Reporting Changes to FDA Approved Drugs

For an FDA-approved drug, you tell FDA about every change to the conditions in the approved NDA. Each change goes through one of three routes, depending on how likely it is to harm the identity, strength, quality, purity or potency of the drug: a prior approval supplement (major change), a 30-day or immediate "changes being effected" supplement (moderate change), or the next annual report (minor change). These rules are in 21 CFR 314.70 ^[1]. Generic drugs (ANDAs) follow the same rules through §314.97 ^[2]. Biologics (BLAs) have their own parallel rule, 21 CFR 601.12, covered at the end.

Approach: I read 21 CFR Part 314 (current eCFR text) in our datasets. I took 21 CFR 601.12 from the official eCFR and the CDER guidance from FDA's website.

General duties (§314.70(a)) ^[1]

• The applicant "must notify FDA about each change in each condition established in an approved NDA beyond the variations already provided for in the NDA," and the notice must "describe the change fully."
• Before distributing product made with a manufacturing change, the NDA holder "must assess the effects of the change."
• If a regulation or guidance allows a less burdensome way to report a change, you "must" use it.
• You must promptly bring promotional labeling and advertising into line with any labeling change.
• Every supplement or annual report must list all the changes it contains.

The three routes

Category	Risk to identity, strength, quality, purity or potency	When you can distribute	Examples in the rule
Prior approval supplement, §314.70(b)	"Substantial potential" for an adverse effect	Only after FDA approves the supplement	Formulation or specification changes; changes needing part 320 bioequivalence studies; changes affecting sterility assurance; drug-substance synthesis changes that may affect impurity profile; most labeling changes; some container closure changes; cell line or master cell bank changes
CBE-30 supplement, §314.70(c)	"Moderate potential"	No sooner than 30 days after FDA receives the supplement	Container closure changes that don't affect quality; some protein-product scale or equipment changes; relaxing an acceptance criterion to comply with a compendium
CBE-0 supplement, §314.70(c)(6)	Categories FDA has designated	When FDA receives the supplement	Tightened specifications or controls; some safety labeling changes based on newly acquired information
Annual report, §314.70(d)	"Minimal potential"	Already implemented; described in the next annual report	Compendial changes; replacing equipment with the same design; shelf-life extension under an approved protocol; editorial labeling changes

All rows cite ^[1].

What each route requires:

• Prior approval supplement: it must contain:

  • a detailed description of the change;
  • the products and manufacturing sites affected;
  • the methods and studies used to assess the change, and their data;
  • validation protocols and SOP lists, for protein products and for sterilization changes.

  You can ask for faster review, for public health reasons or extraordinary hardship, by marking the supplement "Prior Approval Supplement-Expedited Review Requested."

• CBE-30 and CBE-0: label the supplement "Supplement—Changes Being Effected in 30 Days" or "Supplement—Changes Being Effected." Explain the basis for the change and give the date it will be made. You "must not distribute" if, within the 30 days, FDA says the change needs prior approval or that information is missing. If FDA disapproves the supplement, it may order you to stop distributing product made with the change.

• Safety labeling under CBE-0, §314.70(c)(6)(iii): this covers labeling changes based on newly acquired information that do any of the following:

  • add or strengthen a contraindication, warning, precaution or adverse reaction;
  • add or strengthen statements on abuse, dependence or overdosage;
  • add or strengthen dosing instructions that increase safe use;
  • delete unsupported claims.

  Changes to the Highlights information required by §201.57(a) can't go this route; they need prior approval.

• Annual report content: the report must include:

  • a statement that the effects of each change were assessed;
  • a full description of each change and the sites involved;
  • the date each change was implemented;
  • supporting data.

Comparability protocols, §314.70(e): you can submit a protocol for specified types of manufacturing changes as a prior approval supplement. Once it is approved, it "may subsequently justify a reduced reporting category" for those changes ^[1].

Filing the supplement and related limits

• Only the applicant may submit a supplement. It follows the §314.50 application procedures, but only needs the information that supports the change ^[3].
• A 505(b)(2) NDA can't be supplemented to cover a "different drug," meaning a different active ingredient, route, dosage form, or certain excipient differences. A new strength is allowed ^[1].
• An ANDA can't be supplemented to switch to a different reference listed drug; that needs a new ANDA. A new strength is allowed ^[2].
• If you claim exclusivity for a supplement, include the §314.50(j) information, and meet the §314.53 patent information requirements ^[1].

Other postmarketing reports, §314.81 ^[4]

• Annual report: due "within 60 days of the anniversary date of U.S. approval," with Form FDA 2252. Among other items, it includes:
  • a summary of labeling changes;
  • a full description of manufacturing and controls changes that didn't need a supplement under §314.70(b) or (c), listed by date implemented;
  • status reports on postmarketing study commitments.
• NDA Field Alert Report: due to the FDA district office "within 3 working days of receipt." It covers mix-ups of the product or its labeling, bacterial contamination, significant deterioration, or distributed batches that fail specifications.

FDA guidance

CDER's final guidance Changes to an Approved NDA or ANDA (Revision 1, April 2004, docket FDA-1999-D-0049) recommends reporting categories for changes to:

• components and composition;
• manufacturing sites;
• manufacturing process;
• specifications;
• container closure system;
• labeling;
• miscellaneous changes and multiple related changes.

It applies to drugs other than specified biotechnology and synthetic biological products.

Biologics (BLAs), 21 CFR 601.12

The eCFR text of §601.12 uses the same three tiers: prior approval, CBE-30/CBE, and annual report. It also covers changes in "responsible personnel." Its differences from §314.70:

• Annual-report changes are filed within 60 days of the approval anniversary.
• Labeling has its own paragraph, §601.12(f). Safety labeling changes go as a "Special Labeling Supplement—Changes Being Effected."
• After repeated failure to comply, FDA may require prior approval for any change.