Petition Against Increlex Approval Not "Compelling" – Agency Review

Insmed's contention that Tercica's orphan drug Increlex lacked an adequate safety database to justify approval was contradicted by the "very large" amount of data relative to the size of the target population, according to Office of Drug Evaluation II Director Robert Meyer, MD.

Responding to an Aug. 10, 2005 Insmed petition against approval of mecasermin in an Aug. 30 approval memo, Meyer noted that while Tercica's NDA included results from only 71 patients, the data provided "a total exposure of 274 patient-years."

At this level, "the patient-years of experience exceeds or is certainly comparable to that of most routine NDAs, proportionate to the size of the target population," Meyer said.

"For instance, a very generously sized HMG CoA-reductase inhibitor program may have data collected on 10,000 patients…but the target population may be 10 mil. to 20 mil. patients." The target population for Inrelex is "likely in the range of 10,000 patients at most," Meyer said.

Insmed argued in its citizen's petition that the Increlex NDA contained an inadequate overall safety database that was based largely on a retrospective analysis of data from open-label treatment protocols.

In addition, data were lacking for patients with causes of severe IGF-1 deficiency other than Laron's syndrome (growth hormone insensitivity syndrome), and investigators lacked adequate training, according to Insmed. More specifically, Insmed also asserted that there is an excessive risk of hypoglycemia associated with Increlex ( ¹ (Also see "Tercica Increlex Hypoglycemia Risk Mitigated By Dose Timing, Titration – FDA" - Pink Sheet, 15 Nov, 2005.)).

"As the signatory authority for this application, I find these arguments, which are not based on procedural or legal matters, but on matters of medical judgment, to be less than compelling," Meyer said.

In rare orphan indications where withholding treatment raises ethical concerns, "large multi-center randomized trials would be the clear exception, not the rule," Meyer said.

The source of the data used to support Increlex approval - "three clinical trials (limited in size), an extension trial and an investigator trial" - is "not at all atypical for an orphan indication."

"Compared to other experience in this office with orphan drugs for rare conditions, the database from Tercica is quite robust, in terms of quantity and quality," Meyer said.

Furthermore, "we have no reason to believe that the data from the Laron's patients would not be generalizable to [the] broader population" - including those with very low IGF-1 levels, severe growth retardation and normal or high growth hormone of other causes beyond defects of the GH receptor, Meyer said. Laron's patients constituted 61 of the 71 subjects.

"Since Laron's patients have abnormalities in their physiology beyond linear growth alone that may well be more severe than those of others in the extended population, it is reasonable to believe that the Laron's patients would be an appropriately sensitive population to study mecasermin in."

"For hypoglycemia specifically, I know of no scientific basis to believe that the patients studied…would have less sensitivity to…m ecasermin than others."

Addressing the investigator training issue, Meyer noted that "while the investigators who provided the clinical data…at individual sites around the world may not be investigators who routinely perform clinical trials, FDA found no reasons to doubt the veracity or the quality of the data provided."

"In short, Insmed's citizen petition raises many issues which we either explicitly or implicitly considered" in reviewing the Increlex NDA, Meyer said. "I have concluded that Tercica has provided adequate evidence of safety and effectiveness."