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Fw: NATAP: FDA Hepatitis C Hearing Ongoing

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  • Alley Pat
    NATAP http://natap.org/ ... FDA Hearing on Clinical Trials Designs for New Hepatitis C Drugs Reported by Jules Levin Oct 19 is wonderful downtown Silver
    Message 1 of 1 , Oct 21, 2006
      NATAP http://natap.org/


      FDA Hearing on Clinical Trials Designs for New Hepatitis C Drugs

      Reported by Jules Levin

      Oct 19 is wonderful downtown Silver Springs, Maryland at the posh Hilton Hotel the FDA held a unique public meeting of its Antiviral Drugs Advisory Committee to discuss design issues in the development of products for treatment of chronic hepatitis C, including co-infection with HIV. The public open sessions were Oct 19 from 8am to 4pm through Oct 20 until 12 noon. After that is a closed session with pharmacutical companies.

      Several hundred attendees crowded the plush auditorium room at the Hilton where in the past the FDA has held hearings for new HIV drugs. The attendees included all the pharma and small bio companies developing HCV drugs or thinking of developing HCV drugs. The room was bristling like in the old days of the mid to late 90s when HIV protease inhibitors and HAART therapies were being introduced. It is of great interest to these drug developers and to patients how the studies for new HCV drugs will be designed and what requirements the FDA will mandate for these studies. It is also that these issues are very complex. It is clear we are entering a very promising new era for new HCV drugs. There are about 8 new HCV drugs either in or about to begin early pre-clinical & patient studies. Many of them are oral agents, orally administered drugs. It is important to realize, however, that at least for a number of years peginterferon and perhaps ribavirin will be part of any regimen used with new oral agents. Peginterferon is a drug that stimulates an immune response that leads to an antiviral response to the hepatitis C virus. Some feel this type of response to HCV is required even with 2 or more potent oral antivirals. However, some feel that a regimen with 2 or more potent oral antivirals alone will be adequate if it can drive down & suppress HCV viral load to undetectable levels. It is thought that the immune stimulation of peginterferon will be required to keep HCV at bay after viral load reaches undetectable levels. Another key issue is that of HCV drug resistance. There are divergent points of view on drug resistance regarding the new HCV protease inhibitor drugs. Some research developers of the new HCV PIs think that drug resistance is different. HCV is a highly replictative disease, and lots of mutations already pre-exist in a patient before starting therapy. So when a patient starts therapy if HCV is not very quickly suppressed mutations can emerge and be associated with viral rebound; the key they think is to achieve a quick suppression within 2 days to undetectable to prevent the emergence of drug resistance. The school of thought is that these mutations are not archived or 'catelogued', if you will, as are HIV drug mutations. They think that if the patient stops the HCV protease drug the virus will return to wild-type and the mutations will go away, and the drug could be used again by the patient. Of course, the other school of thought is that HCV protease inhibitor drug resistance will pose a considerable problem. I think we will have to wait for the results from the ongoing phase II study of VX-950, the Vertex hepatitis C protease inhibitor in order to perhaps get a better understanding of this.

      On both days, the committee will discuss clinical trial design issues in the development of products for the treatment of chronic hepatitis C infection. This meeting is being convened in response to the growing number of products in development for this indication. The primary objectives for committee deliberations are to discuss issues related to the identification of appropriate control arms, populations for study, endpoints, and long-term follow-up.

      Probably the most discussed issue was in which patient populations should companies be required to conduct studies to get initial approval for their drug from the FDA. The main question is: it it ok to conduct pre-approval studies only in treatment-naïve moninfected patients? Or should companies be required to also conduct pre-approval studies in difficult-to-treat patient populations: nonresponders, HIV/HCV coinfected, cirrhotics, pre & post liver transplantation. Ad if the companies should be required to conduct such studies, how much data is acceptable.

      The meeting opened at 8am with an introduction by Debra Birnkrant, MD, the Directorof the Division of Antiviral Products. This was followed by three talks meant to set the table for discussions for the remainder of the meeting. The 3 talks were by:

      Kenneth Sherman, MD, Director of the Division of Digestive Diseases at the University of Cincinnati.

      Jihn Vierling, MD, Chief of Hepatology at Baylor College of Medicine in Houston.

      Jules Levin
      Executive Director/Founder, NATAP

      This report will be brief and highlight the discussion by the FDA Advisory Committee panelists. During the first two talks, Sherman & Vierling discussed the epidemiology and data regarding why hepatitis C is such a crucial concern for the health of society. Over 170 million people worldwide have chronic hepatitis C virus, and in the USA 4-5 million. There are 25,000 to 40,000 new infections (cases) per year and about 10,000 deaths per year. Moratlity is predicted to increase from 10,000 per year now to 30,000 per year by the year 2010 as the infected populations age. Their talks focused on viral dynamics, immunopathogenesis, disease natural history, current standard of care therapy, and the 4 topics the FDA would like guidance on at this hearing: control arms, populations for studies, endpoints, and long-term follow-up.

      I discussed two key recommendations:
      1. The HIV drug development model should be considered for hepatitis C drug development. New HCV drugs should be considered for Fast Track designation, accelerated Approval, and Expanded Access.
      2. It is crucial to figure out how to conduct studies of multiple investigational drugs. In other words, studies should be conducted prior to their approval of 2 or more new drugs in combination, and I suggested that this could begin in phase IIb after initial studies have been conducted and safety and efficacy of a new drug has been characterized to some degree..

      I asked to accelerate animal & human safety & efficacy studies. I said we need resistance assays for HCV drugs and resistance should we well characterized when companies submit their data to the FDA. I raised concerns that we don't want to expose study participants unwarrantedly to HCV drug resistance. And then I discussed study populations. I emphasized the need to conduct pre-approval study in HIV/HCV coinfected patients including safety, efficacy, and PK, and drug interactions. I also emphasized the need to conduct pre-approval studies in hard to treat populations: nonresponders, cirrhotics, decompensated ciirhotics, pre & and post liver transplant. And I emphasized the importance of studying new drugs in African-Americans and Latinos, but particularly in African-Americans. Regarding HIV/HCV coinfection I emphasized the compelling need for new therapies in coinfected patients. HIV accelerates HCV disease progression. HCV is now the leading cause of death & hospitalization, except perhaps for AIDS, in the USA. Coinfected patients need to be treated quickly & if a drug is approved only in naïve monoinfected, HIV coinfected will use it anyway. It is crucial to have adequate data for coinfected patients upon approval so they can make informed decisions on how to use a new drug.

      I also suggested long-term cohorts be set up to follow patients, and suggested a Hepatitis C Study Consortium. This would be a group designated to design & conduct studies in patients of multiple new investigational drugs.

      So what were key comments from committee participants?

      There was much discussion regarding whether studying only monoinfected naives for initial approval was acceptable. Consider this, only 20% of monoinfected progress to serious disease complications. Will they want to be treated just because there are easy to take successful new therapies? I think that is up for discussion. Clearly, there is a tremendous unmet need & pentup demand for new therapy for nonresponders, HIV coinfected, pre & post liver transplants, cirrhotics, and decompensated cirrhotics.

      There was general agreement by most committee members that pilot studies in all these special patient populations should be considered. There was general agreement that African-Americans should be adequately studied in pre-approval studies, particularly considering HCV disproportionately affects African-Americans, and their response to peginterferon/RBV is subpar.

      A concern was raised regarding treating nonresponders. There are 3 types of nonresponders: null responders, partial responders, and relapsers. Concern was raised that it may be difficult to identify which patients were null responders to peginterferon/ribavirin. The concern is that if they don't respond to peg/RBV they might get resistance to the new drug, the HCV protease inhibitor or polymerase inhibitor. My response is, all the more reason to start multi-investigational drug studies during phase IIB of initial drug development for a new HCV drug. This discussion is ongoing now as the second day of the hearing has started. In today's discussion the 3 nonresponders are being distinguished. The relapser is different and would be a good patient for treatment with a new HCV drug plus Peg/RBV. The concern is patients with an unknown history of prior therapy for patients who are prior nonresponders.

      John Vierling, Richard Haubrich, Ken Sherman, and Ray Chung are strong supporters of requiring pre-approval studies in needy patient populations. Ray Chung suggests a 12-week Peg/RBV lead-in study to identify & characterize nonresponders. Sherman summarized that a null responder is a patient with <1 log by week 12, partial responder 1-2 logs.

      The FDA Background Briefing Document for this meeting is posted on the FDA website at:



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