, and there should be a brief explanation of the context and purpose of the question.

  9. A list of all individuals with their titles and affiliations who will attend the requested meeting from the sponsor’s or applicant’s organization, including consultants and interpreters.

  10. A list of FDA staff, if known, or disciplines, asked to participate in the requested meeting. Note that requests for attendance by FDA staff who are not otherwise essential to the application’s review may affect the ability to hold the meeting within the specified time frame of the meeting type being requested. Therefore, when attendance by nonessential FDA staff is requested, the meeting request should state whether a later meeting date is acceptable to the requester to accommodate the nonessential FDA attendees.

  11. Suggested dates and times (e.g., morning or afternoon) for the meeting that are within or beyond the appropriate time frame of the meeting type being requested. Nonavailability dates and times also should be included.

  12. The proposed format of the meeting (i.e., face-to-face, teleconference, or videoconference).

The sponsor or applicant should define in its written meeting request the specific areas of input requested from CBER or CDER. A well-written meeting request that uses the above

8

Contains Nonbinding Recommendations

components as a guide can help the FDA understand and assess the utility and timing of the meeting related to product development or review. Although CBER or CDER will determine the final meeting type (i.e., Biosimilar Initial Advisory meeting, or BPD Type 1, 2, 3, or 4 meeting), the sponsor or applicant should provide its meeting type assessment as it relates to the product’s development. The list of sponsor or applicant attendees and the list of requested FDA attendees can be useful in providing or preparing for the input needed at the meeting. However, during the time between the request and the meeting, the projected attendees can change. If there are changes, an updated list of attendees with their titles and affiliations should be provided to the appropriate FDA contact at least 1 week before the meeting.

The objectives and agenda provide overall context for the meeting topics, but it is the list of questions that is most critical to understanding the kind of information or input needed by the sponsor or applicant and to focus the discussion, should the meeting be granted. Each question should be precise and include a brief explanation of the context and purpose of the question. The questions submitted within a single meeting request should be limited to those that can be reasonably answered within the allotted meeting time, taking into consideration the complexity of the questions submitted.

VII. ASSESSING MEETING REQUESTS

The meeting request should be accompanied by the meeting package (see section X., Meeting Package Content and Submission, for additional information regarding the content of the meeting package). This ensures that the FDA will have adequate information to assess the potential utility of the meeting and prepare for the meeting. If the meeting package is not submitted to the appropriate division with the meeting request, the meeting request will be considered incomplete and the FDA generally will deny the meeting. The CBER or CDER division director or designee who receives a meeting request will determine whether to hold the meeting and will respond to the sponsor or applicant by granting or denying the meeting within 14 calendar days of receipt of the request and meeting package for a BPD Type 1 meeting, and within 21 calendar days of receipt of the request and meeting package for a Biosimilar Initial Advisory meeting or a BPD Type 2, 3, or 4 meeting.

A. Meeting Denied

If a meeting request is denied, notification to the sponsor or applicant will include an explanation of the reason for the denial. Denials will be based on a substantive reason, not merely on the absence of a minor element of the meeting request or a minor element of the meeting package. For example, as noted in section IV., Participation in the FDA’s Biosimilar Biological Product Development Program, the FDA will deny a BPD Type 1, 2, 3, or 4 meeting if the sponsor or applicant is in arrears with respect to an annual BPD fee for that product.16 Additionally, a meeting can be denied because it is premature for the product development stage or is clearly unnecessary. However, if a sponsor or applicant is not in arrears with respect to an annual BPD

16 See section 744H(a)(1)(E) of the FD&C Act.

page12image27488

9

Contains Nonbinding Recommendations

fee for a product, requests for BPD Type 1, 2, 3, and 4 meetings for that product will be honored except in the most unusual circumstances.

Following denial of a meeting, a subsequent request to schedule the meeting will be considered as a new request (i.e., a request that merits a new set of time frames as described in section V., Meeting Procedures).

B. Meeting Granted

If a meeting request is granted, CBER or CDER will notify the sponsor or applicant in writing of the decision and schedule the meeting by determining the meeting type, date, time, length, place, format (i.e., a scheduled face-to-face meeting, teleconference, or videoconference), and expected FDA participants. All of the scheduling information will be forwarded to the sponsor or applicant as soon as possible following the granting notification, and within the specified BsUFA timelines.

The Center (i.e., CBER or CDER) may determine that a different meeting type is more appropriate and it may grant a meeting of a different type than requested (e.g., if a sponsor or applicant requests a Biosimilar Initial Advisory meeting for a product, but the Center determines that a BPD Type 3 meeting is more appropriate, the FDA may grant a BPD Type 3 meeting instead of a Biosimilar Initial Advisory meeting).

As described in section IV., Participation in the FDA’s Biosimilar Biological Product Development Program, if the FDA grants a request for a BPD Type 1, 2, 3, or 4 meeting for a product, the sponsor or applicant may be required to pay an initial BPD fee or a reactivation fee for the product within 5 calendar days.17

VIII. RESCHEDULING MEETINGS

Occasionally, circumstances arise that necessitate the rescheduling of a meeting either by the FDA or the sponsor or applicant. If a meeting needs to be rescheduled, it should be rescheduled as soon as possible after the original date. A new meeting request should not be submitted and new time frames should not be set for rescheduled meetings. Sponsors or applicants and the FDA should take reasonable steps together to avoid rescheduling meetings. For example, if an attendee becomes unavailable, a substitute can be identified, or comments on the topic that the attendee would have addressed can be forwarded to the sponsor or applicant following the meeting. It will be at the discretion of the appropriate division whether the meeting should be rescheduled depending on the specific circumstances.

The following situations are examples of when a meeting can be rescheduled. This list includes representative examples and is not intended to be an exhaustive list.

17 See section 744H(a)(1)(A) and (D) of the FD&C Act.
10

page13image23264

IX.

 

The review team determines that additional information is needed from the sponsor or applicant for the FDA to address the sponsor’s or applicant’s questions or other important issues for discussion, and it is possible to identify the additional information needed and arrange for its submission in a timely manner.

Essential attendees are no longer available for the scheduled date and time because of an unexpected or unavoidable conflict or an emergency situation.

After the meeting package is submitted but before preliminary responses are sent by the FDA, the sponsor or applicant sends CBER or CDER additional questions or data that are intended for discussion at the meeting and require additional review time.

It is determined that attendance by additional FDA personnel not originally anticipated or requested are critical and their availability precludes holding the meeting on the original date.

CANCELLING MEETINGS

Contains Nonbinding Recommendations

When the FDA grants a request for a BPD Type 1, 2, 3, or 4 meeting for a product, the sponsor or applicant may be required to pay an initial BPD fee or a reactivation fee for the product within 5 calendar days.18 If the sponsor or applicant fails to pay the fee within the required time frame, the meeting will be cancelled.19 If the sponsor or applicant pays the initial BPD fee or reactivation fee after the meeting has been cancelled because of nonpayment, the time frame described in section V., Meeting Procedures, for the new meeting will be calculated from the date on which the FDA received the payment, rather than the date on which the sponsor or applicant originally submitted the meeting request.

Occasionally, other circumstances arise that necessitate the cancelling of a meeting. If a meeting is cancelled for reasons other than nonpayment of a required initial BPD fee or reactivation fee, the FDA will consider a subsequent request to schedule a meeting to be a new request (i.e., a request that merits a new set of time frames as described in sections V., Meeting Procedures, and VII., Assessing Meeting Requests). Both sponsors or applicants and the FDA should take reasonable steps to avoid cancelling meetings (unless the meeting is no longer necessary). Cancellation will be at the discretion of the appropriate division, and will depend on the specific circumstances.

The following situations are examples of when a meeting can be cancelled. This list includes representative examples and is not intended to be an exhaustive list.

If the FDA grants the sponsor’s or applicant’s meeting request, but the sponsor or applicant subsequently fails to pay a required initial BPD fee, annual BPD fee, or

18 See section 744H(a)(1)(A) and (D) of the FD&C Act. 19 See section 744H(a)(1(E) of the FD&C Act.

page14image25456

11

X.

reactivation fee within the time frame required under section 744H(a)(1)(A), (B), or (D) of the FD&C Act, as applicable.

The sponsor or applicant determines that the written premeeting responses to its questions are sufficient for its needs and additional discussion is not necessary (see section XII., Procedures for the Conduct of Meetings). In this case, the sponsor or applicant should contact the CBER or CDER regulatory project manager to request cancellation of the meeting. The division will consider whether it agrees that the meeting should be cancelled. Some meetings can be valuable because of the discussion they generate and the opportunity for the division to ask about relevant matters, even if the premeeting communications seem sufficient to answer the sponsor’s or applicant’s questions. If the division agrees with the sponsor or applicant that the meeting can be cancelled, the division will document the reason for cancellation and the premeeting communication will represent the final responses and the official record of the meeting.

The FDA determines that the meeting package is grossly inadequate. Meetings are scheduled on the condition that appropriate information to support the discussion has been submitted. Adequate planning by the sponsor or applicant should avoid this problem.

MEETING PACKAGE CONTENT AND SUBMISSION

Contains Nonbinding Recommendations

Premeeting preparation is critical for achieving a productive discussion or exchange of information. Preparing the meeting package should help the sponsor or applicant focus on describing its principal areas of interest. The meeting package should provide information relevant to the discussion topics and enable the FDA to prepare adequately for the meeting.

A. Timing of Submission

As discussed in section VII., Assessing Meeting Requests, if the meeting package is not submitted with the meeting request to the appropriate division, the meeting request will be considered incomplete and the FDA generally will deny the meeting.

B. Where and How Many Copies of Meeting Packages to Send

An archival copy of the meeting package should be submitted to the relevant application (e.g., pre-IND, IND, or BLA); if there is no established application, the sponsor or applicant should contact the division for additional instructions. The FDA strongly encourages sponsors or applicants to submit the archival meeting package electronically according to the electronic submission formatting recommendations (see the draft guidance for industry Providing Regulatory Submissions in Electronic Format — General Considerations).20

20 When final, this guidance will represent the FDA’s current thinking on this topic. 12

page15image23168

Contains Nonbinding Recommendations

The number of copies of a meeting package will vary based on the meeting. The responsible point of contact in the division will advise on the number of copies needed for the meeting attendees. To facilitate the meeting process, the FDA strongly suggests that copies of meeting packages provided in electronic format also be provided in paper.

C. Meeting Package Content

The meeting package should provide information relevant to the product, development stage, and meeting type requested (see section III., Meeting Types), in addition to any supplementary information needed to develop responses to issues raised by the sponsor or applicant or division. The meeting package should contain sufficient detail to meet the intended meeting objectives. For example, inclusion of raw data in addition to the derived conclusions may be appropriate in some situations. Similarly, merely describing a result as significant does not provide the division with enough information to give good advice or identify important problems the sponsor or applicant may have missed. FDA guidances identify and address many issues related to biosimilar biological product development and should be considered in planning, developing, and providing information needed to support a meeting with the FDA.21 If a product development plan deviates from current guidances, or from current practices, the deviation should be recognized and explained. Known or expected difficult design and evidence issues should be raised for discussion (e.g., selection of study populations, doses, or endpoints different from those studied for the reference product’s licensure; extrapolation of indications).

To facilitate FDA review, the meeting package content should be organized according to the proposed agenda. The meeting package should be a sequentially paginated document (individual sections can be numbered separately, as long as there is an overall pagination covering the whole submission) with a table of contents, appropriate indices, appendices, cross references, and tabs differentiating sections. Meeting packages generally should include the following information:

  1. The product name and application number (if applicable).

  2. The proposed proper name (or proper name if post-licensure).

  3. The structure (if applicable).

  4. The reference product name.

  5. The proposed indication(s) or context of product development.

  6. The dosage form, route of administration, dosing regimen (frequency and duration), and presentation(s).

21 See the guidances for industry Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product, and Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009.

page16image22384

13

XI.

7.

8.

9. 10. 11.

12.

A list of all individuals, with their titles and affiliations, who will attend the requested meeting from the sponsor or applicant organization, including consultants and interpreters.

A background section that includes the following:

a. A brief history of the development program.

b. The status of product development (e.g., chemistry, manufacturing, and controls; nonclinical; and clinical, including any development outside the United States, as applicable).

A brief statement summarizing the purpose of the meeting. A proposed agenda.

A list of questions for discussion grouped by discipline and with a brief summary for each question to explain the need or context for the question.

Data to support discussion organized by discipline and question. The level of detail of the data should be appropriate to the meeting type requested and the product development stage.

PREMEETINGS AND COMMUNICATIONS WITH SPONSORS OR APPLICANTS

Contains Nonbinding Recommendations

CBER and CDER hold internal meetings, including meeting with the Biosimilar Review Committee (BRC),22 to discuss meeting packages and to gain internal alignment on the preliminary responses to a sponsor’s or applicant’s questions. Our goal is to communicate these preliminary responses to the sponsor or applicant no later than 2 days before the scheduled meeting date. Communications before the meeting between sponsors or applicants and the FDA, including preliminary responses, can serve as a foundation for discussion or as the final meeting responses. Nevertheless, preliminary responses should not be construed as final unless there is agreement between the sponsor or applicant and the FDA that additional discussion is not necessary for any question (i.e., when the meeting is canceled because the sponsor or applicant is satisfied with the FDA’s preliminary responses), or a particular question is considered resolved allowing extra time for discussion of the more complex questions during the meeting. Preliminary responses communicated by the FDA are not intended to generate the submission of a new meeting agenda or new questions. If, however, a sponsor or applicant provides new data or a revised or new proposal, the FDA may not be able to provide comments on the new data or it may necessitate the submission of a new meeting request by the sponsor or applicant.

22 For more information about the BRC, refer to the Web page on implementation of the BPCI Act at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm215089.htm.

page17image22792

14

Contains Nonbinding Recommendations

XII. PROCEDURES FOR THE CONDUCT OF MEETINGS

Meetings will be chaired by an FDA staff member and will begin with introductions and a statement of the agenda. Presentations by sponsors or applicants generally are not needed because the information necessary for review and discussion should be part of the meeting package. If a sponsor or applicant plans to make a presentation, the presentation should be discussed ahead of time with the CBER or CDER point of contact to determine if a presentation is warranted and ensure that CBER or CDER has the presentation materials ahead of the meeting if possible. All presentations should be kept brief to maximize the time available for discussion.

The length of the meeting will not be increased to accommodate a presentation. If a presentation contains more than a small amount of content distinct from clarifications or explanations of previous data and that were not included in the original meeting package submitted to CBER or CDER for review, FDA staff may not be able to provide comments on the new data.

Before the end of the meeting, FDA attendees and the sponsor or applicant attendees should summarize the important discussion points, agreements, clarifications, and action items. Generally, the sponsor or applicant will be asked to present the summary to ensure that there is mutual understanding of meeting outcomes and action items. FDA staff can add or further clarify any important points not covered in the summary and these items can be added to the meeting minutes. The summary can be done at the end of the meeting or after the discussion of each question.

XIII. DOCUMENTATION OF MEETINGS

Documentation of meeting outcomes, agreements and disagreements, issues for further discussion, and action items is critical to ensuring that this information is preserved for meeting attendees and future reference. FDA minutes are the official record of the meeting. The FDA intends to issue the official, finalized minutes to the sponsor or applicant within 30 days of the meeting.

XIV. RESOLUTION OF DISPUTE ABOUT MEETING MINUTES

This section refers to disputes regarding the accuracy and sufficiency of the minutes. A sponsor or applicant who objects to the accuracy of the minutes or who needs additional clarification of the meeting minutes issued by the FDA should contact the assigned FDA point of contact. This process addresses issues with the meeting minutes only. If a sponsor or applicant needs to discuss additional issues that were not addressed at the meeting, it should submit a correspondence or a new meeting request.

If, after following up as described above, there are still significant differences in the sponsor’s or applicant’s and the FDA’s understanding of the content of the official meeting minutes, the sponsor or applicant should notify the FDA in writing with respect to specific disagreements. The sponsor or applicant should submit the correspondence to its application or, if there is no

15

 

Contains Nonbinding Recommendations

application, forward a letter to the office director/division director of the responsible division, with a copy to the point of contact describing the concerns.

The sponsor’s or applicant’s concerns will be taken under consideration by the division and the office director if the office director was present at the meeting. If the minutes are deemed to accurately and sufficiently reflect the meeting discussion, the point of contact will convey this decision to the sponsor or applicant and the minutes will stand as the official documentation of the meeting. If after discussions with the sponsor or applicant the FDA deems it necessary to effect a change to the official minutes, the changes will be documented in an addendum to the official minutes. The addendum will also document any continued sponsor or applicant objections.

XV. PAPERWORK REDUCTION ACT OF 1995

This guidance contains information collection provisions that are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520).

The time required to complete the information collection for a meeting request and information package is estimated to average 15 hours and 30 hours per response, respectively, including the time to review instructions, search existing data sources, and gather the data needed, and complete and review the information collection. Send comments regarding this burden estimate or suggestions for reducing this burden to:

Food and Drug Administration, Center for Drug Evaluation and Research, Office of New Drugs, Attention: Document Control Room, 5901-B Ammendale Road, Beltsville, MD 20705.

page19image14616

An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB control number. The OMB control number for this information collection is 0910-0802 (expires 9/30/18).

page19image18312
 
More Articles...