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Blog & Resources Camargo Blog May 31st, 2011

K-V’s Makena: Part 3: Use of Public Information for 505(b)(2) Approvals

In previous postings (Intro, Part 1, Part 2), I provided background on KV’s Makena (17a-hydroxyprogesterone caproate injection aka 17P). The development and regulatory history contains many lessons. In this posting I’d like to examine the use of public information to substitute for sponsors’ studies.

By definition, the 505(b)(2) application must contain information to which the applicant does not have right of reference. “Information” in this case is that which is considered necessary for approval, generally, human clinical trials or animal studies. In practice, “information” includes any reports that are contained in modules 2-5 of the NDA application.

In 2003, an article in the New England Journal of Medicine reported on 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. The sponsor – Adeza Biomedical Corporation discussed with FDA’s Division of Reproductive and Urologic Products (DRUP) the possibility of basing an NDA on this report and subsequently submitted an NDA in April 2006. The initial NDA relied on the single study and a follow-up safety study of the offspring exposed to 17P in the previous study; the NDA was based solely on published literature.

Note that when we say that the NDA was ‘based solely on published literature‘ we are only referring to the non-clinical and clinical portions of the submission. The phrase typically doesn’t refer to the CMC section, that is, the active ingredient(s) and drug product information. Generally speaking, the formulation can affect the clinical outcome(s). Thus, if a sponsor changes the synthesis of the active ingredient(s) or modifies the formulation during the progress from Phase 1 to Phase 3, a bioequivalence study is often needed to bridge the new to the old information.

In the case of Makena, the product is an injectable. The sponsor was able to convince the FDA that the product used for the published clinical study was the same as the to-be-commercial drug product. All that the sponsor needed to provide in the NDA would be the usual Module 3 information. No pharmacokinetic Phase 1 information was needed because the safety information was established during the clinical trial.

The sponsor used a publicly-funded clinical study as the basis of the NDA. The major questions we always need to consider when using publicly available information are: 1) does it meet the sponsor’s needs and 2) does it meet the FDA standards? Clearly, an affirmative answer to the second question is needed, so let’s start there.

By any objective measure, the published study was not designed to meet FDA standards for drug approval. FDA has published guidelines and the major one applicable in this case – to phase 3 studies, is “Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products.” Chief among the many issues was that the primary endpoint was a surrogate for the desired clinical outcome. The surrogate endpoint is that treatment with Makena reduces the likelihood of the patient from giving birth before the natural term; reduction in preterm births. The clinical endpoint is neonatal morbidity and mortality (survival). From the Medical Officer’s clinical review we see that FDA, not the sponsor, developed the documentation and rationale for use of the surrogate in lieu of the clinical endpoint. It is clear that the FDA felt very strongly about the need for this drug to be given every chance for approval – seldom would we expect the FDA to do the sponsor’s work.

Yet, the intial NDA review found the use of the surrogate endpoint just too troubling. The Agency issued an Approvable Letter listing several deficiencies. Importantly, the Letter was a way for the Agency to add time to the review clock, allowing for the publication of the follow-up safety study of the children (offspring) exposed to 17P in the previous study. Although this study design still did not meet Agency standards, it did support the hypothesis that the drug did not harm and that the risk/benefit was strongly in favor of the intervention using 17P.

Nonetheless, the NDA was approved with the proviso that the sponsor conduct a post-approval trial: ” The findings from this single study alone, based on a surrogate endpoint, were not sufficiently persuasive to support approval without the addition of further confirmatory clinical data that includes an appropriately powered clinical endpoint of neonatal morbidity and mortality. As such, I find the evidence of benefit on this surrogate endpoint sufficient to support approval on the basis of a single clinical trial, with the requirement that an additional confirmatory trial be conducted under Subpart H, in order to evaluate the treatment benefit of 17-HPC on a clinical endpoint, specifically neonatal mortality and morbidity.” (Clinical review, page 8).

In the approval letter, KV was required also required to provide pharmacokinetic data. The FDA stated: “Submission of an academic publication (emphasis mine) of pharmacokinetic data on hydroxyprogesterone caproate and its metabolites in plasma and urine of pregnant women throughout different stages of gestation. If the publication listed in this postmarketing commitment is not submitted by December 31, 2011 or if the results from the publication do not include all the relevant findings (e.g., urinary metabolites), you will conduct the following clinical trial: A non-randomized clinical pharmacokinetic trial of hydroxyprogesterone caproate and its metabolites in pregnant women. This trial will provide data characterizing the pharmacokinetics of hydroxyprogesterone caproate and its metabolites in plasma and urine throughout the different gestational stages.”

What we learned from the approval of Makena includes:

  • a drug product can be approved based on a single published Phase 3 study if there is strong justification
  • a truly unmet need will gain FDA assistance on meeting approval requirements (but for anything else, don’t count on it!)
  • Use of public information requires that it meet FDA standards and the sponsor has to show how it can be used to meet those standards
  • You don’t have to have a reference listed drug be currently marketed
  • Clinical will often trump the other review disciplines
  • Prospective sponsors can look at FDA review documents to obtain essential study designs for new products


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