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Comment on Growth Hormone Therapy and Retinal Changes Mimicking Diabetic Retinopathy¹

Division of Metabolism and Endocrine Drug Products and Division of Drug Risk Evaluation Center for Drug Evaluation and Research Food and Drug Administration Rockville, Maryland 20857

The interest of Radetti, Gentili, and Lepidi (1) in our observation of two cases in which retinopathy developed during the use of recombinant GH (rGH) in the absence of diabetes (2) is appreciated. We applaud their efforts to prospectively assess whether GH treatment induced retinal proliferation in the 85 GH-deficient children under their care. This approach, however, has limitations—primarily related to study size. Their study has the capability to detect any given adverse event that occurs as frequently as one time in every 28 patients exposed to the drug (3). Unfortunately, this study does not have the power to detect less frequent adverse reactions.

Since the introduction of rGH to the United States market in 1985, the Foodand Drug Administration has received 3806 reports of adverse reactions associated with rGH treatment through the MedWatch surveillance system. Some of these reports are duplications or follow-up accounts. Reports from the United States include both serious and nonserious events. The non-United States derived reports delineated only serious events. Among these 3806 reports, only two cases of retinopathy were identified. Although under-reporting of adverse events is common, these data do suggest that this type of event is relatively uncommon.

Small studies amply powered to detect efficacy may not be sufficiently large to detect relatively rare complications. None of the studies that have been submitted to the Food and Drug Administration in support of GH therapy for a variety of indications have enrolled sufficient numbers of patients to detect comparatively uncommon events, and, with the exception of increased mortality in critically ill adults (4), none of the serious adverse reactions found in the label were identified during clinical trials. Rare events are likely to be identified only during the postmarketing period when the number of patients exposed to the drug increases exponentially in comparison to the small number of patients studied in the pre-approval trials.

Footnotes

Address correspondence to: Elizabeth Koller, United States Food and Drug Administration—CDER, Parklawn Building HFD 510, Room 14B04, 5600 Fishers Lane, Rockville, Maryland 20857.

¹ Disclaimer: The contents of this letter represent the view of the authors and do not necessarily constitute an official position of the United States Food and Drug Administration.

Received September 17, 1999.

References

1. Radetti G, Gentili L, Lepidi M. 2000 Comment on GH therapy and retinal changes mimicking diabetic retinopathy. J Clin Endocrinol Metab. 85:923.[Free Full Text]
2. Koller EA, Green L, Gertner JM, et al. 1998 Retinal changes mimicking diabetic retinopathy in two nondiabetic, growth hormone-treated patients. J Clin Endocrinol Metab. 83:2380–2383.[Abstract/Free Full Text]
3. Jonavic BD, Levy PS. 1997 A look at the rule of three. Am Stat. 51:137–139.
4. Takala J, Ruokonen E, Webster NR, et al. 1999 Increased mortality associated with GH treatment in critically ill adults. N Engl J Med. 341:785–792.[Abstract/Free Full Text]

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