In a big win for the Food and Drug Administration (FDA), the D.C. Circuit of the United States Court of Appeals reinforced FDA’s position on what constitutes a “meaningful difference” between prescription and over-the-counter (OTC) versions of a drug product.  Under FDA’s longstanding interpretation, section 503(b) of the Food, Drug, and Cosmetic Act (FDCA) “does not permit the same active ingredient to be simultaneously marketed in both a prescription drug product and a nonprescription drug product, unless a meaningful difference exists between the two that makes the prescription product safe only under the supervision of a licensed practitioner.”

In a judgment filed on Oct. 30, 2018, the court upheld an order FDA issued on Apr. 2, 2018, withdrawing approval of five abbreviated new drug applications (ANDAs) for prescription polyethylene glycol 3350 (PEG3350) laxative products.  Although there were differences in the labeled duration of use between the prescription ANDA products and an approved OTC version of the drug, the court agreed with FDA that these were not “meaningful” differences, and that the ANDA products were therefore misbranded under the FDCA due to being labeled as “Rx-only” products.

Case history

The petitioners in the Oct. 30, 2018 judgment were Breckenridge Pharmaceutical and Nexgen Pharma, sponsors of two of the ANDAs for which approval was withdrawn in FDA’s April 2, 2018 order.  The reference listed drug for the ANDAs was MiraLAX, which FDA originally approved as a prescription PEG3350 laxative product in 1999.  In 2006, FDA approved an NDA switching MiraLAX from prescription to OTC status.  Consequently, FDA sent a letter to the ANDA holders in 2007 explaining that they were required to submit new ANDAs referencing the OTC version of MiraLAX in order to continue marketing their PEG3350 laxative products.  The ANDA holders declined to do so, eventually culminating in FDA’s April 2, 2018 order following a 2008 notice of opportunity for a hearing and a 2014 proposed order denying hearing requests from the ANDA holders and withdrawing approvals of the ANDAs.  Following FDA’s April 2, 2018 order, the petitioners sought review by the D.C. District Court of FDA’s determination that there was no meaningful difference between the prescription and OTC versions of the PEG3350 laxative products.

Court rejects arguments for “meaningful difference” in labeling

FDA had determined – and the petitioners did not dispute – that there was no meaningful difference between the prescription and OTC products with respect to active ingredient, dosage form, strength, route of administration, indication, and patient population.  However, the petitioners argued that there was a meaningful difference between the prescription and OTC products due to differences in labeling regarding the duration of use.  The labeling for the prescription versions of the drug stated:

This product should be used for 2 weeks or less or as directed by a physician.

Whereas the labeling for the OTC version of the drug stated:

Use no more than 7 days.  Stop use and ask a doctor if you need to use a laxative for longer than 1 week.

The court disagreed with the petitioners that these labeling differences were meaningful.  The court noted that there was effectively no difference between the prescription and OTC versions of the labeling beyond the first week of use because in both versions, physician approval was required for continued use of the products.  Thus, the court stated there was no “independent weight” to the prescription version recommending use for 2 weeks or less, versus the OTC version recommending use of no more than 7 days.  FDA had argued that the difference in language was simply due to the different audiences: the prescription labeling was directed to healthcare practitioners and was drafted when the product was considered Rx, while the OTC labeling was directed to consumers and was drafted with lay language based on the determination that no physician intervention was needed to safely use the product.

The court did acknowledge that one difference resulting from the two versions of the labeling was that physician approval was required for the first week of use of the prescription products, but not for the OTC product.  The petitioners argued that this difference could be meaningful because using the OTC product during the first week without physician approval could mask more serious conditions.  But the court did not agree, given that FDA determined that the OTC product was safe for its first week of use without physician supervision.  For individuals with a more serious condition, the court noted that the instructions for the OTC product directed users to see a physician after the first week if symptoms persisted.  The court also observed that some individuals using the OTC product may have done so following physician consultation, which would “obviat[e] masking concerns” for these persons.

Court rejects petitioners’ safety, precedence arguments

The petitioners also argued that physician oversight with the prescription version of the drug amounted to a meaningful difference due to safety concerns with off-label use.  However, the court minimized this argument by responding that off-label use was a broad risk that applied to many drugs, and instead focused on FDA’s finding that MiraLAX was safe for self-medication when used on-label.  The court also pointed to studies suggesting that repeated use of MiraLAX prior to consulting a physician was safe.

The court also disagreed that with an argument by the petitioners that FDA was treating its PEG3350 laxative products differently than other drugs – butenafine, terbinafine, and ibuprofen – where FDA did find a meaningful difference between the prescription and OTC versions.  With each of these other drugs, the court found that there were differences in factors such as indication, dose, and duration of use that supported FDA’s finding of a meaningful difference between the prescription and OTC versions of these products.

Having found the arguments by the petitioners unpersuasive, the court ultimately upheld FDA as being “neither arbitrary nor capricious” in its determination that there was no meaningful difference between the prescription and OTC versions of the PEG3350 laxative products.

FDA delays may render Rx to OTC switches meaningless

FDA Commissioner Scott Gottlieb, M.D., has voiced his support for “increase[d] access to a broader selection of nonprescription drug products for consumers, empowering them to self-treat common conditions and potentially some chronic conditions.”  In light of FDA’s goal of increasing access to OTC drugs, it is noteworthy that more than 12 years have elapsed since FDA approved this switch from Rx to OTC in 2006.  FDA notified the ANDA holders in 2007, but did not issue the hearing notice until 2008.  It was then six years before FDA issued a proposed order denying the hearing requests in 2014, and four more years for the issuance of the order in 2018.

These lengthy time frames need to be considered for sponsors seeking future Rx to OTC switches that involve 3-year exclusivity, which could be rendered meaningless by these delays due to the continued presence of Rx products on the market during these proceedings.  FDA should consider the impact of these delays on the incentives for sponsors to seek such nonprescription status.

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