Long Term Update
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Etanercept: Long-Term Safety Update Mark Genovese, MD Pharmacovigilance Program Jan 7, 2001 A method of going about answering the long-term safety issues. That would be through the development of what might be called the Pharmacovigilance Program. It would be all the ways you might potentially go about trying to follow these over time. If you take a look, these are the current programs that are to assess long-term safety. Surveillance of Etanercept Spontaneous Safety Reports Slide. Pharmacovigilance Program The first one is Safety in Etanercept in Spontaneous Safety Reports. The way the FDA put that really was facilitated consumer reports, and what does that really encompass? Well, it encompasses any of us as practitioners as we fill out a Med Watch Form. A Med Watch Form is the way that any of us, as providers, can report an adverse event. The other way that etanercept Spontaneous Safety Reports can come in, can come in through consumer facilitated reports through an 800 number, which is 1-800-4-E-N-B-R-E-L. This is the largest way, and should I say the majority of the way that adverse events become reporting. Any patient that calls the 800 number for any reason and describes an adverse event, that adverse event will be logged, it will be followed up, and then it will be reported to the FDA. What are the long-term etanercept safety trials? There is a long-term safety trial of etanercept in the United States. There's also a long-term safety trial with etanercept in Europe. These are for all of the patients that were randomized at the double-blind, placebo-controlled studies in the past on etanercept, whether it be placebo or not. These patients are followed long-term, as long as they're willing, and those adverse events can be captured in a systematic way. As well there are safety registers. All patients in Europe that obtain etanercept should be entered in the safety database. In the United States, all pediatric patients treated for JRA are entered into the JRA Safety Registry. And lastly, there's a safety study. This is one that's been done right now in collaboration, both by the FDA and with Immunex, looking at what happens with patients that are at the highest risk of adverse event(s). This study takes 1,000 patients that have comorbidities. In order to get into this study, you have to have insulin-dependent diabetes, you have to have COPD or asthma, you have to have had pneumonia in the last year, or you have to have had at least two upper respiratory tract infections. If you don't have a significant comorbidity, you can't get into this double-blind, randomized, placebo-controlled study. The goal here is to assess do these patients really, or should I say does etanercept really convey increased risk of side effects for patients that have comorbidities? I think this is the best way we're going to answer that question in the short-term and potentially the long-term. Slide. Etanercept Post-Approval Experience Looking at etanercept as a whole, it's been available for clinical use in the United States since November of 1998, available earlier than that in clinical trials, and that's where our long-term safety studies come from. Overall, there have been a total of 80,000 patients in the United States that are receiving Etanercept, and a total of over 60,000 of exposure. How is that relevant? Well, I think it's relevant because you can put ([a perspective]) on the adverse events reporting and changes in labels. Labels get changed for two reasons. Labels get changed predominantly so they can inform providers of potential risks, and so that those providers can assess the risk based on their individual prescribing habits, so they can make decisions about whether or not a therapy is prudent for an individual patient. Moreover, those changes in the label are designed to help patients decide if they believe it's prudent, although most of the time, patients really have not seen a package insert. So for the most part, it's to inform providers of the potential benefits and risks of the therapy, and we should be excited about the fact that labels do get changed over time, because otherwise, most of us would have no good way of knowing what the potential ramifications of any therapy are. Now with that, have there in fact been changes? Slide. Enbrel Label Update-Hematologic Events The first one is hematologic events. You notice that there is a label change that occurred this year and most of you received your doctor letters, whether you're in Europe or North America. What do the safety report or the label update mandate? Well, there are rare reports of pancytopenia, including aplastic anemia, some with a fatal outcome. They were reported in patients with RA that have been treated with etanercept. The problem is they've also been treated with a lot of other things. The causal relationship to etanercept remain unclear. Although no high risk group could be identified, caution should be exercised in treating with etanercept, and patients that had a previous history of significant hematologic abnormalities. Patients should be advised, if they develop signs or symptoms suggestive of a blood dyscrasia or infection, that they should seek medical attention, and should those hematologic abnormalities be confirmed, consideration should be made to discontinue your therapy. Slide. Reported Hematologic Events Now from what was just predicated, there have, in fact, been rare reported cases of pancytopenia in the neighborhood of about 11 cases. In fact, there have been 4 cases of aplastic anemia. Most of these patients have been treated with significant drugs in the past. They've all been on many prior disease modifying drugs. Most of them are on multiple concomitant medications including methotrexate, azathioprine, cyclophosphamide. There was no causal relationship associated with any of these patients. Some patients have been on approximately 4 weeks of therapy. Some had been on every year therapy with etanercept. There was no change recommended in laboratory monitoring of these patients, although I think in honesty, it's prudent that we evaluate the way we measure what white cell count, platelet and hematocrit in our individual patients, based on our perceived risk for that individual patient. Slide. Enbrel Label Update-Neurologic Events Additional changes as a label update associated with neurological events - rare cases of central nervous system demyelinating disorders were described as Spontaneous Adverse Event Reports. The causal relationship to etanercept remains unclear. While no clinical trials have been performed evaluating etanercept therapy in patients with multiple sclerosis, other TNF antagonists administered to patients with multiple sclerosis have been associated with increases in disease activity, and prescribers should exercise caution, considering the use of etanercept patients with preexisting or recent-onset CNS demyelinating disorder. The majority of animal models have suggested that anti-TNF therapy would be beneficial in down-modulating multiple sclerosis or preventing relapse in remitting disease. As it turns out, two patients have been treated with CA2 in 1996. That was the name previously given to infliximab.. These patients demonstrated increased evidence of lesions on MRI. Only two patients and no other patients have been treated with infliximab for multiple sclerosis. The second study was using lenercept, which is P55 fusion protein. This was done in patients with multiple sclerosis. These patients had more exacerbations of potentially greater frequency, as well as greater severity in their exacerbation for multiple sclerosis, but no substantial and no statistically significant MRI changes over time. Overall, what do we know about patients that have been treated with etanercept in demyelinating disease? Slide. Reported Neurologic Events We know right now that there have been rare reported cases, CNS events, associated with demyelinating disease. Overall, we know about four cases of relapse of multiple sclerosis, so patients with MS who had relapsed while on etanercept. We know of two cases that have new development of multiple sclerosis with the treatment of etanercept. We know of a sporadic number of patients of optic neuritis, as well as myelitis, total approximately 9 cases by the FDA abstract. Overall, this is based on 60,000 patient-years. I guess the question is, how often does multiple sclerosis occur as a whole, and how often do we know whether it occurs in RA? Those are difficult questions. Overall, we would expect about 130 cases per 100,000 patients of multiple sclerosis. We might expect relapses to occur about once every 12 to 18 months in patients that have multiple sclerosis. We might expect somewhere in the neighborhood between 2 and 6 cases in any given year. The question really is, and this one we don't know, is multiple sclerosis or any other demyelinating disease occurring at a greater frequency based on the denominator that we have here than it would or without the use of etanercept or any other CNS inhibitor? There have been, rare new cases of multiple sclerosis. The question is, are these, in fact, within the expected range? Based on the data we have now, I suspect they are, but this is one of the things we need to follow over time. Right now no causal relationship has been established, associated with etanercept. In fact, some of these patients have been on etanercept for a short duration; some of these patients have been on etanercept for a longer duration. Again, other TNF antagonists administered to patients with MS have been associated with exacerbation of that disease. Of course, we had not heard publicly about the exacerbations of MS with other TNF agents in RA at this point. There are additional label changes. Slide. Enbrel Label Update-Infections Those include the label changes associated with infection. There have been post-marketing reports of serious infections and sepsis, including fatalities. They're reported with the use of etanercept. Many of these serious adverse events have occurred in patients with underlying diseases that, in addition to their rheumatoid arthritis, could predispose them to infection. Patients who develop a new infection while undergoing treatment with etanercept should be monitored closely, and administration of etanercept should be discontinued in cases of serious infection or sepsis. Treatment with etanercept should not ([be]) initiated in patients with active infection, including chronic or localized infection, and physicians should exercise caution when considering the use of etanercept in patients with a history of recurring infection or underlying conditions, which might predispose the patients to infection such as advanced or poorly controlled diabetes. What has been the underlying cause of a label change there? Slide. Reported Infections There have been infrequent reports of serious infection, some with fatal outcome. The question is, how often is this occurring? Are there associated risk factors? There certainly seem to be on the surface such as diabetes and other comorbid illnesses. The largest safety study looking at comorbid illness with the use of TNF inhibitors is already underway. Slide. Serious Infections and Infection-Associated Mortality The rate of reported infections in ([the]) post-approval database, for the most part, has remained stable within rates reported from other clinical trials. Well, is that in fact true, and what have been the reported rates in other clinical trials? This is what was most recently recorded by the Mayo Clinic looking at population-based statistics from Olmsted County. They are, in fact, 9.2 serious infections based on 100 patient-years with patients with RA, and 0.6 infection-associated mortalities per 100 patient-years in RA patients. How does that correspond with other data? Well, looking at data from the Aramise database would suggest that there is, in fact, a rate of infection associated mortality of 0.36, infection-associated mortalities per 100 patient-years, very much consistent with this, although slightly lower, but still higher than what we're seeing with our active therapies. Prior articles have suggested infection-associated mortality occurring at this rate, depending on which study and which population is looked at. What have we seen as far as etanercept clinical trial data and how does it compare with both our historical controls and our contemporary controls? Looking at placebo-controlled studies, this was the rate of serious infections as seen in the etanercept studies. Infection-associated mortality in the studies was zero here, zero there, and 0.1 infection-associated mortalities per 100 patient-years. And how does that correspond with the overall post-approval spontaneous safety reports that have been reported? Well, right now we're seeing less than one serious infection per 100 patient-years in the spontaneous safety reports, with a rate of 0.1 infection associated mortalities per 100 patients years. The rate of mortality associated with infection in the long-term studies and in open-label, spontaneous or post-marketing experience, still fall shy, ([of]) what we see in the literature, as well as our control(s) from clinical study. Now overall, what is the goal of these post-approval spontaneous safety reports? Slide. Post-Approval Spontaneous Safety Reports They are clearly useful for new therapy, and the goal is to derive a database significantly large enough in size to enable the opportunity to capture uncommon events. More than that, it enables the ability to potentially capture or find events that may constitute a safety signal, so that additional studies can be done, or so that providers and patients can be warned appropriately. It provides an opportunity to inform the medical community. As well, it provides an opportunity to adjust what might otherwise be considered a Pharmacovigilance Program. Long-Term Etanercept Safety Trials (North America and Europe) Slide. Pharmacovigilance Program What we know to date about the long-term Etanercept Safety Trial. Slide. Methods It's been performed in adults with longstanding rheumatoid arthritis that had previously been studied in double-blind, randomized, placebo controls in North America. The evaluations in these patients occur frequently and routinely, every 3 to 4 months, and adverse events are collected in a systematic fashion to enable comparison throughout the database. Slide. Demographics What's been seen is for those 1,628 patients, roughly 53 years of age, the majority of these are women, and the mean duration of disease is approximately 12 years, substantial duration of disease. The majority of these patients are on corticosteroids and NSAIDs. Slide. Duration of Exposure (1336 patient-years) So far, approximately 500 or so have been in this study for a year, another 400 for 2 years, and then smaller numbers have been studied out for 3 and for 4 years. Slide. Discontinuations What we know is that the discontinuation rates have generally been low, and they're broken up fairly uniformly between adverse events, lack of efficacy, and then other logistic reasons such as a refusal or moving out of a particular study area. Slide. Infections Associated with Hospitalization/IV Antibiotics What's been seen as far as infection-associated hospitalization, are you surviving antibiotics, what might be characteristically classified as class 3 or class 4 adverse events. This rate, for the most part, has remained stable in patients over the period of 4 years. More than that, there have been no opportunistic infections reported in this study, no increase in rate over time, and again 88% of these patients have continued on the etanercept. Slide. Malignancy There had been malignancy seen, but they have not occurred at frequency greater than what would be expected for age- and sex-matched controls from the Seer database at the NIH. There's no predominance and type of malignancy. What do we know again about mortality? Slide. Mortality Well, one that comes up most commonly is how infrequently is infection-associated mortality occurring? From the Aramise database, there's a 20% infection-associated mortality in the contemporary cohort of patients. What we're seeing from the Olmsted County population-based database in the Mayo Clinic, which suggests infection-associated mortality of approximately 15%, and what we're seeing with etanercept in the long-term database is approximately 18%. This falls right smack in the middle of what we see between the Mayo Clinic and what we see as the long-term outcomes from Stanford and the Aramise database(s). Slide. Summary Overall, we see an adverse event profile in the open label extension study that is similar to what we see in a placebo-controlled trial. We see that serious infections can occur but they do not occur at increased frequency over time, we have not seen opportunistic infection, and malignancies have occurred at a frequency to what would have been expected for age- and sex-match(ed) control(s). There's been no cumulative toxicity that's been evident based on clinical trials or in the long-term post-marketing surveillance. The rare events have been reported with ([the]) post-approval database, and they have, in fact, led to label updates. The rates and the types of adverse events seen in these remain stable, up to 4 years of treatment in this clinical trial, and a large number of patients with RA have received substantial benefit from etanercept over time. So it's important to put this in the appropriate context. |
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