Off-Label Use of Recombinant IGF-I to Promote Growth: Is It Appropriate?

Abstract

Recombinant human (rh) IGF-I (mecasermin) was approved by the U.S. Food and Drug Administration (FDA) in 2005 for the orphan indication of severe primary IGF-I deficiency (IGFD) in individuals unresponsive to rhGH as a result of GH receptor or postreceptor defects or who have GH gene deletion with the development of GH inactivating antibodies after rhGH treatment. The clinical andbiochemicaldefinition includedheight SDscoreandbasal IGF-I SD score 3 or less, with normal or elevated GH. This indication applies to probably no more than a few hundred children worldwide, about 70 of whom provided the databasefortheFDAapproval (1).Therefore, it isnotunexpected that the manufacturer would promote the product beyond the orphan indication, dropping the severe qualification. “Approximately 1 million children in the United States have short stature, and we believe that there are an equal number of children with short stature in Western Europe. Of the approximately 380,000 children in the United States referred to pediatric endocrinologists for evaluation of possible short stature, we believe that approximately 30,000 in the United States and an equal number in Western Europe, for a total of 60,000 children, have primary IGFD and may be treated with (rhIGF-I)” (2). The clinical rationale for such off-label promotion of mecasermin, however, has been challenged (3). The comprehensive report by Midyett et al. (4) in the current issue of the Journal of Clinical Endocrinology and Metabolism provides important information about this approach. Described is one year of treatment of children with idiopathic short stature (ISS) thought to have partial defects in GH sensitivity resulting in IGFD, based on a single measurement of circulating IGF-I less than 2 SD for chronological age. The FDA approved the use of rhGH for the treatment of ISS in 2003, after nearly 20 yr of such use (5), a decision that has not been without controversy (6, 7). Nonetheless, there is considerable experience of improvement in adult stature with rhGH treatment of ISS (5, 8, 9). It is against this background of long and safe use of rhGH that the introduction of an alternative hormonal approach must be viewed. Considering the FDA approved use of rhGH for growth promotion in children with ISS and the potential limitations of simply enhancing endocrine IGF-I and suppressing GH secretion and thereby local GH effects of chondrocyte proliferation and autocrine/paracrine secretion of IGF-I (3), the design of a trial of rhIGF-I would be expected to include a rhGH treatment arm. The randomized,unblinded,no-treatment-controlled studyofMidyett et al. (4) is seriously limited by not including a rhGH comparator arm for safety and efficacy. Other concerns that have been previously expressed (3) and persist with this report include the use of a single IGF-I measurement as an inclusion criterion, the notion of partial GH insensitivity as justification for rhIGF-I treatment of a substantial number of children with ISS, absolute and relative efficacy (compared with rhGH or no therapy), and safety.