Abbreviated Applications and the Patent Certifications

An abbreviated application does not prove that a drug works. It proves that a drug is the same as one already shown to work, and then borrows the earlier finding. That substitution is what makes the route fast and cheap, and it is also what makes the definition of sameness the entire battleground.

What the applicant must show

Section 355(j) sets out the showings. The conditions of use proposed in the labeling must have been previously approved for the listed drug. The active ingredient must be the same. The route of administration, the dosage form and the strength must be the same. The proposed labeling must be the same as the labeling approved for the listed drug, subject to permitted differences such as those attributable to a different manufacturer or to aspects protected by patent or exclusivity.

Sameness is not a loose resemblance. Same active ingredient means the same active moiety, and disputes about salts, esters and complexes have been litigated repeatedly. Same dosage form and strength are compared against the reference product as approved, not against what the applicant would prefer to make. Where an applicant cannot match one of these elements, the abbreviated route is closed to it unless the statute's petition mechanism opens a narrow door.

Inactive ingredients need not be identical, but a difference must be shown not to affect safety. The applicant must also describe its manufacturing methods, facilities and controls in the same way a full application would, because the abbreviated route abbreviates the efficacy showing and nothing else. Applications routinely fail on chemistry and facility grounds long before anyone examines the bioequivalence data.

Bioequivalence and how it is demonstrated

Bioequivalence means the absence of a significant difference in the rate and extent to which the active ingredient becomes available at the site of drug action, when administered at the same molar dose under similar conditions in an appropriately designed study. It is a comparison, not an absolute measure.

Study design conventions follow from that. Bioequivalence studies are typically crossover designs in healthy volunteers, comparing measured concentration over time against the reference product, with the comparison expressed as a ratio and assessed against acceptance limits. Reserve samples of both the test and reference products are retained so that the material actually studied can be examined later, a requirement that exists because the integrity of these studies has been a recurring enforcement problem.

Part 320 sets a hierarchy of acceptable evidence. In vivo pharmacokinetic measurement of the active ingredient in blood, plasma or serum over time is the preferred approach where it can be done. Where it cannot, the regulation permits pharmacodynamic measurement, comparative clinical trials, in vitro approaches correlated with in vivo data, and other approaches the agency considers adequate. Products acting locally without systemic absorption are the hard cases, because the preferred method measures the wrong thing.

The four certifications

For each patent claiming the listed drug or a method of using it, the applicant certifies one of four things. Paragraph one, that no patent information has been filed. Paragraph two, that the patent has expired. Paragraph three, that the patent will expire on a stated date and approval is sought only after that date. Paragraph four, that the patent is invalid, unenforceable, or will not be infringed by the manufacture, use or sale of the drug for which the application is submitted.

The first three set a date and generate no litigation. The fourth is an accusation, and the statute treats it as one. The applicant must give notice to the holder of the approved application and to the owner of the patent, and that notice must include a detailed statement of the factual and legal basis for the applicant's opinion that the patent is invalid or not infringed. The statement is what the patent owner uses to decide whether to sue.

The stay, the exclusivity and the strategy around them

If the patent owner brings an infringement action within the window the statute allows after receiving notice, approval of the application is stayed for a defined period unless the patent expires or a court decides the patent is invalid or not infringed before it ends. The stay is automatic in the sense that it requires no injunction and no showing of likely success, which is what makes it valuable and what makes it controversial.

The statute also rewards the first applicant to file a paragraph four certification with a period of exclusivity against later applicants, subject to forfeiture events that can extinguish it. Because that reward is substantial, filing strategy is driven by dates and by what the applicant is prepared to defend, and the eventual patent litigation turns on expert testimony about formulation and pharmacokinetics of the kind governed by the gatekeeping standard for expert testimony.

Labeling is the other recurring flashpoint. Where a listed drug is approved for several uses and one is protected by a method-of-use patent, an applicant may seek approval with that indication omitted, which raises questions addressed in required labeling content and how it is changed and, when the product is used for the omitted indication anyway, in what may be said outside approved labeling. The reference product itself was approved through the process described in the new drug application and its review cycle.