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At first, Monday’s (11/16/09) news from CombinatoRx said that the FDA had told the company “that the NDA in its current form would not be sufficient to form the basis for approval of Exalgoâ„¢ under Section 505(b)(1)”. Then, on Friday (11/20/09), the company said that the FDA had extended the PDUFA review date by 3 months in order to review a recent amendment.

First, let’s get the players straight. Neuromed acquired the marketing rights to Exalgo (hydromorphone HCl extended release tablets) from ALZA Corporation in April 2007. Neuromed and CombinatoRx entered into a merger agreement on July 2, 2009, after Neuromed had sold the commercial rights to Exalgo to Mallinckrodt, Inc. a Covidien company on June 17, 2009.

The exact development program is unknown; however, Neuromed issued a press release in October 2007 indicating that the FDA has “completed its review” of the IND and “successfully reached an agreement with the FDA under the Special Protocol Assessment (SPA) process for the planned pivotal Phase 3 clinical trial …” . The Phase III trial was initiated the following month (November 2007), enrollment completed one year later, and successful results announced 16 months later on March 23, 2009.

The regulatory history is also uncertain. At some early point, FDA issued an Approvable Letter. After the Phase III clinical trial was completed, on May 22, 2009 Neuromed submitted a response to this Approvable Letter. This fact is contained in the press release announcing the sale of U.S. rights of Exalgo to Mallinckrodt. According to this press release “[o]n June 12, 2009, the FDA informed Neuromed that the Exalgo submission would be classified as a Complete, Class 2 Response with a corresponding PDUFA date of November 22, 2009.”

What we know is that the company had submitted a 505(b)(1) NDA. This is very surprising given that immediate release hydromorphone has been on the market for many years (for example, Purdue Pharma has marketed Dilaudid-HP injectable since 1984). Under a 505(b)(1), the sponsor would have the burden of showing all safety and efficacy of the product based on its own data.

In general, to obtain an approval of the first extended release product where an immediate release product exists requires suitable Phase 1 data tailored to the ER characteristics and at least a single Phase III study. Perhaps ALZA thought this was a 505(b)(1) because that is what it is used to and they did the initial studies and sold the rights to Neuromed to complete the Phase III study. Neuromed went ahead with the 505(b)(1) filing and found that the FDA wouldn’t accept it. Instead, CombinatoRx’s latest press releases indicate that they might need to resubmit under 505(b)(2) to assure that a complete NDA is filed; there is a need to reference existing data in previously approved NDA’s.