Generic Safety Labeling: FDA’s new regulation – Part 1

Nov 13, 2013
Bart Cobert

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

On November 8, 2013 FDA published an announcement in the Federal Register regarding new labeling requirements for generic drugs.  (See It was officially published November 13, 2013.  There will be a 60 day comment period and then, presumably, FDA will make the regulations final and they will take effect – probably early to mid 2014 unless heavy responses and lobbying occur.

This is a complex and litigious area and we will review the current labeling situation and the new proposals in two postings.  In this posting, we’ll review the current situation.

Following much discussion and lobbying and court cases, the FDA is changing the regulations that forbid generic manufacturers from changing their own  products’ safety labeling unless the reference branded drug label is changed.  That is, the generic versions of branded drugs had to use essentially the same label as the brand label.  This posed lots of issues in terms of liability and who could be sued.    In a sense, this tied the hands of the generic drug companies and they could not make label changes for safety unless the brand did.  This meant that the generic houses would collect SAEs and AEs and report them to FDA in their PADERs (or rarely PSURs) and could signal but could not change the label.

What this translated to was that pharmacovigilance was often minimal at generic houses.  Since most consumers and physicians did not pay much attention to the manufacturer when they took or prescribed, respectively, generic products, few SAEs/AEs were reported to the manufacturer or FDA.  Most people took the view, usually unwisely, that a generic is a generic is a generic.  This also meant that the PADERs and PSURs rarely contained many SAEs/AEs but did have literature cases.  And if there are two dozen generic versions of a product on the market FDA would get two dozen PADERs summarizing the same literature with few SAEs/AEs

The new regulation will change this significantly.

The Current Situation

Under current regulations, NDA and ANDA holders may, with the appropriate data and evidence add or strengthen a contraindication, warning, precaution, adverse reaction, a statement about drug abuse, dependence, psychological effect, or overdosage, dosage and administration that is intended to increase the safe use of the drug product and delete false, misleading, or unsupported indications for use or claims for effectiveness.

When such a label change proposal is submitted to FDA, the agency will review it and if the information “changes the benefit/risk balance of the drug,” FDA will take appropriate action including approving the label change.

When a branded manufacturer feels it needs to change its labeling, particularly for “substantive” changes, the NDA holder must submit a prior approval supplement to FDA and the FDA must approve it before it can be put in place.  An exception to this is that certain safety information (as noted above) can be changed more or less immediately without prior FDA approval.  These are called “changes being effected” supplements (CBE-0 supplements) and the changes may be implemented upon receipt of the request by FDA.  FDA will still review the changes and may require that they be modified, withdrawn etc.  This was done as a public health measure to ensure that now important safety information is delayed and reaches the public asap.  Companies now do this to avoid being accused (and sued) for sitting on important safety information and putting patients at grater risk.

Generic drugs are approved either through an ANDA or a “petitioned ANDA” (a type of ANDA used where the generic drug differs from the branded drug in dosage form, route of administration, strength, or active ingredient but which FDA determines does not require new clinical studies for safety and efficacy). In either case, the drug is determined to be therapeutically equivalent to the reference branded drug and have basically the same labeling.

If the generic company feels safety information should change based on new data, it sends this information to the FDA which will then decide whether to change the labeling for all the generic drugs and the reference brand.  This does not occur frequently.

Originally, FDA felt it was important that the generic and branded drugs have the same labeling as they were equivalent.  The view now at FDA is: “In the current marketplace, in which approximately 80 percent of drugs dispensed are generic and, as we have learned, brand name drug manufacturers may discontinue marketing after generic drug entry, FDA believes it is time to provide ANDA holders with the means to update product labeling to reflect data obtained through postmarketing surveillance, even though this will result in temporary labeling differences among products.”

Nonetheless, the generics (and the branded company) must “promptly review all adverse drug experience information obtained or otherwise received by the applicant from any source, foreign or domestic, including information derived from commercial marketing experience, postmarketing clinical investigations, postmarketing epidemiological/surveillance studies, reports in the scientific literature, and unpublished scientific papers” submit expedited and aggregate reports and propose label changes as appropriate.

Court Cases

This labeling situation has produced very complex legal issues.  Broadly speaking, (I’m not a lawyer so this is my layman’s view), there was a contradiction between federal and state law.  State law basically says that the manufacturer is responsible for the contents of its label (whether generic or branded) and the label should be complete and have all the appropriate safety and warning information.  However, the federal law prevents the generic manufacturer from changing the label to be complete and have the appropriate safety and warning information without going through the complex submission to FDA.

So the question was whether the federal law or the state law applied.  Lawsuits filed by patients harmed by drugs claimed that the state law applied and generic companies were guilty of “failure to warn” in their labeling.  This went to the US Supreme Court and after two major cases (see the above URL for a more detailed review), the upshot is that “an individual can bring a product liability action for failure to warn against an NDA holder [the branded manufacturer], but generally not an ANDA holder [the generic manufacturer], and thus access to the courts is dependent on whether an individual is dispensed a brand name or generic drug.”

The FDA then coyly states that this decision “alters the incentives for generic drug manufacturers to comply with current requirements to conduct robust postmarketing surveillance, evaluation, and reporting, and to ensure that the labeling for their drugs is accurate and up-to-date.”  This is a gentle way of saying that there is little incentive for generic houses to do robust drug safety and PV.

There has been a lively discussion (and some heavy lobbying) about this and now the FDA is proposing these regulation changes to ensure that generic drug companies “actively participate with FDA in ensuring the timeliness, accuracy, and completeness of drug safety labeling in accordance with current regulatory requirements.”  That is, generic houses now have to do serious drug safety, PV, signaling and actively (proactively) ensure that their labels are correct and up to date in regard to safety.  This will create “parity between NDA holders and ANDA holders” regarding “safety related labeling changes based on new information.”

The Proposed New Regulation

The proposed new regulation has several components:

  • Equality for NDA and ANDA holders on “Changes Being Effected”

The obligation to keep labeling accurate and up to date now covers NDA and ANDA holders.

Now, if both generic and branded houses, while doing their pharmacovigilance, find new important safety information, they may submit a CBE-0 supplement to change the labeling.  The generic company may also send out Dear HCP letters as branded houses do.  If additional communications are required (e.g. by FDA) under a REMS that is in place, this too may be done.

There are implications.  The labels will start to diverge and there will be differences (at least temporarily) between the brand and the generics and between generics and generics.  FDA acknowledges that this can get messy and that, realistically, HCPs are not likely to review product labeling for each generic drug!  To (hopefully) help diminish the problems this brings, FDA is going to set up a web page on to promptly post this new information.  There will be a free email subscription service available to get new postings.

FDA expects that once a new submission for a CBE-0 change is done by one generic it will be followed by a similar request by the brand and by the other generics.  FDA notes a rather elaborate mechanism to keep everyone up to date on the status of the new submissions by other companies will be in place and implies that this is a bit klunky.  This is the case since there may be multiple proposals, submissions and differing labels in place for a product at the same time with changes possibly occurring daily. FDA also has to keep the on-line labeling repository up to date (  FDA “invites comment on this approach”.  There are other regulatory (bureaucratic) complexities involved such as the submission of final printed labeling in structured product labeling format at the time of submission of the CBE-0 supplement.  See the URL for more detail on this.

The FDA is also proposing to require that the company that has submitted its supplement verify that the information that FDA posts’ on its web page is correct! If it isn’t the company must contact the FDA within 5 business days.  That is, the company is now doing QA for the FDA!

  • Notification of the NDA (branded) holder

The generic company submitting the label change supplement must also notify the branded NDA holder of its submission and send a copy of the information such as SAEs, literature reports etc. supporting the change (redacting personally identifiable information) to the NDA holder.  The NDA holder will then evaluate this information and, since the NDA holder has much more information than the generic houses, and send information and or comments and or a label change proposal to FDA.  The agency again coyly states “FDA’s analysis of whether the labeling change proposed by an ANDA holder in a CBE-0 supplement should be approved (and required for inclusion in the labeling of all versions of the drug) would benefit from the views of the NDA holder…”.  It does not appear that the other generic houses will get the source information that the NDA holder gets.  This will probably prove to be controversial and I would expect a lot of comments on this.

FDA also expects other generic houses to carefully track the web page and submit their own CBE-0 supplements to FDA regarding a pending supplement from another generic house.

FDA has a proposed flow chart describing this:

Generic Labeling Image 1


It gets more complex however.  FDA notes that it “is expected that a valid safety concern regarding a generic drug product also would generally warrant a change to the labeling…by the NDA holder for the RLD and, as a consequence, other generic drug products that reference the RLD. In the event that the NDA holder for the RLD does not submit a…FDA may send a supplement request letter to the NDA…” So if FDA doesn’t get a prompt request from the branded company to change the labeling, it may ask that company to do so.

FDA further says that based “on our experience, we expect that NDA holders will implement safety-related labeling changes requested by FDA even if not required” to do so.  “…if the NDA holder declined to submit a supplement to make the change that FDA has concluded is appropriate, FDA would consider whether the NDA holder’s failure to update its labeling would warrant the initiation of proceedings to withdraw approval of the NDA.” (emphasis added).

FDA also notes that if the branded company has stopped marketing the drug and the NDA is still open, then the branded company must continue to update its label as noted in this regulation.

FDA also notes that if the agency does not approve a CBE-0, the manufacturer must cease distribution of the product with the revised labeling.

If FDA does approve a CBE-0 supplement and if it applies to all generics, they will now have 30 days to submit their own CBE-0 supplement for conforming label change rather than “at the very earliest time possible”.

If there is a single shared REMS in place, this may alter timing of these requirements.

These new requirements will also apply to the Highlights section of the labeling which now may also be changed by this procedure.

In the next posting, we will look at the implications of this.

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