Growth Hormone Post-Marketing Surveillance: Safety, Sales, and the Unfinished Task Ahead

Twenty-five years ago, the pediatric endocrinology community was stunned by news of Creutzfeldt-Jakob disease transmitted by treatment with pituitary-derived GH (pit-GH). With remarkable serendipity, recombinant DNA-derived human GH (rhGH) became available within months. In an environment fertile with concerns about unexpected adverse effects, postmarketing surveillance studies (PMSSs) were established, managed, and supported by manufacturers of rhGH, of which the Genentech National Cooperative Growth Study (NCGS) has been the largest and most comprehensive in scope. This action appeared prescient when, in the late 1980s, a possible link between GH therapy and new-onset leukemia waspublished(1).Thisassociationwaslaterdisproved(2,3), but a number of possible rhGH-associated adverse effects were subsequently identified, systematically tracked, analyzed,andreported. Inthis issueofJCEM,Belletal. (4)report more than 20 yr of NCGS safety data covering approximately 55,000 patients and nearly 200,000 patient-years of rhGH exposure. The gathering and analysis of this vast amount of drug experience information will likely not be accomplished again, making its value, in some respects, inestimable. It validates for the sponsoring company and participatingphysicians therationale,commitmentofresources, and hopes for the NCGS that marked its inception. The data confirm and extend prior NCGS reports (5, 6), summarized by these general clinical implications for rhGH therapy: 1) certain adverse effects associated with rapid growth (scoliosis progression, slipped epiphyses) and others of unknown mechanism (intracranial hypertension, pancreatitis) occur rarely and merit anticipatory guidance and close monitoring; 2) overt hyperglycemia is rare, but insulin sensitivity is reduced, and a possible increase in risk for type 2 diabetes mellitus (T2DM) may be obscured by its rising general pediatric population incidence; 3) in the rare occurrence when a child already at higher risk for sudden death dies during rhGH therapy, a possible contributing role of rhGH (e.g. reduced cortisol availability in hypopituitary children or airway compromise in children with Prader-Willi syndrome) cannot be excluded; and 4) rhGH does not increase risk for new malignancy in children without risk factors, but may slightly increase or hasten the onset of second malignancies in patients previously treated for cancer. Although the data on the whole are reassuring, caution is warranted when extrapolating these findings to future safety of rhGH. Like any drug, rhGH could cause adverse events that otherwise occur rarely in the reference population (e.g. malignancy) and/or increase the frequency of relatively common events (e.g. T2DM). In addition, adverse events can occur shortlyafter initiationofdruguse,onlywith long-term use, or remotely after the drug has been discontinued (7). This full spectrum of potential rhGH adverse effects is not comprehensively elucidated by PMSSs due to: 1) inherent weaknesses in patient cohort surveillance dependent on physician reports; 2) changes in rhGH dosage and/or recipient characteristics that may alter risk for adverse effects; and 3) failure to capture adverse events that only become manifest after treatment. A separate but important issue unique to rhGH treatment is to define a “tolerable” level of risk for the newest and potentially largest rhGH-treated group in the future—essentially healthy, but short children. As noted by others (8), there are potential pitfalls in relying on data from PMSSs such as the NCGS. Patient enrollment is often incomplete; approximately 75% of eligible rhGH product-treated children are tracked by the