Regulatory Focus™ > News Articles > Experts: FDA's Generic Drug Labeling Rule Likely Illegal

Experts: FDA's Generic Drug Labeling Rule Likely Illegal

Posted 15 November 2013 | By Alexander Gaffney, RAC

The US Food and Drug Administration's (FDA) recent proposal to overhaul the manner in which generic drug manufacturers may update the safety warnings on their labels may be receiving warm praise from some legislators and industry watchers, but it might not be legal, say several legal experts.


Generic drugs are those approved under the 505(j) pathway of the Federal Food, Drug and Cosmetic Act (FD&C Act) and submitted to the agency through an abbreviated new drug approval (ANDA) application. Once an existing drug's marketing and patent exclusivity has expired, generic drug manufacturers can file an ANDA with FDA to approve their drug based on safety and efficacy data from the original drug their application references, also known as the reference-listed drug (RLD). Instead of conducting new trials, they are required to submit data, such as bioequivalence data, showing that their drugs are for all intents and purposes identical to the RLD.

If approved by FDA, the drugs are required to contain the exact same labeling with respect to the claim for which they obtained approval. For example, if the RLD contains a warning that the drug could cause a heart attack, the generic drug would be required to list that side effect as well.

However, this labeling paradigm does not work both ways. Under present statutes and regulations, if a generic drug manufacturer is made aware of a risk that is not present on the RLD, they are not able to unilaterally update the label on their drug. Instead, they must ask the owner of the RLD (if they even still exist, which is not always the case) to do so on a voluntary basis, or can petition FDA to update the label. While the Supreme Court has ruled in two cases that this restriction shields generic companies from legal liabilities, public health advocates and FDA have expressed their concern that this asymmetry in labeling authority could harm patients.

As a result, FDA recently proposed granting generic drug manufacturers the authority to update their safety labeling on a unilateral basis using a changes being effected 0-day (CBE-0) application. The application essentially allows a company to immediately make changes to a label while FDA reviews it for appropriateness.

FDA's proposed regulation would leave a temporary discrepancy between the labeling of the RLD and its generic competitor(s), but said changes would eventually be harmonized for both the RLD and the generic(s).

Potential Problems

As Focus wrote earlier this week, the proposed rule has received a range of responses. While some have been warm, others have pointed to potential problems with it. For example, the US Chamber of Commerce has said it would open generic manufacturers to potentially massive legal liabilities under so-called "Failure to Warn" statutes, and would create confusing differences between branded drugs and their generic competitors.

But according to several legal experts, the proposed rule may have a much more fundamental flaw: It might not be legal.

In its proposed rule, FDA cites legal authority from the FD&C Act (21 USC 301) and the Public Health Service Act (PHS Act, 42 USC 201), both of which provide FDA with the legal authority to regulate drug products and their labeling. FDA said that FD&C Act Section 502 allows it to consider a drug misbranded if it bears inadequate directions for use or insufficient warnings. It also claims authority under Section 701 to regulate CBE supplements and their use.

Notably, the agency also makes the following contention: "Nothing in the Hatch-Waxman Amendments or subsequent amendments to the FD&C Act limits the Agency's authority to revise the CBE-0 supplement regulations to apply to ANDA holders to help ensure that generic drugs remain safe and effective under the conditions of use prescribed, recommended, or suggested in the labeling throughout the life cycle of the generic drug product."

Beck: 'Simply Not True'

Not quite, said several legal experts.

"The trouble is, this global 'nothing in Hatch/Waxman' statement is simply not true," wrote James "Bexis" Beck of the law firm Reed Smith. "The 'sameness' requirement that underlies preemption is in the statute, and is unique to generic drugs."

Beck continued that the statute requires that information in the labeling proposed for the ANDA "is the same as the labeling approved for the listed drug," minor (and statutorily defined) differences notwithstanding.

"Hatch/Waxman thus does not confer any right upon an ANDA applicant to submit any generic drug with labels that differ/are-not-the-same in ways that affect the safety and effectiveness of that drug," Beck added, further noting that FDA is also explicitly not permitted to change the "Warnings" section of the labeling.

"[The law] prohibits revisions that seek to change 'warnings' - which is precisely what the CBE provisions involved in the current proposal purport to do," he continued. "Several maxims of statutory construction would seem to preclude the FDA from doing what it seeks to do here."

HPM: 'Sameness' Confusion

Hyman, Phelps & McNamara's Jennifer Thomas raised similar, though less specific, concerns in a posting on the company's FDA Law Blog on 12 November.

"Given the serious questions surrounding [FDA's authority], this Proposed Rule seems as likely to go the way of the dodo as to ultimately be finalized," she wrote.

Calling such concerns "unavoidable," Thomas observed that generic drug statute "requires applicants for generic drug approval to provide 'information to show that the labeling proposed for the new drug is the same as the labeling approved for the listed drug . . . except for changes required because of difference approved under a [suitability petition], or because the new drug and the listed drug are produced or distributed by different manufacturers.'" 

FDA, she noted, seemed to be attempting to get around this point by waiting to approve the labeling-hence the CBE-0 application-avoiding the statute's requirement of "sameness" in the drugs' respective labels.

Pollack: 30 Years to Get Here. Now What?

Bob Pollack, a senior advisor with the generic drug-focused consultancy Lachman Consultants, also called attention to this point. In postings on the company's blog and at Pharmalot, Pollack pointed to the preamble to FDA's 1992 ANDA regulation, which states: "FDA reminds applicants that the labeling for an ANDA products must be the same as the labeling for the listed drug product except for differences due to different manufacturers."

Asked Pollack, "[H]ow does the FDA propose to ignore the statutory requirement for sameness of labeling?"

"It took 30 years to get to the Mensing decision - a clarification consistent with the Hatch-Waxman Statute and the regulatory framework that was 'hatched' from a delicate balance of the rights and responsibilities of the brand and generic industry in turn for certain period of patent and market exclusivity," Pollack concluded. "Let's make certain we don't create a bigger problem when trying to solve one that might have a more simplistic solution."


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