Analysis of Reportability of Changes to NDA OTC Product Labeling

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

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 

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

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

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 

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

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

Annual report. 

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

Level of support: Regulation

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

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

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

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

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
 

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

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)

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

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

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

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

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

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

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

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

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

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.