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Mary Jean Slugs It Out in Gaithersburg

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tagline May 2001

Roche’s Valganciclovir is Recommended for Approval


On 27 February at the sad and lonely Gaithersburg Holiday Inn, the FDA’s Antiviral Drug Advisory Committee (ADAC) held a hearing to discuss Hoffmann-La Roche’s NDA for valganciclovir for the treatment of CMV retinitis in people with AIDS. One would have thought that CMV - once the second leading cause of death in PWAs - was an infection on par with toe fungus by the meager audience turnout. It was, however, an historic day for CMV research:the first oral drug with real efficacy to treat CMV was about to be recommended for approved. One couldn’t help but wonder, “Where was this drug ten tears ago when we really needed it?” The ADAC committee was absent of some of its members, most notably Roy “Trip” Gulick, the acting-chair. Roger Pomerantz filled in nicely for Trip, and luckily old-time HIV experts Princy Kumar (Georgetown) and Chris Mathews (UCSD)were present for a reality check. The advisory committee was infused with some well-respected ophthalmologists who unfortunately got “stuck-on-stupid” during the question and answer period. Roche’s Mary Jean Stempien, who is considered the mother of IV ganciclovir from the late 1980s, was back at the helm presenting the valganciclovir safety and efficacy data. Emory’s Dan Martin, the consummate overaccruer and good-natured ophthalmologist, was on-hand to answer the technical ophthalmologic questions.

I had wondered why the FDA’s Antiviral Drug Products Division requested a public hearing on valganciclovir, the valine-ester prodrug of IV ganciclovir. The valganciclovir data are excellent and there are years of experience treating thousands of people with IV ganciclovir. A source close to the Division told me the hearing was needed because: 1) only one trial of 160 people was being used for efficacy analysis; and 2) the sponsor was requesting an indication for CMV induction and maintenance therapy but only had efficacy data from the 4-week randomized valganciclovir vs. IV ganciclovir induction phase. Roche pointed out three reasons it deserved an indication for maintenance therapy:

1. Valganciclovir provides systemic exposure (AUC) comparable to IV ganciclovir;

2. Valganciclovir’s efficacy in the induction phase—the most rigorous test of a CMV drug—was similar to IV ganciclovir;

3. Valganciclovir offers exposure 10-times that of oral ganciclovir (and it’s approved for maintenance), valganciclovir should be considered at least as effective for maintenance.

Mary Jean Stempien and Dan Martin were on their toes the entire day answering questions and showing a myriad of back-up slides. Some of the pharmacology questions were interesting (i.e., “Is using AUC the best gauge for determining bio-equivalence”), but most of the others were too painful to sit through. I wondered if some of the ophthalmologists really knew HIV clinical care and understood the entire HIV-positive individual,not just his or her eyes. One ophthalmologist did not like the rate of anemia attributed to valganciclovir during the open-label maintenance phase. He repeatedly wanted to know if Roche would consider lowering the maintenance dose. Mary Jean began answering his questions simply and calmly, but when he just wouldn’t let up, she lost her polite and professional tone of voice and let him have it. I have paraphrased her comments below.

Since the ADAC already had a straightforward TAG statement that recommended valganciclovir for approval, I decided to discuss the questions which were soon to be voted on. With regard to its efficacy, I said that valganciclovir was comparable to ganciclovir, and it’s surprising that even one study was ever completed during the HAART era. I reminded them that after 20 years of AIDS, an effective oral CMV treatment is still not available. I also reminded them that Roche headquarters in Basel wanted to stop the development of valganciclovir because of fear that CMV had gone away and there would be no market. As for its safety, I said valganciclovir is IV ganciclovir in a pill and all good HIV doctors know how to manage ganciclovir’s hematological toxicities. When it came to the question of valganciclovir’s effectiveness as maintenance, I informed the ADAC that most CMV drugs were approved for induction and maintenance therapy using an immediate versus deferred trial design. Such studies only told us that the drug was better than nothing (deferring) and were stopped so early by a DSMB that no real maintenance data exist. Why was the bar being suddenly raised for valganciclovir?”