Regulatory Focus™ > News Articles > FDA Proposes Groundbreaking Overhaul of Generic Drug Labeling Regulation

FDA Proposes Groundbreaking Overhaul of Generic Drug Labeling Regulation

Posted 11 November 2013 | By Alexander Gaffney, RAC

In a long-awaited announcement, the US Food and Drug Administration (FDA) has announced that it will permit generic drug manufacturers to unilaterally update the labeling on their drugs in light of new safety risks even if the labeling of its reference-listed drug (RLD) in the Orange Book had different safety warnings.


Under the Federal Food, Drug and Cosmetic Act (FD&C Act), generic drug products must-with minor exceptions-adhere exactly to the FDA-approved labeling borne by the drug it references in its 505(j) application, otherwise known as an abbreviated new drug application (ANDA).

In theory and practice, this is to ensure that generic drug manufacturers don't seek to take shortcuts in the drug approval process, or downplay safety risks associated with a drug. But it has also meant that some generic drug manufacturers, aware of rare safety risks not currently reflected in the labeling, have been unable to update their own labeling, potentially opening them up to legal liabilities.

This was most notably seen in the cases of Mutual Pharmaceuticals v. Bartlettand Pliva v. Mensing, two cases decided by the Supreme Court in 2013 and 2011, respectively.

The Bartlett case involved a plaintiff who was prescribed the generic NSAID Clinoril (sulindac) to treat shoulder pain. Clinoril was manufactured by Mutual Pharmaceutical. Soon after taking the drug, the plaintiff suffered what the court described as an "acute case of toxic epidermal necrolysis," severely and permanently disfiguring and nearly blinding her.

Notably, the label did not include a warning about the possibility of the condition that the plaintiff suffered. Lower courts found Mutual guilty of a failure to warn charge, and awarded the plaintiff $21 million in damages, but the Supreme Court overturned that ruling, saying that generic companies were under no such obligation to either warn or remove their products from the market.

The case was widely seen as further enforcing the Mensing decision, which came to a similar conclusion in a similar case.

Calls for Change

But in the wake of the decision, consumer advocates and legislators sounded the alarm. How could consumers be adequately protected from risks if the companies were under no obligation to warn them? Some were especially concerned that if the original new drug application (NDA) holder had gone out of business, the generic company would effectively have no way to update the label.

FDA regulators appeared to agree with that assessment. In July 2013 they released their yearly regulatory agenda, which contained an announcement that they would soon propose a rule entitled "Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products."

FDA said the proposed rule "would describe the process by which information regarding a 'changes being effected' (CBE) labeling supplement submitted by an NDA or ANDA holder would be made publicly available during FDA's review of the labeling change."

In addition, the proposed rule would also "clarify requirements for the NDA holder for the reference listed drug and all ANDA holders to submit conforming labeling revisions after FDA has taken an action on the NDA and/or ANDA holder's CBE labeling supplement," FDA wrote. "These proposed revisions to FDA's regulations would create parity between NDA holders and ANDA holders with respect to submission of CBE labeling supplements."

New Rule

On 8 November 2013, FDA finally released that proposed rule, saying it would have a broad benefit for consumers.

At its most basic, the rule allows generic manufacturers to immediately issue a labeling change for reasons related to safety under a CBE-0 application. This then puts the onus onto FDA to find a reason why the labeling change should not be made. If such a reason is found, FDA may order the labeling change to be reversed or otherwise altered.

FDA's intent, it said, is to permit differences to exist between the NDA and the ANDA on a "temporary basis."

ANDA holders would need to send the NDA holder both the labeling change and a copy of the information supporting the change.  This requirement is waived if the original NDA has been withdrawn, but would otherwise "ensure that the NDA holder for the RLD is promptly advised of the newly acquired information that was considered to warrant the labeling change."

Any changes would affect both the generic and RLD owners' labeling, FDA said.

Generic drug manufacturers would also be able to distribute "Dear Health Care Provider" letters

FDA said it would create a Web page dedicated to posting information regarding the CBE-0 labeling supplements. Other changes could be submitted using a prior approval supplement (PAS).

In addition, FDA said under the proposed regulation it would be able to withdraw generic drugs if the labeling "is no longer consistent with the labeling for the RLD, subject to certain exceptions."

Change Philosophy

So why the change? "At the time of FDA's adoption of the generic drug regulations in 1992, FDA believed it was important that product labeling for the RLD and any generic drugs be the same to assure physicians and patients that generic drugs were, indeed, equivalent to their RLD," FDA explained. However, as the generics market has matured, there has come a need to keep the public aware of potential safety issues as well, FDA said.

"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."

Potential Problems

Both FDA and outside groups have already noted potential problems with the policy.

FDA, for example, has said there could be potential confusion if multiple generic manufacturers submit CBE-0's at the same time for different issues. Healthcare providers in particular might be inclined to ignore a bevy of notifications about pending changes.

Other groups, such as the US Chamber of Commerce-a powerful Washington trade group which advocates on behalf of business interests-said the change would create new liability standards for generic drug manufacturers under the same failure-to-warn standards that have resulted in huge fines for many branded drug manufacturers.

"The proposed change would make warning labels inconsistent and confusing for consumers. It would also force generic manufacturers to conduct costly research and create a structure to assess their labels, which would in turn lead to higher drug costs," the Chamber added.

One of the more interesting questions: What happens if a generic drug company is made aware of an issue, petitions FDA to change the label, but FDA refuses? Could this open the company up to a failure-to-warn challenge, or would the federal preemption standard established under Mensing and Bartlett still hold?

Yet another problem could lie in potential differences between the generic and the RLD. FDA has recently grappled with differences between Wellbutrin and its generics, resulting in several generics being pulled off the market for not being bioequivalent. Some branded manufacturers have complained that problems with generic manufacturers' products could, by extension, become theirs as well.

Whatever their reaction, members of industry and the public have 60 days (on or about 13 January 2014) in which to submit comments to FDA.

Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products

FDA Voice Blog

FDA Press Statement

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