April 11, 2002
Jeffrey Greenstein, MD; Temple University School of Medicine,
PA James Miller, MD; New York Presbyterian Hospital, Columbia University, NY
William Stuart, MD; MS Center of Atlanta, GA
For the 300,000 people in the U.S. who have multiple sclerosis, the Food and Drug Administration's recent approval of a drug called Rebif is important news. The FDA approval broke a monopoly held by Biogen, the maker of Avonex, under a government program meant to encourage treatment research for uncommon diseases such as multiple sclerosis. Under this government program, Avonex's status as an "orphan drug" meant that no competitor could be approved for sale in the United States before May 2003 unless it was shown to be safer or more effective.
The US approval was based on a short-term comparison trial with Avonex called the EVIDENCE trial, as well as a long-term placebo-controlled trial, known as the PRISM trial, which led to its earlier approval in many countries outside the US.
For patients, this approval opens the door to one more treatment option for a difficult and incurable disease. Below, MS experts discuss the recent Rebif approval.
Is this approval good news for the MS treaters and patients?
JAMES MILLER, MD: It's heartening in that we have another drug to use. And it's been sustained that these drugs really do have a relatively potent effect on multiple sclerosis.
What kind of data was the approval based on?
JEFFREY GREENSTEIN, MD: The study was essentially based on the first 24 weeks of treatment, which showed that patients on Rebif had slightly fewer attacks compared with patients on Avonex. However, the 48-week extension of the study has shown that they're fairly even with regard to reduction of attacks.
JAMES MILLER, MD: The longer term studies of Rebif that have been done show approximately the same effects as you get with the other two medications ( Avonex and Betaseron) that are available here.
The recent EVIDENCE trial included 677 relapsing, remitting MS patients between the ages of 18 and 56 who had not been treated with any interferon before. These patients underwent repeated clinical and MRI assessments while taking either Rebif or Avonex for a period of 24 weeks. How did this study compare to most other MS trials?
JEFFREY GREENSTEIN, MD: The design of the study was different from the designs that we've seen in longer-term studies. This study was done as what we call an open-label study, which means that the subject getting the treatment, and the examining physician, both knew which drug the patient was on. This is in contrast to longer-term studies, which are blinded studies, where neither the treating physician nor the patient getting treatment know what they're on. An open-label study can introduce potential bias because people know which treatment they're on.
What are the advantages of an open-label study?
WILLIAM STUART, MD: They're inexpensive and quick. Double-blind, randomized trials are very, very expensive, difficult to set up and time-consuming.
JEFFREY GREENSTEIN, MD: Open-label studies have certain advantages. For example, if you're looking at long-term safety, it doesn't matter that the individual knows which treatment they're being given. However, when you're looking at drugs comparatively, to see if they differ in terms of their efficacy in treatment, you have to blind the studies because you don't want to introduce potential bias, which can skew the outcome of the study.
Since MS is a lifelong chronic condition, how do you place the results of a short-term trial in perspective?
WILLIAM STUART, MD: If you look at all MS patients, relapse rates occur, on an average, once a year. So if you've got a 24-week trial, you could find many patients that would randomly have their relapse in that first 6 months.When you carry on a long-term trial over the two-year period, then you've got a chance to let events occur and you don't risk bias affecting your statistics.
JEFFREY GREENSTEIN, MD: The major outcome we were trying to look for in treating patients with MS, particularly since it's a chronic disease that's going to last for many, many years, is the improvement and prevention of progression of the disease. This is the most important outcome in a clinical study. It's important to reduce attacks of MS. However, they're not as serious in terms of long-term outcome compared with progression of the disease.
So what should people with MS do if they're considering stopping or even switching from their current medication?
JEFFREY GREENSTEIN, MD: Well, some individuals who hear about the study might feel inclined to switch from the treatment they're on to Rebif. If they're on a medication that is working for them, I don't see any reason for them to change to another medication. The availability of Rebif, however, does give us some different options that were not available before.
JAMES MILLER, MD: I have patients who are still on Betaseron, which is a relatively older drug. I wouldn't suggest that they switch to anything else if they're doing well. And this also holds true for those patients doing well with Avonex.
WILLIAM STUART, MD: As a doctor, I want to get a patient on a drug that they can stay on for a long period of time that won't cause them any side effects and that remains effective.
So what are some of the considerations for patients and doctors in choosing among treatments?
JEFFREY GREENSTEIN, MD: I think when one looks at choosing amongst the drugs, the most important considerations are long-term disability, cognitive function, and "brain atrophy".
In addition to considering how the treatments will affect these factors, patients need to think about convenience and lifestyle issues -- such as frequency of injection and site of injection, as well as the occurrence of side effects.
The most common side effects associated with interferons are flulike symptoms. What are some of the other common side effects?
JEFFREY GREENSTEIN, MD: About 90% of patients on Rebif will have skin reactions at the injection sites compared with about 3-4% of people on Avonex.
Interferons can also have long-term side effects such as elevated liver enzymes and low white blood cell counts. How significant are these side effects?
JAMES MILLER, MD: These effects are usually not very consequential, but they can be. They tend to occur more frequently -- both the liver and the white cell count depression in the use of the high frequency, high-dose drug such as Rebif and Betaseron, as opposed to Avonex.
What is the most important message you would like to send to people considering treatment for MS?
JEFFREY GREENSTEIN, MD: About half the people living with MS in the U.S. should be on treatment and are not. I think one of the major issues we have to deal with is why people don't go on treatment. There are a number of different reasons for this, including fear of injections, insurance coverage concerns, and so on.
The most important message we can give somebody with MS is that treatments
are available, and some of the hurdles that might seem to be there to prevent
them from getting treated can be overcome.
Copyright 2002 Healthology, Inc