Lessons from the national cooperative growth study

Background: We report the case of a patient with an uncommon association of isolated growth hormone deficiency (IGHD) due to GH1 gene deletion and Chiari malformation type I. The patient presented with intracranial hypertension during recombinant human GH replacement therapy. Methods: GH deficiency (GHD) was diagnosed based on auxiological data and standard biochemical tests. Molecular analysis of the GH1 gene was performed using polymerase chain reaction amplification and SmaI enzyme restriction. The central nervous system (CNS) was evaluated by computed tomography (CT) and magnetic resonance imaging (MRI). Results: Molecular analysis showed that IGHD was due to homozygotic deletion of the 6.7-kb GH1 gene. After 28 months of GH treatment, CT and MRI scans showed enlargement of the third and lateral ventricles but a normal fourth ventricle, herniation of the cerebellar tonsils by the foramen magnum, presence of dysplastic cerebellar tonsils involving the medulla oblongata, absence of the cisterna magna and compression of the cerebellar tonsils and spinal cord by the posterior arch of the atlas. The patient underwent endoscopic third ventriculostomy, which resulted in complete symptom relief. Conclusions: This case illustrates the importance of CNS evaluation, including detailed examination of the posterior fossa, in patients with GHD.

Section: Discussionmentioning

confidence: 88%

Isolated Growth Hormone Deficiency due to <i>GH1</i> Gene Deletion: Central Nervous System Hypertension during Growth Hormone Treatment

Antonini

Faleiros

Machado³

et al. 2007

“…Therefore most of the currently available pharmacovigilance information has been obtained from large post-marketing studies sponsored by GH manufacturers. These studies have identified safety issues occurring during GH treatment, such as diabetes [15], slipped capital femoral epiphyses [16] and intracranial hypertension [17], but could not address issues occurring after treatment is stopped (such as neoplasms) as patients are mostly lost to follow-up once GH treatment is discontinued.…”

Section: Somatropinsmentioning

confidence: 99%

Similar Biological Medicinal Products Containing Recombinant Human Growth Hormone: European Regulation

Pavlovic¹,

Girardin²,

Kapetanovic³

et al. 2007

The concept of similar biological medicinal products (‘biosimilar’ medicinal products) allows pharmaceutical companies to develop products based on an abridged dossier once the marketing protection of the ‘reference’ biological medicinal product has expired. A biosimilar medicinal product can be granted a marketing authorization provided that its similarity to a reference product is established in terms of quality, safety and efficacy (step-wise comparability exercise). A decision to launch a biosimilar medicinal product on the market is taken if it has a similar efficacy and comparable or better (less) immunogenicity than the chosen reference biological medicinal product. However, this decision is based on limited data and the comparability program may detect substantial differences in immunogenicity profiles but is likely incapable of detecting rare events. This is why clinical experience, through clinical trials and extensive pharmacovigilance programs, remains the most reliable way to assess the immunogenicity and tolerance profile of recombinant therapeutic proteins. Substitution of one biological medicinal product by a biosimilar medicinal product is not currently recommended before long-term clinical efficacy and safety have been acquired in all relevant populations. Here we review recent regulatory guidelines provided by EMEA and comment on the marketing authorizations and risk management plans of two recently approved biosimilar somatropins.

“…Further, even though there is regular reporting by all companies to the authorities, it is not apparent to the treating physician that the approved preparations can be considered equal as far as long-term safety is concerned. Until now, data about the long-term safety of rhGH are limited to publications on the prescription monitoring of two manufacturers (NCGS, KIGS/KIMS) [15,45,46,47,48], whose products can be considered the ‘leading substances’ as regards safety. Other manufacturers have not yet published results with data of comparable size.…”

Section: Pharmaceuticals Biosimilars and Approval Proceduresmentioning

confidence: 99%

New Preparations Comprising Recombinant Human Growth Hormone: Deliberations on the Issue of Biosimilars

Ranke¹

2007

Manufactured recombinant human GH (rhGH) has been available for more than 25 years. In the meantime, the GH produced by various manufacturers has been approved for application in replacement therapy in children and adults with GH deficiency or a number of disorders involving small stature in children. Until recently approval for each individual diagnosis was only granted after extensive studies on the long-term efficacy (e.g. adult height reached) and safety of the various products. Meanwhile, the European approving agency, the European Medicines Evaluation Agency (EMEA), has relinquished this restrictive stance. Thus, new rhGH preparations can count on gaining approval for existing indications even without conducting standard clinical studies of their efficacy and safety for each of these indications. The EMEA’s reconsideration is apparently based on the rationale that recombinant GH can, in effect, be considered equivalent to the tried and tested preparations in wide use, provided certain specifications are met. The term ‘biosimilars’ was coined to denote the similarities between the products rather than their parity, as is the case with generics for instance. The higher complexity of biopharmaceuticals relates not only to the substances themselves but also to the manufacturing process. It is generally believed that modifications to a manufacturing process – which are a prerequisite for a patent – may cause modifications of the active substance which then may lead to different long-term effects. Thus, the term ‘biosimilar’ does not indicate that complex biopharmaceuticals deriving from the same substance are entirely identical, nor does the approval of a ‘biosimilar’ ensure this. The factual information provided here is offered towards clarification of some uncertainties and as a contribution towards resolving open questions relating to the topic of biosimilars. The final choice of product to be prescribed must be made by the informed, independent physician.