Quality Assessment in Multiple Sclerosis Therapy-The QUASIMS Survey

Disease-modifying therapy, such as the interferons, have altered the clinical course of patients with multiple sclerosis. And with 3 interferons available, clinicians want to know, of course, how they stack up against one another.

A prospective trial comparing Avonex, Rebif, and Betaseron, however, is not available. An analysis was presented at ECTRIMS last September and extended with an abstract at the American Academy of Neurology's annual meeting here in San Francisco.

Dr. Volker Limmroth and colleagues presented data from the QUASIMS study. QUASIMS stands for "Quality Assessment in Multiple Sclerosis Treatment," and it looked at over 4700 patients with a mean duration of therapy of nearly 4 years.

Joining me today to discuss QUASIMS are Dr. Volker Limmroth, lead author of the study, and Dr. Jeffrey Greenstein. Dr. Limmroth is an associate professor of neurology and vice chairman of the department of neurology at the University of Essen and the director of the Multiple Sclerosis Center at the University Hospital of Essen. Dr. Jeffrey Greenstein is director of the Multiple Sclerosis Institute in Philadelphia.

Welcome to both of you.

VOLKER LIMMROTH, MD: Thank you.

JEFFREY GREENSTEIN, MD: Thank you.

HOLLY ATKINSON, MD: Thank you for joining me.

VOLKER LIMMROTH, MD: Thanks for having us.

HOLLY ATKINSON, MD: Volker, let's start with you. Describe for us the study design of QUASIMS.

VOLKER LIMMROTH, MD: Well, QUASIMS is a retrospective study and, as you pointed out, we don't have, at this point, prospective studies covering, actually, all 4 available interferon preparations. So we decided to have a retrospective study to include as many patients as possible. And the inclusion criteria were that the patient would have to be treated for at least 2 years without any interruption, and the exclusion criteria were any type of interruption within these 2 years.

HOLLY ATKINSON, MD: And, in fact, we saw that it was nearly 4 years; 3.7 was the average duration. Before we talk about the results of the study, Jeff, review for us the comparative studies that have been done to date before the QUASIMS data.

JEFFREY GREENSTEIN, MD: Well, there have been a number of comparative studies done of the interferons. The majority of them have really been open-label studies. Some of them have been randomized, but many of them, not. And so we have a real mixed bag in terms of design of these different studies.

2 of the studies have demonstrated some differences between the interferon products, particularly differences between Avonex and Betaseron and Avonex and Rebif. However, these differences have not been verified in all of the other studies that have been done. And so, in comparison with these 2 studies, we actually have 8 studies that don't show any differences.

The vast majority of individuals who have been studied have been in these 8 studies. And so, I think, overall, we have a considerable body of evidence that would suggest against significant therapeutic differences between the interferons.

HOLLY ATKINSON, MD: And, in fact, there were some major weaknesses in the 2 studies that did show a difference, were there not?

JEFFREY GREENSTEIN, MD: Yes, very significant weaknesses. One of the studies, the INCOMIN study, has a major problem in that there's a mismatch between the 2 groups of patients in the study. In addition, it was not adequately powered to actually demonstrate definitively and statistically that there were differences between the subjects who were studied. And, in fact, if one does a sensitivity analysis, it shows that there's very weak degree of significance, even in the study as it was conducted.

The other study comparing Rebif and Avonex, likewise, was a prospective and randomized study. However, it seems, in retrospect, in analyzing the study, that there clearly is a reporting bias in the sense that there was a difference in the way that patients were handled in referral to the examining physicians to verify whether they had had exacerbations. And that, in itself, could have explained some of the differences that occurred between these 2 groups.

HOLLY ATKINSON, MD: Now, Volker, that's really one of the strengths of the QUASIMS study is that it has tremendous power. That the number of subjects that you have are quite substantial.

VOLKER LIMMROTH, MD: We were lucky enough to have 510 sites who were willing to participate, and we were able to include about 4888 patients and, of those, 4754, I believe, had complete documentation. So we were able to include over 4700 patients with the study.

HOLLY ATKINSON, MD: Jeff, review for us the strengths and weaknesses of the QUASIMS study.

JEFFREY GREENSTEIN, MD: Well, I think, again, one of the great strengths is the fact that there were so many subjects in the study and that in itself tends to overcome some of the statistical problems one has with smaller studies. There were some difficulties in the study because, particularly with the Rebif 44 group, it was a relatively small number of subjects compared with the other 3 groups of individuals. They were relatively well-balanced and so, at least as far as we can see, they're relatively comparable groups for analysis.

Obviously, there's always some disadvantage in having a retrospective study in terms of study design. But, again, I think it's offset by the size of the study and the structure and conduct of the study, which I think have given us very robust data.

HOLLY ATKINSON, MD: Now, Volker, talk to us about the differences in the baseline of the EDSS findings on the patients. Because there were some differences here that need to be highlighted.

VOLKER LIMMROTH, MD: Right, there were some differences, which basically are due to the fact that the interferons entered the market at different time points. As you know, Betaseron entered the market as the very first one; Avonex was second. Then, unlike in the U.S., we had Rebif 22 entering the market, and then the last member in the family, so to speak, was Rebif 44, which came in '99.

So the treatment duration, that's one point, was pretty different because we had, of course, an average treatment duration in the Betaseron group that was over 5 years and the shortest group, actually, in the Rebif 44 group, about 3.8 years, basically representing the time points at which these drugs entered the market.

Furthermore, we had different mean EDSS scores. The highest, actually, in the Betaseron group, the lowest in the Rebif 22 group and the Avonex group was, I think, 2.4 and the Rebif 44 group 2.5.

And, as well, we had a different disease duration in these groups-shortest for the Rebif 44 group and longest, actually, for the Betaseron group. Again, reflecting, to a certain extent, the different time points at which these drugs were approved and introduced into the market.

HOLLY ATKINSON, MD: Now do you see that as a weakness in the study?

VOLKER LIMMROTH, MD: Well, not necessarily, because, since we have so many patients, we can adjust these differences, actually, statistically. And, by doing that we basically are able to homogenize the treatment groups, which is probably not possible if you have a study with just a few hundred patients. But since we had at least a thousand patients in the Betaseron, the Avonex group, we were able to adjust for these differences.

HOLLY ATKINSON, MD: Now, Jeff just mentioned that there were actually 4 arms in the study. Briefly review for us the design of those 4 arms, and then we'll talk about the outcomes in those groups.

VOLKER LIMMROTH, MD: Well, again, we included patients who were treated for at least 2 years. And, of course, we included patients (for instance, in the Betaseron group) which had been treated earlier already with Betaseron when compared, for instance, to the Rebif 44 group. Those patients were basically treated later because the drug came later to the market.

However, there is probably another little difference because colleagues in Europe tend to put patients with a suspected high disease activity directly on Rebif 44. However, I have to mention that, still, the vast majority of colleagues who are using Rebif are using Rebif 22. So the percentage of patients who were put directly on Rebif 44 were just like 6%, which still reflects kind of the current situation in most of the European countries.

HOLLY ATKINSON, MD: And tell us what the outcomes were for these various arms.

VOLKER LIMMROTH, MD: Well, the main outcome, I think, was that, with regard to the main outcome parameters, disease progression, relapse rate, annualized relapse rate, we didn't really see any significant differences between the treatment groups. So, especially within these-for the parameter disease duration, we saw actually an amazing similarity between the treatment groups.

We did see some subtle differences between the groups; I'm talking about relapse rates. But since disease progression is the most important parameter, I think we can deliver, as the most important message, that the drugs do not really different with regard to disease-with regard to the change of disease progression when they are used for a period of 2 years.

HOLLY ATKINSON, MD: Jeff, what do you make of these outcomes data?

JEFFREY GREENSTEIN, MD: Well, I think they confirm what many of us have thought before, based on the other studies, that the outcomes were going to be relatively comparable.

I think what it also tells us is that, with the interferons at currently used therapeutic doses, we essentially have maximized the benefit that patient with MS might get from these therapies. And I think, if patients don't get any further benefit from any of these drugs, we really should be thinking about having an impact on other mechanisms of disease, rather than an interferon-mediated disease.

And so I personally would not be one who would recommend switching people between interferons in the belief that one might, in fact, get therapeutically different outcomes. And I think the study really amply demonstrates to us that they're comparable, despite the fact that they have different doses, different dosing regimens, and different modes of administration. But the basic clinical outcomes are really what we have to pay attention to, and I think the study really emphasizes that.

HOLLY ATKINSON, MD: Volker, you're shaking your head yes-you're agreeing here.

VOLKER LIMMROTH, MD: I absolutely agree. That is our interpretation as well and I think one important other message from QUASIMS is that patients probably don't really benefit from being switching front and back. And one should ask, we, as treating physicians, should ask ourself, if a patient really suffers from a high disease activity, still, under the treatment with an interferon, and has been treated for 2 years, does it really make sense to switch that patient to another interferon, then wait another 2 years to see whether it has any impact on the disease activity? Or should we rather, then, really consider a combination therapy or, as we say, escalation therapy with an immune suppressant or a chemotherapeutic?

JEFFREY GREENSTEIN, MD: I guess there's one aspect that's actually rather interesting with this because you do have some patients who did switch in the study.

VOLKER LIMMROTH, MD: Right.

JEFFREY GREENSTEIN, MD: Perhaps you might want to comment about there's sufficiently valuable data on those patients. Did they differ in their disease progression when they were changed from one drug to another?

VOLKER LIMMROTH, MD: Well, what we tried to do was to differentiate between patients that received the drug as their initial treatment, so to speak. They got diagnosed with MS and then they were treated with the interferon for 2 years, so no other treatment in-between. And we differentiated those patients (or we separate those patients) from patients who already were treated with another interferon prior to the 2-year treatment period that then went into our database.

We are calling this treatment "followup treatment" and we did see, indeed, that those patients who received interferon as their followup treatment performed worse than those patients who received it as their initial treatment. Again, confirming what Jeff emphasized already that patients probably do not benefit from switching from interferon to another.

HOLLY ATKINSON, MD: And what about the "more is better" philosophy? What did the results say about that, Jeff?

JEFFREY GREENSTEIN, MD: Well, I think it really is what we've already discussed. The fact that we really don't have hard data to support that assertion. I think that there is a curve of efficacy for each of the interferons, but I think once they reach the plateau of that curve, they're comparable. The doses of the individual drugs are different, but I think they're on their plateau, essentially, and that's why I think we're seeing comparable data outcomes for these different arms of the study.

HOLLY ATKINSON, MD: Is there anything, Volker, you wished you would have learned from this study that you didn't?

VOLKER LIMMROTH, MD: Hm-mm. Well, I think QUASIMS has another important lesson to tell. It's that if, at baseline, the groups are not really balanced and especially if we have different disease activity within the groups, different disease activity, then you might even have a drug that is superior to another drug. You won't be able, really, to show this superiority.

So, in other words, drug trials and drug study trial design has to be very, very looked at with regard to disease activity prior to treatment initiation. And I think that is a shortcoming in many other studies that have been conducted so far.

And I think we may even have to look at other studies that have been conducted so far, again, regarding this aspect. How worse really was the disease activity at baseline once the treatment was initiated?

I think that was an important lesson to me, and I don't know whether I learned, really, anything I wouldn't like to know. But I think that was a very important lesson for me and maybe for colleagues as well.

HOLLY ATKINSON, MD: Hm. Jeff, what about side effects and patient compliance. That obviously plays a role here in the real world. And neurologists have to discern between agents here. What do these data mean about that? If efficacy is basically similar, how do you go about choosing an agent for a particular patient?

JEFFREY GREENSTEIN, MD: Well, my understanding, in this particular study, is that the range of side effects that occurred was generally comparable with the range of side effects that we've seen in the larger pivotal studies of each of these individual drugs.

And so I think that we can anticipate, for example, more skin reactions with patients who are being treated with the subcutaneous compounds. I think we have a higher profile of hepatic and bone marrow effects of Betaseron and Rebif, comparable to what we've seen in the other studies. I think the interferons are relatively similar when it comes to the flulike symptoms. So, in that respect, I think that the study has confirmed the side effect profile that we've been experienced to seeing in these other patients.

The study was not designed to look at the issue of neutralizing antibodies, but we know, from other studies--for example, the Danish study, which was a large study with all patients who were treated with all interferons in Denmark, that there clearly are differences in the extent to which antibody, neutralizing antibodies, are formed. And, as time passes, these 2 have an impact on disease progression, particularly relapses, but perhaps, over a longer period of time, disease progression as well.

This has not come out from QUASIMS, which essentially was looking at the issue of whether the doses are comparable, but I think they could potentially go back and examine that question as well.

We've not seen any side effect profiles that have been different from what we've seen in other studies, but I think the importance of the study goes back to the issue of answering the question of whether there's comparability of these compounds and their impact on disease.

HOLLY ATKINSON, MD: Volker, take-home points for the practicing neurologist?

VOLKER LIMMROTH, MD: I think one of the major points should be treatment has to be individualized. The colleague has to discuss with the patient where he or she is in his personal life and has to make the treatment decision according to the needs and the individual situation of the patient. QUASIMS probably doesn't really give the recommendation to use a drug A, B, or C but emphasizes that, since we probably can look at these drugs having a similar efficacy, that we can focus in the selection of the drug more on the need of the patient and I think that is another important issue.

HOLLY ATKINSON, MD: Final thoughts, Jeff?

JEFFREY GREENSTEIN, MD: Well, I, first of all, agree very much with Volker's comments. I think that this is a matter of individualizing therapy for patients. I think that this study really summarizes a body of data that has accumulated and these study--these patients or the subjects in this study really account for about 50% of the data that we have in all studies comparatively looking at interferon and their effects in MS. And I think the results are particularly persuasive.

I think that it hopefully will go some way to resolving this concern that has existed in the neurology world of differences in therapeutic outcomes in these different compounds.

HOLLY ATKINSON, MD: Well, thank you both for joining me. It was a great discussion.

VOLKER LIMMROTH, MD: Thank you for having us.

JEFFREY GREENSTEIN, MD: Thank you.

HOLLY ATKINSON, MD: And thank you for joining me. I'm Dr. Holly Atkinson.