Update on Generic-Drug Labeling Requirements

US Pharm. 2015;40(6)(Generic Drug suppl):41-46.

ABSTRACT: On November 13, 2013, the FDA issued a proposed labeling rule to expedite the communication of new safety information regarding generic drugs to healthcare professionals and their patients. Brand- and generic-drug manufacturers must report adverse events to the FDA; however, only brand-drug manufacturers are able to update their drug labeling to reflect newly obtained safety information prior to FDA approval of the change. Under the proposed rule, generic-drug manufacturers would be able to update their product labeling to reflect new safety-related changes prior to FDA review, accelerating the dissemination of up-to-date safety information.

Over 80% of all prescription drugs dispensed in the United States are generic.¹ Generic drugs are bioequivalent to their brand-name counterparts and must be similar in dosage form, route of administration, strength, labeling, and indication.² To ensure safety and efficacy, the FDA requires generic-drug manufacturers to comply with the same quality standards and safety surveillance measures as brand-drug manufacturers.

On November 13, 2013, the FDA issued a proposed labeling rule to expedite the communication of new safety information regarding generic drugs to healthcare professionals and their patients. The proposed rule would provide generic-drug manufacturers with the same authority as brand-drug manufacturers to update safety information in the product labeling prior to the FDA’s review and approval of the change.¹

Generic-drug manufacturers must submit an Abbreviated New Drug Application (ANDA) in order to obtain FDA approval of a generic medication. The ANDA contains information supporting the bioequivalence of a generic drug to the corresponding brand-name medication or reference listed drug (RLD) and ensures that they are the same in regard to active ingredient, dosage form, route of administration, strength, labeling, and indication.² In addition, generic-drug manufacturing sites must meet the same requirements for quality and practice as brand-drug manufacturers. Both brand- and generic-drug manufacturers must also conduct postmarketing surveillance, evaluation, and reporting of adverse events to the FDA. However, only brand-drug manufacturers are able to update their drug labeling to reflect newly obtained safety information prior to FDA approval of the change. With a large percentage of dispensed medications being generic and the discontinuation of many brand-name medications following approval of a generic counterpart, the FDA now wants to provide generic-drug manufacturers with the ability to update their product labeling to reflect new safety-related changes even though this will result in temporary differences between the generic and corresponding brand labeling.¹

Current Labeling Rule

Current FDA guidelines require both brand- and generic-drug manufacturers to monitor and review drug safety information and expedite reports of new updates requiring changes to the product labeling. Under these regulations, generic-drug manufacturers may update safety information in their product labeling only after the FDA approves the update for the RLD. Brand-drug manufacturers, however, are authorized to promptly update and communicate new safety information through submission of a changes being effected (CBE-0) supplement to the FDA.³ CBE-0 supplements may be implemented when new safety information requires addition or strengthening of a contraindication, warning, precaution, or adverse reaction. Statements regarding drug abuse, dependence, psychological effect, or overdosage as well as dosage and administration and indications for use may also be updated through this method.² When generic-drug manufacturers receive new safety information requiring a change in product labeling, they must first notify the FDA of this information and then wait until the FDA and brand-drug manufacturer develop an updated product label. The resulting delay in communication underlies the need for a faster method to disseminate new safety information regarding generic medications.³

FDA Proposed Rule

Under the FDA’s proposed rule, generic-drug manufacturers would be able to change their product labeling to reflect new safety information independently of what is stated in the product labeling for its RLD and prior to FDA review of the change through a CBE-0 supplement.¹ Through the CBE-0 supplement process, temporary differences in product labeling will exist until the FDA reviews the proposed change and makes an approval decision, which will apply to both the generic and brand labeling. The generic-drug manufacturer will also be required to notify the brand-drug manufacturer of the proposed labeling change, including data supporting the change when the CBE-0 supplement is submitted to the FDA unless approval of the RLD has been withdrawn. This requirement ensures that the brand-drug manufacturer is aware of the new safety information warranting the change in the generic labeling. If approval of the RLD has been withdrawn, the FDA will consider the proposed labeling change for medications containing the same active ingredient. This proposed rule will provide generic-drug manufacturers the means to expedite the dissemination of newly acquired safety information to healthcare providers and patients.¹

To facilitate the communication of new safety changes in drug labeling and provide healthcare practitioners and patients access to information from CBE-0 supplements undergoing review, the FDA proposal includes a provision for the development of a website or adaptation of an existing FDA website that will be promptly updated with new information from submitted CBE-0 supplements.¹ The website will feature changes due to safety concerns proposed in CBE-0 supplements. This will include the active ingredient, brand name, application holder, supplement submission date, description and information supporting the proposed change, link to the current drug label updated with the changes being effected, and review status of the pending CBE-0 supplement. Healthcare providers and patients will be able to see if the CBE-0 supplement is still undergoing FDA review, has been approved, or has been determined to not meet the criteria for a labeling change. CBE-0 supplements would be available on the FDA website until the review process is completed and an action letter is issued.

If the proposed labeling change in the CBE-0 supplement is approved by the FDA, the final drug label will be available through a link on the website, which will transfer viewers to the FDA’s online label repository. After a sufficient amount of time to communicate the approval of the CBE-0 supplement and allowing for the submission of supplements by the corresponding brand-drug and other generic-drug manufacturers, the original supplement for labeling change will be archived. The approved drug label would continue to be available on the FDA’s online label repository at http://labels.fda.gov.¹

CBE-0 supplement submissions for changes in generic-drug labeling based on newly acquired safety information would be approved after approval of the same change in the corresponding brand-drug labeling.¹ Under current FDA guidelines, generic-drug manufacturers are required to update drug labeling to match the corresponding brand labeling “at the very earliest time possible.”⁴ To address the wide range of time frames in submission of conforming labeling, the proposed rule sets a 30-day deadline during that all generic-drug manufacturers must submit CBE-0 supplements with the same change in labeling after the FDA approves the CBE-0 supplement for the corresponding brand-name drug.

The proposed rule will also allow manufacturers to submit CBE-0 supplements for changes in the Highlights of Prescribing Information section of drug labeling, which includes boxed warnings and contraindications featured in the Physician Labeling Rule (PLR) format. Finally, the FDA proposal will revise current rules to allow for temporary differences between generic and corresponding brand labeling due to changes submitted in a CBE-0 supplement.¹

Concerns for New Proposal

While the FDA’s proposed rule will ensure new safety information is communicated to the public in a timely and effective manner, many drug manufacturers have concerns about some of the provisions.⁵ Many believe a majority of the proposed labeling changes will be implemented based on insignificant information obtained from spontaneous adverse event reports. In addition, the temporary differences between generic and corresponding brand-drug labeling may cause confusion as well as doubt in the therapeutic equivalence of generic drugs to their corresponding brand-name product. The current proposal does not set a time limit for FDA review and response to CBE-0 supplements, which could lead to extended periods of discrepancy between brand and generic labeling. There is also concern that multiple CBE-0 supplements addressing the same safety issue will be submitted.⁵

The FDA proposal was open to public comment until March 13, 2014.¹ Comments are currently being reviewed by the FDA and will be reflected in the final rule, which will be published in the Federal Register and become effective 30 days after the date of publication.²

Conclusion

The FDA’s proposal for labeling changes acknowledges the responsibility of both generic- and brand-drug manufacturers to efficiently review safety information for their medications and effectively communicate new updates to ensure that their products are accurately labeled and contain current information essential for prescriber assessment of risk versus benefit. The proposed rule would provide generic-drug manufacturers with the same authority as brand-drug manufacturers to update safety-related information in their product’s labeling prior to the FDA’s review and approval of the change.¹

In addition, generic-drug manufacturers will be responsible for relaying information about the new change to the corresponding brand-drug manufacturer. While the new regulation would permit differences to exist between brand- and generic-product labeling for a brief period of time, the proposed method will accelerate the dissemination of up-to-date safety information necessary for the adequate consideration of medication safety.³

REFERENCES

1. Woodcock J. Examining concerns regarding FDA’s proposed changes to generic drug labeling. FDA. April 1, 2014. www.fda.gov/NewsEvents/Testimony/ucm389606.htm. Accessed November 20, 2014.
2. FDA, HHS. Supplemental applications proposing labeling changes for approved drugs and biological products. Fed Regist. 2013;78(219):67985-67999.
3. Walsh S. FDA takes action to speed safety information updates on generic drugs. FDA. November 8, 2013. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm374171.htm. Accessed November 20, 2014.
4. FDA. Guidance for industry: revising ANDA labeling following revision of the RLD labeling. May 2000. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072891.pdf. Accessed November 20, 2014.
5. Levitt G. Submission of comment-supplemental applications proposing labeling changes for approved drugs and biological products (78 Fed Reg 67,985; Nov. 13, 2013). Pfizer Inc. March 13, 2014. http://bit.ly/1cUijSu. Accessed November 20, 2014.

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