The US Food and Drug Administration's (FDA) ambitious attempt to allow generic drug manufacturers to temporarily update their labeling to reflect newly discovered safety risks has unleashed the wrath of dozens of Republican lawmakers, who say the proposed rule is illegal.

Background

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).

Is This Even Legal?

But almost as soon as the rule was released, several experts began to claim that it was likely illegal.

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."

Not quite, said several legal experts, who said nothing in the Hatch Waxman Act allows deviations from the "sameness" requirements of the law on the scope FDA has proposed.

"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," James Beck of the law firm Reed Smith wrote in an online posting.

FDA is also explicitly not permitted to change the "Warnings" section of the labeling, Beck said.

Several other experts consulted by Focus raised similar points, while others said the rule could actually fuel lawsuits against generic manufacturers and branded drug companies by forcing them to acknowledge drug risks and pick preferred labeling changes.

Perhaps sensing the firestorm of controversy it had unleashed, FDA moved in December 2013 to give members of industry more time to comment on the proposed rule, saying they now had until 13 March 2014 to submit comments. The notice was somewhat unusual in that FDA was extending the comment period before the existing one had ended. It most often extends the comment period after the existing one has ended.

Congressional Scrutiny

But now FDA has a major obstacle in its way to finalizing the rule: Nearly all the Republican members of Congress with legislative authority over the agency.

In a sharply worded and unambiguous letter sent to FDA Commissioner Margaret Hamburg on 22 January 2014, Republican members of the House Energy and Commerce (E&C) Committee and Senate Health, Education, Labor and Pensions (HELP) Committee said the rule "would conflict directly with the statute, thwart the law's purposes and objectives, and impose significant costs on the drug industry and healthcare consumers."

"It is important that we fully understand how FDA came to this decision and what impact the agency believes such an approach would have on patients and providers," said Fred Upton, chairman of the House E&C Committee. "For years, the 'sameness' requirements have made it easier for both patients and providers to understand the benefits and risks, providing peace of mind and encouraging competition in the generic drug market. The proposed changes by FDA raise a number of concerns and potentially significant costs that FDA needs to explain to Congress and the American people."

The letter goes on to list eleven questions which seem geared toward calling into question both the appropriateness and need of FDA's proposed rule. For example, legislators asked if FDA had considered alternatives or had considered the impact of the rule on various types of drugs. Legislators also seemed skeptical about FDA's cost estimates of the program, which FDA pegged at between $4,237 and $25,852.

"No explanation is given as to how the FDA derived such a low estimate," the legislators wrote.

Hamburg has until 5 February 2014 to reply to the letter, per the legislators' request.

It remains to be seen how Hamburg responds, but given near-unanimous pushback from industry and now a block of influential legislators, FDA's generic drug labeling rule is either dead in the water or headed toward a rocky rollout and likely legal challenges.

 

E&C Press Statement and Letter

HELP Committee Statement