Analysis of Reportability of Changes to NDA OTC Product Labeling

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Voluntary Codes and Guidelines |

Adopted:
March 2019

The CHPA Analysis of Reportability of Changes to New Drug Application (NDA) Over-the-Counter (OTC) Product Labeling Table (table) was developed to assess the reportability of changes to over-the-counter (OTC) products subject to new drug applications (NDAs) (see Appendix A). It does not apply to OTC medicine products marketed under an abbreviated new drug application (ANDA) or the OTC monograph. For each of the changes listed in the appendix below, the table shows:

  1. CHPA’s view on the reportability of the change and the basis for that view, and
  2. an assessment of the level of support in relevant law, regulations, or guidance. 

The table is intended to establish a general approach for submissions to FDA with regards to labeling changes to OTC medicines marketed under an NDA. For OTC medicines sold under an approved NDA, CHPA member companies may use the table (revised 02.12.19) as their reference point for regulatory decision-making regarding the appropriate submission pathway for labeling changes under an NDA. 

There may be labeling changes that occur which are not currently listed in the CHPA table or there may be unique circumstances impacting the type of submission utilized by a sponsor. The table is not intended to serve as advice on specific product changes, which may differ due to particular facts of individual cases. In those instances, the sponsor, either independently or in consultation with FDA, will determine the appropriate submission type needed (if any) based on existing statutes, regulations and/or Agency guidances. Because individual changes may differ, sponsors should still rely on their legal and/or regulatory assessment in the event there are factors which impact the proposed submission type listed in the table. Sponsors are expected to ensure regulatory compliance based on their assessment of changes requested, with the CHPA table serving as a reference tool if desired.

Note relevant FDA regulations have not changed, but along with Agency guidance, the regulations served as the foundation for the positions stated in the table. 

Statutes and Regulations Referenced in the CHPA Analysis of Reportability of Changes for New Drug Application Over-the-Counter Product Labeling Table:

  1. 21 CFR 314.70
  2. FDA Guidance for Industry: Changes to an Approved NDA or ANDA (April 2004). Available at https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm077097.pdf as of January 31, 2019. 
  3. FDA Guidance for Industry: Labeling Human OTC Drug Products – Questions and Answers (December 2008). Available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078792.pdf as of January 31, 2019.

The table includes three sections to reflect general categories of changes that are commonly made to OTC products marketed under an NDA. Those categories include: 

  1. Changes to labeling for products regulated under general labeling provisions (21 CFR 201) excluding changes to Drug Facts. Examples of these types of changes include changes to the proprietary name of the product; adding or changing the National Drug Code (NDC) number; or changes to graphics (such as colors, symbols, trademark, or graphical representation of an approved flavor). 
  2. Changes to net content. Examples include change to net quantity that does not require supporting chemistry manufacturing and controls (CMC) data; bonus packs, and buy-one, get-one (BOGO) co-packaged products.
  3. Other (such as coupons and promotions). Examples include instant redeemable coupons (IRCs) and in-pack coupons.

CHPA Analysis of Reportability Changes to NDA OTC Product Labeling

This chart is designed to assess the reportability of changes to over-the-counter (OTC) products subject to new drug applications (NDAs). For each of the changes listed below, the chart shows: (1) CHPA’s view on the reportability of the change and the basis for that view1 and (2) an assessment of the level of support in relevant law, regulations, or guidance.

Changes to Labeling; Excluding Drug Facts and Labeling Regulated Under General Labeling Provisions (21 CFR Part 201)2

  Type of Change Proposed Submission Type
1 Change to Brand name

PAS for products marketed under NDAs.

21 C.F.R. § 314.70(b)(2)(i) generally provides that “changes in labeling, except those described in paragraphs (c)(6)(iii), (d)(2)(ix), or (d)(2)(x)” require a PAS. There are no regulations or guidance that exempt a change in the brand name from the PAS requirement.

Level of support: Regulation and Other

2 Endorsements by third parties (e.g., ADA), HCP preferred (i.e., superiority) claims on label

PAS. 

FDA’s Changes Guidance at 25 states that the Agency regards “[C]laims of superiority to another drug product” as major changes to labeling, and FDA could take the view that third-party endorsements or HCP-preferred claims are implied superiority claims.

Level of support: Guidance at 25 

3 Add/Change NDC number

Annual report. 

21 C.F.R. § 314.70(d)(2)(ix): “A change in the labeling concerning the description of the drug product or in the information about how the drug product is supplied.”

Level of support: Regulation

4 Change to UPC number

Annual report. 

21 C.F.R. § 314.70(d)(2)(ix): “A change in the labeling concerning the description of the drug product or in the information about how the drug product is supplied.”

Level of support: Regulation

5 Changes to graphics: colors, logo (on label)

Annual report.

FDA’s Prior Approval Supplement (PAS) and Changes Being Effected (CBE) reporting requirements hinge on the substantial or moderate “potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product.” 21 C.F.R. § 314.70(b) and (c). A change in the colors or logo on the exterior container appears unlikely to affect the identity, strength, quality, purity, or potency of a drug. At most, such changes would typically be “editorial” in nature. See 21 C.F.R. § 314.70(d)(2)(x). However, any such changes should be consistent with applicable requirements, such as the color contrast required for title/headings in the Drug Facts (DF) panel. See, e.g., 21 C.F.R. § 201.66(d)(3).

Level of support: Regulation 

6 Relocating approved labeling text (excluding Drug Facts and text on PDP whose placement is dictated by labeling legislation e.g., Net Contents) from one location to another

Annual report.

Provided the relocation complies with general labeling requirements (21 CFR Part 201) with minimal potential to have an adverse effect on the identity, strength, quality, purity or potency of the drug product. 21 C.F.R. § 314.70(d) & (d)(2)(x). FDA’s Changes Guidance at 26 provides that “changes in the layout of the package or container label...without a change in the content of the labeling” are appropriately included in the Annual Report.

Level of support: Regulation and Guidance at 26

7 Addition of non-superiority claims (e.g., third party claims such as Dr. recommended, HCP recommended) Annual report.
8 Editorial changes to Labeling; excluding Drug Facts and labeling regulated under General Labeling Provisions (21 CFR Part 201) (i.e., addition of a phrase to the trademark statement, package insert change, support programs)

Annual report.

See 21 C.F.R. § 314.70(d)(ix) for editorial changes to product descriptions: “A change in the labeling concerning the description of the drug product or in the information about how the drug product is supplied.”

Editorial changes with no changes to the Drug Facts labeling are not likely to have a substantial, moderate, or even minimal “potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product.” 21 C.F.R. § 314.70(b)-(d). FDA’s Changes Guidance at 26 states that “changes in the layout of the package or container label...without a change in the content of the labeling” are appropriately included in the Annual Report.

Level of support: Regulation and Guidance at 26

9 Change to phone number or website (on product labeling)

Annual report. 

21 C.F.R. § 314.70(d)(2)(x): “An editorial or similar minor change in labeling.” 

Level of support: Regulation

10 Addition or strengthening of warnings

CBE-0, if warning is based on new evidence that meets the standard for warnings set forth in 21 C.F.R. § 314.70(c)(6)(iii)(A) (“Changes in the labeling…to accomplish any of the following: To add or strengthen a contraindication, warning, precaution, or adverse reaction.”). This type of change is an exception to the PAS requirement.

Level of support: Regulation

11 Addition of instructions for use (shake well, wipe nozzle after use)

CBE-0 if made to “add or strengthen an instruction about dosage and administration that is intended to increase the safe use of the drug product”, 21 C.F.R. § 314.70(c)(6)(iii)(C), or Annual Report if related to customer convenience and the “change in the labeling concern[s] the description of the drug product or in the information about how the drug product is supplied, that does not involve a change in the dosage strength or dosage form,” 21 C.F.R. § 314.70(d)(2)(ix).

Level of support: Regulation

12 Changes to inactive ingredients (i.e., change to formulation)

Depends on the specific changes.

PAS: Elimination of an excipient

As a general matter, these changes would be regarded as a multiple related change — i.e., a CMC change in excipients and a change to the labeling of inactive ingredients. As indicated in FDA’s Changes Guidance at 28, if the reporting categories for the CMC change and the labeling change differ, the changes should be reported according to the more restrictive category.

Level of support: Guidance at 28

13 Change to information in Drug Facts

PAS.

Changes to the substantive content of the Drug Facts section do not meet the regulatory standard for a CBE or Annual Report and are therefore a PAS by default. See 21 C.F.R. § 314.70(b)(2)(v)(A) (“Changes in labeling, except those described in paragraphs (c)(6)(iii), (d)(2)(ix), or (d)(2)(x) of this section.”) And FDA’s Changes Guidance at 26 provides that where there is “a change in the content of the labeling,” other changes to the label are not appropriately included in an Annual Report.

Level of support: Regulation and Guidance at 26

14

Change between formats (i.e., standard to modified and vice versa) 

Change to flow of Drug Facts (e.g., horizontal to vertical orientation on carton; change from one panel to multiple panels), with no change to content

Annual report.

No change to regulatory text, just a re-formatting of layout (e.g., moving text without changing order of bullets due to available space on carton such as a different carton configuration). See 21 C.F.R. § 201.66 (standard to modified format). Provided the change in orientation complies with the General Labeling Provisions (21 CFR Part 201), then this would have a minimal potential to have an adverse effect on the identity, strength, quality, purity or potency of the drug product. 21 C.F.R. § 314.70(d) & (d)(2)(x). This does not include changes such as re-ordering bullets.

To the extent that the change in flow is consistent with the formatting requirements for the Drug Facts, FDA’s Changes Guidance at 26 states that “[C]hanges in the layout of the package or container label that are consistent with FDA regulations (e.g., 21 CFR part 201) without a change in the content of the labeling” would be regarded by the Agency as minor, and are appropriately included in the Annual Report.” This type of change is an exception to the PAS requirement.

Level of support: Regulation and Guidance at 26
 

15 Change in orientation of the carton (e.g., horizontal ⇔vertical)

Annual Report.

Provided the change in orientation complies with general labeling requirements (21 CFR Part 201) then this would have a minimal potential to have an adverse effect on the identity, strength, quality, purity or potency of the drug product. 21 C.F.R. § 314.70(d) & (d)(2)(x).

FDA’s Changes Guidance at 26 provides that “Changes in the layout of the package or container label...without a change in the content of the labeling” are appropriately included in the Annual Report.

Level of support: Regulation and Guidance at 26

16 Relocating “Questions” and/or “Tamper Evident” statement from Drug Facts to outside Drug Facts

Annual Report.

Annual Report because there is no change to regulatory text, just a relocation consistent with the General Labeling Provisions (21 CFR Part 201). It does not have the potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. 21 C.F.R. § 314.70(d)(1); see also 21 C.F.R. § 211.132(c)(1)(ii) (providing that labeling statements concerning tamper evident features need only be “prominently placed on the package”) & 21 C.F.R. § 201.66(c) (stating that the Questions heading is optional). The FDA’s Guidance: Labeling OTC Human Drug Products - Questions and Answers (Dec. 2008) states this explicitly.3

Level of Support: Regulation and Guidance (at Q&A 15)

17 Changes to storage conditions as a result of CMC changes

Depends on the specific changes.

As a general matter, these changes would be regarded as a multiple related change — i.e., a CMC change and a change to label to reflect new storage conditions. As indicated in FDA’s Changes Guidance at 28, if the reporting categories for the CMC change and the labeling change differ, the changes should be reported according to the more restrictive category.

FDA’s Changes Guidance also indicates at 25 that a change in labeled storage conditions, unless exempted by regulation or guidance, would be regarded by the Agency as a major change that should be reported in a PAS. It also provides at 28, however, that a change in storage condition made to comply with ICH guidance is appropriate for an Annual Report.

Level of support: Guidance at 25 and 28

 

Change to Net Contents

 

  Type of Change Proposed Submission Type
18 BOGO, or similar (same category drug product), shrink-wrapped or packaged together in some way

Not reportable (as long as all Drug Facts labels are visible independently in the shrink-wrapped or co-packaged product at the retail shelf).  Annual Reportable when a tertiary label is created.

Although a BOGO (or similar) offer may be considered to be labeling, so long as the offer is consistent with the regulations governing promotional labeling for OTC drugs (e.g., claims supported by substantial evidence), such an offer is not likely to have a substantial, moderate, or even minimal “potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product.” 21 C.F.R. § 314.70(b)-(d). Moreover, FDA does not pre-approve such offers as part of an OTC NDA approval.

Level of support: Regulation

19 Change to net quantity

CBE-30, or annual report.

  • An annual report is acceptable for “[a] change in the number of units (e.g., tablets, capsules) or labeled amount (e.g., grams) of a nonsterile solid dosage form in a multiple-unit container.”
  • A CBE-30 is acceptable for “[a] change in the labeled amount (e.g., grams, milliliters) of drug product for a nonsterile drug product in a multiple-unit container, except for solid dosage forms.”4

Level of support: FDA’s Changes Guidance at 22

20 X free tablets, capsules, etc. (Bonus Packs)

CBE-30 or annual report.

So long as the number of free units is clearly marked on the package and the modifications to the label to indicate that there are free units do not lead to a label change that must be reported as a PAS or CBE-30, FDA’s Changes Guidance at 22 states that:

  • An annual report is acceptable for “[a] change in the number of units (e.g., tablets, capsules) or labeled amount (e.g., grams) of a nonsterile solid dosage form in a multiple-unit container.”
  • A CBE-30 is acceptable for “[a] change in the labeled amount (e.g., grams, milliliters) of drug product for a nonsterile drug product in a multiple-unit container, except for solid dosage forms.”4

Level of support: FDA’s Changes Guidance at 22

21 Consumer or physician samples (not for sale), with no change in approved Drug Facts content

Samples could be viewed as a change to a smaller number of doses in the same container closure system. 

A drug sample is required to “bear a label that clearly denotes its status as a drug sample, e.g., ‘sample,’ ‘not for sale,’ ‘professional courtesy package’,” per 21 C.F.R. § 203.38(c). That label change with no other changes could be considered a “change in the labeling concerning the description of the drug product or in the information about how the drug product is supplied, that does not involve a change in the dosage strength or dosage form,” per 21 C.F.R. § 314.70(d)(2)(ix). FDA’s Changes Guidance at 21-22 further indicates that the reporting requirements may vary by type of container and dosage form.

  • PAS for a change in the material of the container closure system
  • CBE-30 for “[a] change in the number of units (e.g., tablets, capsules) or labeled amount (e.g., grams, milliliters) of a nonsterile drug product in a unit-of-use container.”5
  • CBE-0 for “[a] change in the labeled amount (e.g., grams, milliliters) of drug product for a nonsterile drug product in a multiple-unit container,6 except for solid dosage forms.”
  • Annual report for “[a] change in the number of units (e.g., tablets, capsules) or labeled amount (e.g., grams) of a nonsterile solid dosage form in a multiple-unit container.”
  • Annual report for no change to a marketed product (no change to size and material of container closure system, no change to formulation and no change to net quantity) but now labeling as a physician sample, not for resale

Level of support: Regulation and Guidance at 21-22

22 Consumer or physician samples (not for sale), with changes in approved Drug Facts modified format but no change to the order of the Drug Facts information

Annual report.

Provided the formatting changes comply with the General Labeling Provisions (21 CFR Part 201), these may be included in the Annual Report.  21 C.F.R. § 314.70(d)(2)(x).  

FDA’s Changes Guidance at 26 also states that “[C]hanges in the layout of the package or container label that are consistent with FDA regulations (e.g., 21 CFR part 201) without a change in the content of the labeling” would be regarded by the Agency as minor (i.e., Annual reportable).

Level of support: Regulation and Guidance at 26

23 Consumer or physician samples (not for sale), with changes in approved Drug Facts content (non-formatting changes)

PAS.

PAS because these would constitute “changes in labeling” other than those set forth in the regulations as being appropriate for a CBE or Annual Report, per 21 C.F.R. § 314.70(b)(2)(v)(A).

Level of support: Regulation

 

Other (Coupons, Promotions, etc.)

  Type of Change Proposed Submission Type
24 Instant redeemable coupon (IRC), assuming attached or presented in a way to not obscure or change other required labeling

Not reportable.

Although a coupon is considered to be labeling, so long as the coupon is consistent with the regulations governing promotional labeling, a coupon does not have a substantial, moderate, or minimal “potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product.” 21 C.F.R. § 314.70(b)-(d).

Level of support: Other

25 In-pack coupons

Not reportable.

Although a coupon is considered to be labeling, so long as the coupon is consistent with the regulations governing promotional labeling, a coupon does not have a substantial, moderate, or minimal “potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product.” 21 C.F.R. § 314.70(b)-(d).

Level of support: Other

26 “Something” inside or attached: non-drug, non-FDA regulated product

Annual report, or not reportable.

To the extent that the “something” inside: (1) is a product that is not subject to FDA jurisdiction (e.g., a sticker, rather than a non-drug product such as a dietary supplement or medical device), (2) could not reasonably be expected to have an interaction with the drug product (e.g., the packaging of the “something” is inert, and/or the “something” is not a dispensing device that could influence the administration of the drug product), and (3) the modifications to the label to indicate that there is “something” inside do not lead to a label change that must be reported as a PAS or CBE, this change could be annually reportable or not reportable depending on whether any change to the drug labeling is made.

 


1 This chart is intended for the purpose of considering a general approach to FDA on the subject of OTC NDA changes; it is not intended as advice on specific product changes, which may turn on the particular facts of individual cases. Notwithstanding the analysis presented here, FDA recommends in guidance that if an assessment of a proposed manufacturing change adversely affects the identity, strength, quality, purity, or potency of a drug product, that the sponsor submit the change in a prior approval supplement regardless of the recommended reporting category for the change. Food and Drug Administration, Guidance for Industry: (April 2004) at 7. 

2 The CHPA Working Group members believe the changes outlined in this table are supported by the FDA Guidance for Industry: Changes to an approved NDA or ANDA (2004), Labeling section X. D. (“FDA’s Changes Guidance”), and the regulations as cited. Accessed at https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm077097.pdf on November 10, 2017. 

3 FDA Final Guidance titled “Guidance for Industry: Labeling Human OTC Drug Products – Questions and Answers (December 2008). Accessed at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078792.pdf on December 14, 2017. 

4 The Changes Guidance does not comment specifically on the reportability of a change in quantity of a product with a semi-solid dosage form.

5 Unit-of-use container is defined as a container that “contains a specific quantity of a drug product and is intended to be dispensed to the patient without further modification except for the addition of appropriate labeling.”

6 Multiple unit container is defined as a container that “permits withdrawal of successive portions of the contents without changing the strength, quality, or purity of the remaining portion. This type of container is not distributed directly to patients but is used by health care practitioners who dispense the drug product in smaller amounts to a patient in accordance with a physician’s instructions.”

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