Biotech Values

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Gentium (GENT) Pulls NDA, Was This Predictable?

http://www.gekkowire.com/?p=8318

Yesterday, Gentium announced that they had to withdraw their NDA filing for Defibrotide to treat severe VOD (veno-occlusive disease). The company said yesterday that during the FDA’s initial review the FDA raised concerns regarding the completeness of the datasets for both the treatment and prevention studies. The FDA requested that the Company conduct additional quality reviews of the original datasets and databases. The FDA also requested additional details regarding the conduct and monitoring of the trials by the independent review committee. Believe it or not, this is not a new problem with Gentium.

I had previously been doing background research into Gentium in preparation for a possible PDUFA. Since the company pulled their NDA filing, I guess there is no harm in releasing some of the research I had dug up on the company’s troubled U.S. Clinical Trial for the drug.

I’ll be honest, the withdrawal of their NDA is not a huge surprise to me, nor would have been an RTF. In fact, I was prepping this article to be released about a week before the 60 day NDA window that the FDA usually decides whether or not to accept an NDA, but since I the company pulled the NDA earlier than that there is no harm in releasing some of the back research I had done.

The efficacy of Defibrotide to treat hepatic VOD in HSCT patients is supported by data from a multi-center Phase 3 historicallycontrolled trial, evaluating Defibrotide for the treatment of severe VOD (patients with VOD and multi-organ failure), a Phase 2 dose finding study, and interim data reported from the ongoing Phase 3 expanded access U.S. Treatment IND program in patients with severe hepatic VOD. Additional data include a Phase 3 randomized controlled study of Defibrotide in the prevention of hepatic VOD in pediatric HSCT patients.

Investors, might not be aware of the issues the company faced in the supporting trial that was completed in the U.S. Originally, the supporting Phase 3 trial of Defibrotide had a primary endpoint of survival at 100 days after stem cell transplantation, and a secondary endpoint of complete response.

Fast forward to the end of 2007 and June of 2008 and it became openly apparent that the company was having very serious problems in completing the trial.

The company had announced in December 2007 that they had “filed an amendment to the protocol for its Phase III clinical trial of Defibrotide to treat Severe VOD. The trial previously had a primary endpoint of survival at 100 days after stem cell transplantation, and a secondary endpoint of complete response. The amendment reversed those endpoints, making complete response the primary endpoint and survival a major secondary endpoint.” Changing of Primary Endpoints while clinical trials are running is a big red flag for biotech investors. While it does not always produce a negative outcome it certainly does heighten suspicion as to the company’s ability to perform a clinical trial properly.

But the matter didn’t get better with the next quarterly update, in fact the next quarterly update in June 2008 was an utter and complete disaster. The company said that a Data Safety Monitoring Board (DSMB) had performed an interim safety analysis and found no safety concerns, but what they did find was utterly unacceptable.

The company disclosed that the DSMB asked the Company to clarify and supplement certain trial data in order to complete the remainder of the interim analysis. Gentium then goes on to disclose in the Press Release that the DSMB “recommended reconfirmation of the patient enrollment criteria, and “data clean-up” as is stated in the trial protocol.” In other words, the DSMB didn’t seem to be sure the company was enrolling the proper patients nor was the data thought to be “clean,” data clean up activities are measure that are typically required to prepare study data for regulatory: analysis and evaluation. From my perspective this was basically a big telegraph for Biotech investors that something was very wrong with the company’s ability to perform a solid trial and at a minimum practice good record keeping.

I think there is a significant risk that the company may be required to run another trial in the U.S. to support an NDA. Granted the company has data from an expanded access program, but from my perspective something is clearly very wrong with the trial data and its reliability.