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Posted 08 July 2016 | By Zachary Brennan 

Generic Drug Labels: FDA Offers Draft Guidance on Updates After Reference Products are Withdrawn


The US Food and Drug Administration (FDA) on Friday released draft guidance describing the process for drug companies when they have to update a generic’s label after the reference product (for which the generic is based) is withdrawn for reasons other than safety or effectiveness.

The guidance focuses on a problem that has long plagued the generic industry, as generic labels are required by law to mirror their reference product counterparts at the time of approval but sometimes rely on drugs that have been withdrawn for economic reasons.

Most recently, FDA pushed back its finalization of a rule (to April 2017) that would require generic drugmakers to update labels when safety events become known and ahead of FDA’s acceptance of such label changes, as brand name companies have done for three decades. Congress, however, has been looking to force FDA to re-write the rule.

But as FDA notes in Friday’s draft guidance, the agency seems intent on ensuring that both new drug application (NDA) and abbreviated new drug application (ANDA) holders update labels as quickly as possible when new safety events become known.

“As a general matter, all holders of marketing applications for drug products (both NDAs and ANDAs) have an ongoing obligation to ensure their product labeling is accurate, and not false or misleading. When new information becomes available that causes the labeling to become inaccurate, false or misleading, the application holder must take steps to update its labeling,” FDA says.

New Draft Guidance

And unlike the proposed rule, this latest 12-page draft guidance offers more information for generic companies that can no longer rely on their reference listed drug’s (RLD) label.

“Where approval of an NDA RLD has been withdrawn, the NDA holder can no longer update labeling for the withdrawn RLD. The labeling of ANDAs that rely on the withdrawn RLD might eventually become inaccurate and outdated, resulting in labeling that is false and/or misleading, for example,” FDA explains.

Similarly, new original ANDAs that rely on the withdrawn RLDs might include proposed labeling based on the last approved RLD label and include outdated information, FDA warns.

This draft guidance “clarifies that consistent with the statute, where the RLD is withdrawn, certain labeling changes may continue to be made for

pending ANDAs and marketed ANDAs. This draft guidance sets forth a process for making such changes.”

Proprietary Data?

ANDA holders are responsible for reviewing postmarketing data and published literature to satisfy applicable reporting requirements FDA says, though the agency also notes that it, as well as ANDA holders and applicants, “may be aware of data relevant to labeling updates in a variety of situations. For example, relevant data may already be reflected in the updated labeling of other drugs in the same pharmacologic or therapeutic class (e.g., class labeling); in non-product specific literature; or in postmarketing information.”

However, FDA makes clear that the “updates contemplated by this guidance generally would not involve reliance on product-specific, proprietary information about another drug. Any changes proposed under this guidance must be consistent with the requirement that an ANDA include sufficient information to show that the conditions of use have been previously approved for the RLD.”

Examples of when labeling changes under this guidance may be needed, include:

  • 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, where appropriate
  • To correct outdated information related to a previously approved indication
  • To achieve consistency with applicable regulations and current FDA labeling guidelines

FDA adds that examples of updates “contemplated by this guidance” might also include (the list is not intended to be exhaustive):

  • Updating the indication statement 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 a drug in specific situations
  • For systemic antibacterial drug products, including the required statement about antimicrobial resistance in the "Indications and Usage" section
  • 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.”
  • 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)
  • Revising the "Warnings and Precautions" section of a label to include current steps to prevent, mitigate, monitor for, or manage a clinically significant adverse reaction or risk
  • Revising the "Adverse Reactions" section to include a new adverse reaction based on postmarketing experience, or 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 or with products in the ANDA’s class
  • Revising the "Overdosage" section to include overdose management strategies that are consistent with current Poison Control recommendations.
  • For systemic antibacterial drug products, updating susceptibility test interpretive criteria, susceptibility test methods, and quality control parameters in the "Microbiology" subsection of the "Clinical Pharmacology" section.
  • Making changes to keep up to date with class Medication Guides (e.g., if there is a class Medication Guide for nonsteroidal anti-inflammatory drugs (NSAIDs), all ANDA NSAID products -- including those with withdrawn NDA RLDs -- should have the current version of the class NSAID Medication Guide)
  • Making changes requested by FDA prior to withdrawal of an NDA RLD that are determined to be necessary for safe and effective use.

ANDA holders can submit any labeling updates contemplated by this guidance through the submission of a prior approval supplement (PAS), FDA says.

“If FDA determines that a change proposed in this manner is appropriate and approves the supplement, the Agency may request that other ANDA holders and any ANDA applicants relying on the same withdrawn RLD make the same updates, where appropriate. This latter step is intended to ensure that labeling remains uniform across generic drugs that rely on the same RLD,” the draft says.

Comments on the draft can be submitted over the next two months. 

Updating ANDA Labeling After the Marketing Application for the Reference Listed Drug Has Been Withdrawn: FDA Draft Guidance for Industry


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