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FDA Issues Draft Guidance On Updating Labels for Generic Drugs
Of Counsel, Greenblum & Bernstein, P.L.C.
The U.S. FDA recently issued a Draft Guidance for updating generic drug labeling in situations where an update in labeling is required, but the reference listed drug (the “RLD” or, colloquially, the brand-name drug) is no longer on the market. The Draft Guidance, entitled “Updating ANDA Labeling After the Marketing Application for the Reference Listed Drug Has Been Withdrawn, Guidance for Industry” (“Draft Guidance”), (published at 81 FR 44883) was posted 11 July 2016. 1
Background
“Labeling” 2 for drug products must conform to specific standards set by FDA. Those who have approval to market drug products, and those who seek approval from FDA (“applicants”) to market drug products have a continuing duty to ensure that the labeling for a drug product is accurate, and not false or misleading. 3 A drug is “misbranded” if its labeling information is false or misleading, or does not provide adequate directions for use or does not provide adequate warnings. 4 Therefore, when new information becomes available so that the labeling becomes inaccurate, false or misleading, the applicant must take steps to update its labeling. 5 The duty to update the label rests with the owner of the RLD dossier.
In general, FDA requires a generic drug to have the same labeling as the RLD. 6
Thus, when there are changes in labeling for the RLD, those marketing generic drugs (ANDA holders) are generally expected to update the labeling for the generic product accordingly. 7 However, it sometimes happens that the RLD is withdrawn and no longer marketed, while generic products remain on the market. In these cases, there have been questions regarding who has the duty to update labeling.
Draft guidance
The Draft Guidance describes a process for updating labeling for abbreviated new drug applications (ANDAs) in cases where FDA has withdrawn approval of the new drug application (NDA) for the ANDAs reference listed drug (RLD) for reasons other than safety or effectiveness. The Draft Guidance is pertinent to pending or approved ANDAs that rely on an RLD that has been withdrawn. FDA anticipates that the guidance will “help facilitate labeling updates for approved ANDAs as well as the approval of certain pending ANDAs where the NDA for the RLD has been withdrawn.” 8
ANDA holders and applicants have a responsibility to review relevant information on an ongoing basis, and to satisfy applicable reporting and labeling requirements raised by such information. FDA anticipates that the contemplated labeling changes would include any changes necessary to ensure that the labeling information is adequate to enable safe and effective use; that the information is accurate and meets current standards, and/or that the labeling is not false or misleading. The changes may also be based on data that have become available since withdrawal of the RLD.
The Draft Guidance specifically states that such labeling changes may be necessary to achieve consistency with the labeling of other products that have the same active ingredient, or an active ingredient in the same pharmacologic or therapeutic class, or with the labeling of other products approved for the same indication. Other appropriate situations include the correction of outdated information relating to previously approved indications, or to conform to other applicable regulations, guidelines, or another guidance. 9
The Draft Guidance provides specific examples of contemplated labeling updates, such as
10
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“Updating the indication statement in the INDICATIONS AND USAGE section to reflect current disease terminology (e.g., changing ‘Juvenile Rheumatoid Arthritis’ to ‘Juvenile Idiopathic Arthritis’) or to modify the description of an outdated restriction on the use of the drug in specific situations.” “For parenteral products, including the following required statement or appropriate modification in the DOSAGE AND ADMINISTRATION section: ‘Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit’ (21 C.F.R. § 201.57 (c)(3)(iv)).” “Removing a risk from the CONTRAINDICATIONS section if the benefit outweighs the risk of use in the situation or subpopulation (e.g., the risk is theoretical) (see 21 CFR 178 201.57(c)(5)).” “Revising the ADVERSE REACTIONS section to include a new adverse reaction based on postmarketing experience.” “Revising the ADVERSE REACTIONS section to include the following recommended statement or appropriate modification before the presentation of adverse reactions from spontaneous reports: The following adverse reactions have been identified during postapproval use of drug X. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.” “Adding a new clinically significant drug interaction in the DRUG INTERACTIONS section based on postmarketing data showing that a newly approved product interacts with the active ingredient in the ANDA product or with products in the ANDA product’s class.” “Revising the OVERDOSAGE section to include overdose management strategies that are consistent with current Poison Control recommendations.”
These are, of course, merely exemplary, and other similar changes should be made as applicable.
The actual updating of the labeling information will be done as provided by the FDA in the normal course of business. Thus, ANDA holders may submit any contemplated labeling updates through the submission of a Prior Approval Supplement (“PAS”). If FDA determines that a change is appropriate, the FDA may request other ANDA holders/applicants to make the same updates, thereby ensuring that labeling remains uniform across generic drugs that rely on the same RLD. FDA may also request changes on the basis that it has determined such changes are needed.
Conclusion
Comments were scheduled to be submitted to FDA by 9 September 2016. The Guidance (once final) would detail when and how generic drug companies should update their labeling information in the foregoing circumstances. The guidance discussed herein is in draft form, and when finalized 11 will represent the position of the FDA. Such guidance documents are not binding on the FDA or the public, but generic companies would do well to either go by the Guidance, or else use an alternative procedure that furthers the same policy and result.