In November 2013 the FDA put forth a proposed rule allowing generic drug makers to use the same process as brand drug manufacturers to update safety information in product labeling. This would speed the dissemination of new safety information about generic drugs to health professionals and patients. FDA’s Proposed Rule would allow generic manufacturers to independently updateproduct safety labeling through the “changes being effected” (CBE-0) supplement process that is currently only available to branded drug manufacturers. Under the Proposed Rule, generic manufacturers could unilaterally change their safety-related product labeling, and those changes could take effect simultaneously with the companies’ notification of FDA and of the branded drug manufacturer—no prior approval is required.

The current regulatory scheme only permits generic manufacturers to use CBE-0 to update their labels in conformance with the branded drug label. Practically speaking, this means that the branded drug manufacturer must change its labels first, followed by the generics.

The FDA has long held the view that the labeling ofgeneric drugs must be identical to that of the listed drug to ensure patient safety. This is mainly because a generic drug’s approval is based on safety and efficacy studies of the reference listed drug (RLD). The FDA also acknowledges that there may be concerns about temporary differences in safety-related labeling for drugs that FDA has determined to be therapeutically equivalent. Nevertheless, the agency argues that the changing prescription drug landscape, in which greater than 80% of the drugs dispensed in the U.S. today are generic, has altered the risk-benefit balance between clarity and consistency on the one hand, and speedier access to safety information on the other. The push behind generic drugs as the preferred drug class of choice is driven by Congress’ quest to drive down payer costs and overall healthcare costs. It is also the key to guaranteeing the health of populations in developing countries with safe therapies that are affordable. Generic drugs are being prescribed as alternatives to the branded product, often under the assumption that they are truly identical.

The truth is that generic drugs can differ significantly from their branded counterparts, especially with regard to their pharmacokinetic characteristics. The criteria for establishing bioequivalence are broad – perhaps too broad; in fact, a survey of neurologists regarding generic antiepileptic drugs (AEDs) found that 81.6% did not think FDA standards for evaluating bioavailability were stringent enough. Furthermore, some physicians’ organizations have stated that certain methods for determining bioequivalence for some specific drug dosage forms may be flawed. Thus bioequivalence may provide a false sense of uniformity between generic drugs and branded drugs.

This variation may be due to the use of different excipients or containers, or to discrepancies in the drug manufacturing processes. Having the same active ingredients does not guarantee equivalence, because inactive ingredients, pH, container materials, and preservatives may interfere with penetration, absorption, and bioavailability of active agents at their sites of action. Such variables have led to generic drugs that can have substantially different properties from their branded counterparts.

The legal precedent driving this proposed rule change is the Supreme Court summary decision that concluded that generic manufacturers’ lack of independence with respect to drug safety labeling makes it impossible for them to complywith both Federal druglabeling requirements. State tort law requirements (i.e. failure to warn or design defect) conclude that the only way to correct a design defect to a drug that cannot be reformulatedis through labeling. State lawsuits have been preempted by federal law. “Preemption” is defined as “a doctrine based on the Supremacy Clause of the U.S. Constitution that holds that certain matters are of such a national, as opposed to local, character that federal laws preempt or take precedence over state laws. As such, a state may not pass a law inconsistent with the federal law.”

If finalized, this rule would change the entire regulatory and liability landscape for generic drug manufacturers and give patientsan avenue for recovery fromgeneric drug companies after suffering an injury.

There are many questions surrounding this proposed change such as whether FDA has the authority to implement the proposed rule change. The agency acknowledges that a new regulatory scheme would result in at least a temporary multiplicity of labels for the “same” drug, a result that the statute appears to prohibit except in enumerated circumstances.

To address the seeming contradiction, the agency isdancing on a thin line. FDA is careful to point out that the statute requires a generic drug label to be identical to the branded drug “at the time of approval.” We note that onlyFDA regulations take the position that generic drug labeling must maintain the same label as the branded drug throughout the lifecycle of the generic product. The FDA is proposing to address the inevitable confusion regarding multiple versions of safety labeling through increased transparency with a website listing all of the pending CBE-0 supplements for safety-related labeling changes.

The consequences of this proposed rule change would be profound for consumers and manufacturers alike. One benefit may be a strategic shift amongst generic drug manufacturers to a higher quality paradigm. An unintended consequence of such a shift would be to limit the number of ex-U.S. drug manufacturers that can compete in this new litigious playing field. The main benefit is of course greater patient safety as generics manufacturers examine how to fully assess the differences between their generics and branded drugs.

NOTE: The comment period on FDA’s Proposed Rule will be open at least 60 days after its publication in the Federal Register (until Jan. 12, 2014) and likely longer. The docket number is FDA-2013-N-0500.

References

1. Amicus Brief of the United States at 15, n. 2, Mutual Pharm. Co.,Inc. v. Bartlett, 133 S. Ct. 2466 (2013) (No. 12-142).
2. Sandy Walsh, FDA Takes Action to Speed Safety Information Updates on Generic Drugs, FDA News Release, November 8, 2013
3. 57 Fed. Reg. 17,950, 17,961 (Apr. 28, 1992)
4. Wilner AN. Therapeutic equivalency of generic antiepileptic drugs: results of a survey. Epilepsy Behav2004;5:995–8.
5. Brechue WF, Maren TH. pH and drug ionizationaffects ocular pressure lowering of topical carbonic anhydrase inhibitors. Invest Ophthalmol Vis Sci1993;34:2581–7
6. LeLorier J, Duh MS, Paradis PE, et al. Clinical consequences of generic substitution of lamotrigine for patients with epilepsy. Neurology2008;70:2179–86
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8. PLIVA, Inc. v. Mensing, 131 S. Ct. 2567 (2011); Mutual Pharm. Co., Inc. v. Bartlett, 133 S. Ct. 2466 (2013)
9. Title 21 United States Code. § 355(j)(2)(A)(v)