Press room ... 1996 archive

Project Inform Support for
Accelerated Approval of Ritonavir

February 29, 1996

San Francisco, CA—Project Inform today announced its support for accelerated approval of the Abbott protease inhibitor ritonavir (Norvir) for all HIV-infected people for whom therapy is indicated. Due to many unanswered questions about the use of the drug, Project Inform did not support the manufacturer’s request for “traditional” approval, an FDA mechanism which would not technically require any confirmatory studies or a secondary review by the FDA. Project Inform Founding Director Martin Delaney commented, “This is truly a very promising drug but we feel that the research about how to use it has only begun. In our view the study data submitted in support of ‘traditional’ or ‘full’ approval does not warrant an unqualified endorsement and may in fact lead to widespread misuse of the drug.”

Abbott Laboratories, maker of ritonavir, submitted a study in which either the drug or a placebo was given to people with advanced HIV disease, for use in addition to whatever other therapy, if any, the patients chose to use. Used in this fashion, the manufacturer reported that the drug produced slightly less than a 43% reduction in the death rate and a 58% reduction in the rate of new infections or death after four months of use. “While this outcome is significant,” Delaney continued, “it overlooks two other important facts from the study. It is our understanding that the majority of the deaths reported in this data occurred within the first six weeks of treatment, raising questions as to whether the outcome reflects the true longer-term effect of the drug. More importantly, we are very concerned that the data shows a rapid loss of antiviral activity, probably due to the development of drug resistance, within six months when used in this fashion. Since resistance to this drug confers resistance to most other protease inhibitors, there is good reason to fear that such a use of the drug may lead only to short-term benefit followed quickly by long-term multi-drug cross resistance to many of the key products in the field of protease inhibitors. There is evidence that the drug can work far better when used properly; giving too much weight to this data may promote use of the drug in this sub optimal fashion.”

Ben Cheng of Project Inform added, “In light of this, along with other concerns about the large number of drug interactions and the lack of any long-term safety database with this drug, it seems premature and unnecessary to grant traditional or full approval. We gain nothing from ‘full’ approval. The accelerated approval mechanism will provide full access to the drug while also requiring a second look after additional data is collected. We should also be very sensitive to the fact that this is the first major anti-HIV drug to seek approval without having any meaningful period of expanded access, which is our usual first source of real world safety data in large numbers of people. At this point, less than 500 people have been on the drug for longer than 6 months.”

Aside from the question of the approval mechanism, Project Inform expressed great hope for ritonavir and other drugs in this class. “Clearly,” said Ben Cheng, “protease inhibitors are the most powerful tool we have yet seen for suppressing HIV viral activity. We have never before seen drugs which can produce this level of short-term effects, and at least when the drugs are used properly, there is every reason to believe that long-term effects can be sustained.”

Project Inform believes that data from any of the individual protease inhibitor drugs should not be assessed in a vacuum, but in the context of all the data from the study of similar drugs. Other studies clearly demonstrate that when used alone as single agents, protease inhibitors can quickly induce the development of resistance, and that resistance to some drugs, such as ritonavir or indinavir, confers cross-resistance to most other protease inhibitors. Because of this problem, the most significant data submitted thus far by all manufacturers favored the use of protease inhibitors in carefully selected three drug combinations. Delaney said “The three drug combinations have consistently shown the largest and best sustained suppression of virus and viral resistance, as well as the best improvement in immunologic markers. Therefore, we think it is critical that Abbott make clear to physicians and patients that great care should be employed in how these drugs are used. Simply adding them without thought to existing therapy is unlikely to produce a lasting benefit, while running a large risk of creating multi-drug cross resistant strains of virus. This has implications for the individual and for the public health as well, since this cross-resistant virus could be transmitted to others.”

Project Inform urges Abbott Laboratories to collaborate with the Federal government and other manufacturers in a broad new program of clinical trials designed to answer the many questions now raised by the advent of this new generation of more powerful therapies.