On August 30, 2017, the FDA responded to three older petitions all submitted by the same law firm relative to Digoxin products.  See FDA’s full response here.  The petitions addressed three basic issues: 1) 3-year Hatch-Waxman exclusivity; 2) bioequivalence requirements for this narrow therapeutic index drug; and 3) dissolution and blend uniformity requirements.  The petitions were approved in part, denied in part, and, on the issue of 3-year Hatch-Waxman exclusivity (which really caught my eye), the FDA punted on making an outright determination of the specific question raised in the petition by declaring the petition moot.

The NDA for Lanoxin (digoxin) was approved in strengths of 0.0625mg, 0.125mg, 0.1875mg, 0.250mg, 0.375mg, and .500mg on September 30, 1997.  However, the original NDA holder did not choose to market all strengths at the time of approval.  In addition, prior to approval, there was a site transfer and the firm had indicated that they planned to market only the 0.125mg and .250mg tablet at the new site.  Upon approval, the FDA noted that all 6 strengths were approved and assigned a 3-year period of Hatch-Waxman exclusivity, that expired on September 30, 2000 for all strengths.

Subsequently, in 2011, the NDA was acquired by another firm and the firm decided to bring the 0.0625mg and the 0.1875mg to market.  They discussed the requirements with the FDA and, in August 30, 2012, the new owner of the NDA submitted a prior approval supplement (PAS) to introduce the two previously approved strengths into the market.  On October 17, 2013, the FDA approved the PAS.

The law firm argued in the petition that, because the two strengths in the PAS were never marketed, they should be entitled to 3-year Hatch-Waxman exclusivity.  FDA explained that 3-year Hatch-Waxman exclusivity is awarded only for a PAS when it contains the results of “new clinical studies that are essential for approval” of the supplement.  The firm did not submit any new clinical studies to support the PAS.  The FDA explained in the petition response that this is consistent with the statutory and regulatory scheme for award of 3-year exclusivity.  However, FDA stopped short of saying (which I believe to be true) that exclusivity that is awarded at the time of approval begins to run from the date of approval whether or not the product is marketed.  Instead, FDA said: “As noted above, the 0.0625mg and 0.1875mg strengths were approved on September 30, 1997 when FDA approved the Lanoxin NDA, and like the other strengths approved in the NDA, there strengths were protected by 3-year exclusivity until September 30, 2000.  However, even if Lanoxin was eligible for 3-year exclusivity for the 0.0625mg and 0.1875mg tablet strengths beginning on October 17, 2013, the requests in the Exclusivity Petition are moot because the exclusivity would have expired on October 17, 2016.  Accordingly, the Exclusivity Petition is dismissed as moot.”

The FDA petition response relative to the bioequivalence petition noted the Agency did revise the bioequivalence guidance in August 2017 for digoxin (here) to require both fasting and fed, single dose, 2 treatment, 2-sequence, 4-way, fully replicated crossover in vivo studies.  FDA did not, however, agree to narrow the confidence interval as requested in the bioequivalence petition.

This petition is an interesting read and should inform firms on the issue and complexity of narrow therapeutic index products as well as this very interesting exclusivity question which was raised (but not fully and definitively answered) in the FDA’s response.