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KV’s Makena®: A trove of 505(b)(2) Lessons

On February 3, 2011 Hologic, Inc. (subsequently sold assets to KV Pharmaceuticals) received 505(b)(2) approval of Makena®, its 17?-hydroxyprogesterone caproate injection (17P) to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. The subsequent announcement that the price would be set at $1500 per injection caused a firestorm of media attention and public outcry. Previous to this approval the drug had been available through compounding pharmacists as an unapproved drug at a much lower cost. Rather than get embroiled in the pricing issue, I reviewed the regulatory and development history of this drug and found a trove of information relevant to 505(b)(2) drug development. In this post, I’d like to provide the background on the regulatory history of this drug. In subsequent posts I’ll cover the following topics:

Part 1: 505(b)(1) or 505(b)(2)?

Part 2: Accelerated Approval” Subpart H

Part 3: Use of Public Information for 505(b)(2) approvals

Part 4: Statistical versus Clinical Significance

Part 5: Advisory Committee

Part 6: Post Approval Requirements


In 2003, Meis et al. published an article in the New England Journal of Medicine reporting results of a clinical trial that was sponsored by the National Institute for Child Health and Human Development and conducted by the Maternal-Fetal Medicine Units Network. The double-blind, placebo-controlled trial examined the potential of 17P to prevent recurrent preterm birth. Adeza Biomedical Corporation discussed with FDA’s Division of Reproductive and Urologic Products (DRUP) the possibility of basing an NDA on this report. Based on this meeting Adeza submitted an NDA in April 2006 with the proposed tradename Gestiva. The initial NDA relied on the single study and a follow-up safety study of the children (offspring) exposed to 17P in the previous study; the NDA was based solely on published literature. The NDA was the subject of an August 2006 meeting of the Advisory Committee for Reproductive Health Drugs. Since these studies were not designed to meet FDA requirements for pivotal studies for NDA approval, FDA had a number of concerns and issued an Approvable Letter in October 2006. [Readers will note that an Approvable Letter means that there are deficiencies that prevent approval of the drug.] Subsequently, Adeza was acquired by Cytyc Corporation in April 2007 which in turn was acquired by Hologic, Inc. in October of 2007. Hologic provided the first response on January 2009 under the newly proposed tradename Makena. The same month, the FDA sent another letter containing clinical deficiencies. The second response was submitted by Hologic on July 12, 2010 and the drug product approved February 3, 2011.

Note: As I write this posting (May 2011), the complete NDA review is not available at Drugs@FDA. Portions of the review are available on the PREA website and I will link to the applicable review document in subsequent postings.