## Facts

- Zeneca manufactured Diprivan (propofol), an injectable anesthetic approved through a New Drug Application (NDA).
- Zeneca later obtained FDA approval for a reformulated Diprivan that added the preservative disodium edetate (EDTA) to reduce microbial contamination risk, and the FDA granted Zeneca three years of exclusivity for the reformulation.
- Gensia sought approval of a generic propofol product through an Abbreviated New Drug Application (ANDA); it initially proposed EDTA but amended the ANDA to use a sulfite preservative instead.
- Zeneca objected, asserting the sulfite formulation raised safety concerns (particularly for sulfite-sensitive patients) and required additional clinical investigations rather than reliance on Diprivan’s existing safety and efficacy data.
- Zeneca filed an administrative petition requesting that the FDA refrain from approving any generic propofol with an antimicrobial additive other than EDTA unless supported by appropriate safety data.
- The FDA denied Zeneca’s petition and approved Gensia’s ANDA without requiring new clinical trials, instead requiring labeling that disclosed sulfite content and included precautions regarding sulfite sensitivity.
- Zeneca challenged the petition denial and ANDA approval in federal district court; the court granted summary judgment for the FDA and Gensia.
- Zeneca appealed to the Fourth Circuit.

## Issues

1. Whether FDA approval of an ANDA for a generic drug that substituted a different preservative (sulfites for EDTA) without requiring new clinical investigations complied with the FDCA and FDA regulations governing ANDAs.
2. Whether the FDA’s decision to address preservative-related risk through labeling, rather than requiring new clinical trials, was arbitrary or capricious under the APA.

## Decision

- The Fourth Circuit affirmed the district court’s summary judgment for the FDA and Gensia.
- The court held the FDA’s approval of the sulfite-preserved generic propofol was consistent with the FDCA and FDA implementing regulations.
- The court held the FDA’s action was not arbitrary, capricious, an abuse of discretion, or otherwise unlawful under the APA.
- The FDA could reasonably conclude that enhanced warnings and disclosure on labeling adequately addressed sulfite-related risk without necessitating new clinical studies.

## Legal Principles

- Under the FDCA’s ANDA framework, a generic applicant may rely on the reference listed drug’s prior safety and efficacy findings and need not duplicate full clinical investigations if statutory and regulatory requirements are met.
- Differences between a generic drug and the reference product (including certain excipients such as preservatives) may be permissible if the FDA reasonably determines safety and effectiveness are not compromised and any material risk is adequately managed, including through labeling.
- Reviewing courts apply APA arbitrary-and-capricious review to FDA approval decisions and generally defer to the agency’s scientific and technical judgments when the FDA considered relevant factors and provided a rational basis for its choice.
- Labeling requirements may be a lawful risk-management tool where the FDA reasonably finds that disclosure and warnings sufficiently mitigate identified risks.

## Conclusion

The Fourth Circuit upheld the FDA’s approval of a generic propofol product that used sulfites instead of EDTA, concluding that the FDCA and FDA regulations permitted reliance on labeling warnings rather than new clinical trials and that the agency’s technical judgment was reasonable under APA review.


Zeneca, Inc. v. Shalala, 213 F.3d 161 (4th Cir. 2000)