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MS treatment: Postmarketing studies
Journal of the Neurological Sciences 259 (2007) 42 – 45 www.elsevier.com/locate/jns
MS treatment: Postmarketing studies X. Montalban⁎ EUI planta 2, Unitat de Neuroimmunología Clínica, Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain Received 16 February 2006; accepted 10 October 2006 Available online 26 March 2007
Abstract Multiple sclerosis (MS) is an inflammatory chronic demyelinating disease. Nowadays, there are several registered drugs aimed to control the disease activity. Because these drugs are given parenterally for years, it is of utmost importance to attain maximum adherence to treatment through close and permanent care of patients. The efficacy of the different registered drugs has been compared against placebo. Observational and head-to-head studies have shown controverted results in the degree of efficacy between the products. Despite the efficacy reported, a high proportion of patients will have a lack of response to treatment. Early identification of these patients is therefore essential in order to attempt other therapeutic approaches. © 2007 Elsevier B.V. All rights reserved. Keywords: Multiple sclerosis; Interferon; Observational studies
1. Introduction Treatment of multiple sclerosis (MS) has experienced a radical change in the last decade. Nowadays, we have several formulations of immunomodulatory drugs (IMD) approved and registered for the treatment of the disease. Clinical trials with IMD in the past few years have demonstrated to exert a reduction of the disease activity [1–6]. Nevertheless, in most cases these data of efficacy emerge from clinical trials with durations under 4 years. Due to their short-term follow-up, clinical trials in RRMS can render erroneous clinical results [7,8]. Moreover, such results can be only partially reproducible in the daily clinical practice, because of the varying demographic backgrounds and clinical factors of the populations studied. Observational cohort studies bear the benefit of relatively easy long-term monitoring and can supply data on the behaviour of cohorts during extended treatment periods [9]. Although randomized, controlled trials must be considered the “gold standard” for research design,
⁎ Tel.: +34 932746202; fax: +34 932746084. E-mail address: [email protected]. 0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2006.10.022
agreement between their results and those from observational studies support the potential value of the latter. Several reviews approaching meta-analysis have shown that results from observational studies consistently match the data obtained in randomized, controlled trials [10–12]. Nevertheless, there are factors that may hinder the analysis of such observational studies, including the very lack of randomization, variation in duration of treatment, incomplete monitorization, dropouts and unaccounted drug switches [9]. 2. Factors related with dropouts and drug switches One of the problems that new IMD therapies pose is a relatively inconvenient administration procedure, side effects and the long periods on therapy. These factors can contribute to diminishing a patient's adherence to treatment. Bearing in mind that there is no efficacy in the event of IMD interruption and with the aim to obtain maximum benefit from the drug, it is paramount to help patients adhere to treatment. Awareness of the factors influencing discontinuation of IMD therapy in MS can help to find approaches to patient management with the aim to establish more specific indications and also to attain more optimal patient selection
X. Montalban / Journal of the Neurological Sciences 259 (2007) 42–45
in future clinical trials. Besides, the patients included in clinical trials are probably different from those in the daily clinical practice who receive less intensive monitoring. Reasons for interruption reported in clinical trials can hence be different from those in the clinical practice. A recent study including a long follow-up period and with a very low dropout rate, has demonstrated an overall discontinuation rate of 17%, one of the lowest reported in the literature [13]. Another recently published study shows that in a cohort of patients followed for at least 3 years, 61% stayed on treatment with IMD [14], although this proportion raises to about 80% in cohorts with thorough and careful follow-up. It has been suggested that the critical period for stopping IMD is set within the first 6 months of therapy and regular patient support during this time is paramount [14,15]. Other authors, however, found that a very small proportion of patients (1.7%) stopped IMD therapy during the first 6 months of follow-up [13], Nevertheless, half of the patients stop treatment within the first 2 years into therapy. Thus, care and support must be constantly available during the first few years of therapy. Probably, as other studies have shown, the implementation of a treatment protocol through expert and trained professionals who can explain the real treatment expectations and also give personalized healthcare services centered on the patient, allows for easy and quick contact with their neurologist and MS nurse resulting in a lower rate of patients discontinuing IMD [17]. The proportion of patients stopping IMD is significantly higher in the SPMS patient group than in the RRMS group. In a similar way, clinical trials report higher dropout rates and reduced efficacy for patients with SPMS [18,19]. Hence, IMD treatment should be accurately prescribed in the case of SPMS patients and the real expectations of the pros and cons of treatment clearly explained in order to avoid undesired dropouts. Patients with greater disability at therapy entry will also have a high risk to stop IMD. This probably points to a higher likelihood of short-term disability progression and the fact that they can become non-responders as shown in the natural history studies [8,20]. Recently published papers show that dropout patients have a worse response to treatment than patients who stay on treatment, thus favoring selective retention of responders to treatment [21]. In the light of this, it is paramount to follow up patients that become study dropouts after inclusion in therapeutic trials. Because they probably represent the group with poorer clinical evolution, the information provided by dropout patients is a cornerstone to result interpretation in clinical trials. Thus, quality care and thorough service given to patients initiating IMD is fundamental when aiming to attain low dropout rates. On the other hand, it needs to be pointed out that patients who stop IMD therapy are usually those who will develop higher disability in the short run. Thus, the early identification of this group of patients can aid clinicians when approaching other therapeutic strategies.
43
3. Post-marketing efficacy Recently, a study describing the behaviour of a large cohort of RRMS patients treated with different formulations of interferon beta has been published [22]. This is the study with the longest follow-up time reported to date. In this independent, open-label, non-randomized, observational study conducted to assess the efficacy and safety of IFNβ in a large cohort of RRMS patients representative of the general population on IFNβ therapy, the authors studied 495 RRMS patients. All patients initiated therapy with interferon because they had an active disease with two or more relapses in the previous 2 years with an EDSS score between 0 and 5.5. Patients were given information regarding the available therapies in RRMS including efficacy data from pivotal phase III studies as well as information regarding the safety profile of each agent. After a detailed discussion with the neurologist, patients made a final decision of selecting treatment: IFNβ-1b (Betaferon), IFNβ-1a (Avonex) or IFNβ-1a (Rebif). Clinical outcome measures of efficacy were the proportion of relapse-free patients at 2 and 4 years and those with confirmed and sustained disability progression at 2 and 4 years. Additionally, the changes in annualized relapse rate, proportion of decrease in relapse rate, proportion of patients reaching EDSS 6 at 4 years and number of patients who discontinued treatment due to inefficacy were also studied. The results of this study evaluating the effects of IFNβ-1b (Betaferon), IFNβ-1a (Avonex) and IFNβ-1a (Rebif) as used in the clinical practice, are in agreement with the efficacy and safety results of phase III trials of IFNβ in relapsing MS. The proportions of relapse-free patients during the first 2 and 4 years of follow-up were not statistically different among the three groups. Each treatment group showed a significant reduction in relapse rate after 24 and 48 months of treatment ( p b 0.0001). There were no differences in relapse rate within the first 2 years of treatment nor in the percentage change from baseline in relapse rate among the three IFN formulations. At 4 years of treatment, the three formulations were associated with significant reductions from baseline in relapse rates. The difference between groups in the percentage change in relapse rate induced by the three formulations at 4 years was not significant. The proportions of patients in the various groups with confirmed and sustained disability progression (increase of at least 1 EDSS point) after 2 years of follow-up were not different; all three products were safe and well tolerated, although skin reactions from subcutaneous IFNs were significantly more frequent. The adverse events profile for each IFNβ product in the present study is similar to that reported in each of the pivotal phase III trials [1–3]. No differences in the proportion of patients who dropped out because of adverse events were observed. In recent years, several head-to-head comparative studies with direct comparisons on the efficacy of IFNβ products in the treatment of relapsing–remitting MS have been published
44
X. Montalban / Journal of the Neurological Sciences 259 (2007) 42–45
[23–27]. The only two randomized studies, EVIDENCE for Interferon Dose-Effect: European North American Comparative Efficacy study and the INCOMIN, Independent Comparison of Interferon Study, showed significant differences in clinical efficacy between Rebif 44 mg versus Avonex and Betaferon versus Avonex, respectively [23,24]. However, other open label studies [25 26] have showed no differences in clinical efficacy between IFNβ products. Nevertheless, measures as relapse-free patients, used as primary end-points in EVIDENCE and INCOMIN, may be flawed mainly in the short-term studies. Moreover, because a measure as “attack free” will render the same type of information regardless of the actual number of relapses, the use of an outcome as “attack rate” that captures such clinically relevant information, might be preferable [28]. The choice of the appropriate medication for each patient remains an individual's decision since the effects of the different interferons seem to be similar. 4. Response definition The evaluation of a response to therapy relies on outcome measures that may directly or indirectly reflect the progression of a disease. At present, there is no clear definition for the lack of response to IFNβ in RRMS. In the absence of a cure and with a number of therapeutic options, it is sensible to have a framework for deciding when a given treatment is not producing the desired effect. A treatment failure definition requires setting the criteria so as to assess deterioration a priori, unequivocally. Relapses and disability progression are the two basic clinical phenomena of MS, and clinical response to IFNβ is based on these two measures. In the literature, different definitions of non-responders have been proposed [8,29–34], although none have been validated in the long-term follow-up. Long-term disability data are crucial in order to set the most clinically meaningful definition of non-response. Validated definitions to classify patients according to their response to therapy would facilitate rational evidence-based therapeutic decisions and would allow for improved design of future clinical trials, thus permitting to better correlate biomarkers with therapeutic response [34,35]. Definitions of response based on the reduction in the number of relapses are less sensitive to detect those patients with a higher disability after several years of follow-up. Nevertheless, the criteria based on the increase of disability have showed great sensitivity and specificity in predicting long-term disability. The criteria based only on the increase of disability already have shown in prior studies, with shorter time of follow-up, good sensitivity and specificity [8]. Some predictors of poor response to IFNβ have been pointed to in several studies [8,32]. These factors include a higher relapse rate and longer disease duration before and older age at IFNβ therapy initiation or ethnicity. However, these data remain preliminary and it's difficult at this time to implement them in our therapeutic practice.
5. Conclusions Treatment of multiple sclerosis has experienced a very important change in the last years. The appearance of new IMD can change the natural history of the disease. Nevertheless, these new drugs are not free from inconveniences and side effects. Taking into account that efficacy is related to staying on treatment, it is convenient to retain the patients on therapy for years. In this sense, the care and the attention given to patients can reduce the number of dropouts and, thus, help to optimize treatment. There are several available IMD for the treatment of MS, all of which have shown significant efficacy when compared against placebo. After several years of observational studies, there is no clear evidence on higher efficacy of one drug over another in the daily clinical practice. In spite of the efficacy shown by the IMD, there is a proportion of patients who still will not respond. The early identification of disability increase in these patients is crucial to avoid irreversible neurological impairment and to approach other therapeutic strategies. Long-term efficacy is essential in a chronic long-term disease such as MS. Major clinical parameters relevant in MS in the long-term are: disability progression, persistency and tolerability. References [1] The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:655–61. [2] Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, et al. Intramuscular interferon β-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996;39:285–94. [3] PRIMS Study Group. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing–remitting multiple sclerosis. Lancet 1998;352:1498–504. [4] Paty DW, Li DK, for the University of British Columbia MS/MRI Study Group and the IFN? Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing–remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebocontrolled trial. Neurology 1993;43:662–7. [5] Simon JH, Jacobs LD, Campion M, et al, for the Multiple Sclerosis Collaborative Research Group. Magnetic Resonance studies of intramuscular interferon β-1a for the relapsing multiple sclerosis. Ann Neurol 1998;43:79–87. [6] Li DK, Paty DW. Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-controlled study of interferon-β1a in relapsing–remitting multiple sclerosis. Ann Neurol 1999;46:197–206. [7] Noseworthy JH, O'Brien P, Erickson BJ, Lee D, Sneve D, Ebers GC, et al. The Mayo Clinic Canadian-Cooperative Trial of Sulfasalazine in active multiple sclerosis. Neurology 1998;51:1342–52. [8] Rio J, Nos C, Tintore M, Borras C, Galan I, Comabella M, et al. Assessment of different treatment failure criteria in a cohort of relapsing– remitting MS patients treated with interferon beta. Implications for clinical trials. Ann Neurol 2002;52: 400–6. [9] Wingerchuk DM, Noseworthy JH. Randomized controlled trials to assess therapies for multiple sclerosis. Neurology 2002;58(8 Suppl 4): S40–8. [10] Benson K, Arthur HJ. A comparison of observational studies and randomized controlled trials. N Engl J Med 2000;342:1878–86.
X. Montalban / Journal of the Neurological Sciences 259 (2007) 42–45 [11] Concato J, Shah N, Horowitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000;342:1887–92. [12] Pocock SJ, Elbourne DR. Randomized trials or observational tribulations? N Engl J Med 2000;342:1907–9. [13] Río J, Porcel J, Téllez N, Sánchez-Betancourt A, Tintoré M, Arévalo MJ, et al. Factors related with treatment adherence to IFNβ and glatiramer aceate therapy in multiple sclerosis. Mult Scler 2005;11:306 –309. [14] Tremlett HL, Oger J. Interrupted therapy. Stopping and switching of the β-interferons prescribed for MS. Neurology 2003;61:551–4. [15] Taus C, Taffi R, Morelli M, Fie A, Angeled VA, Sgolastra M, et al. Adherence to IFNB therapy in multiple sclerosis: an Italian clinical setting. Mult Scler 2001;7(suppl 1):S55. [17] Mohr DC, Goodkin DE, Masuoka L, et al. Treatment adherence and patient retention in the first year of a Phase III clinical trial for the treatment of multiple sclerosis. Mult Scler 1999;5:192–7. [18] Goodin DS, Frohman EM, Garmany Jr GP, Halper J, Likosky WH, Lublin FD, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology 2002;58:169 –178. [19] Neilley L, Goodin DS, Goodkin DE, Hauser SL. Side effect profile of interferon beta-1b in MS: results of an open label trial. Neurology 1996;46:552–4. [20] Weinshenker BG, Issa M, Baskerville J. Long-term and short-term outcome of multiple sclerosis. A 3-year follow-up study. Arch Neurol 1996;53:353–8. [21] Milanese C, La Mantia L, Palumbo R, Martinelli V, Murialdo A, Zaffaroni M, et al. A post-marketing study on interferon beta-1b and 1 a treatment in relapsing–remitting multiple sclerosis: different response in drop-outs and treated patients. J Neurol Neurosurg Psychiatry 2003:1689–92. [22] Rio J, Tintore M, Nos C, Tellez N, Galan I, Montalban X. Interferon beta in relapsing–remitting multiple sclerosis An eight years experience in a specialist multiple sclerosis centre. J Neurol July 2005;252(7):795–800 [Electronic publication ahead of print 2005 Mar 18]. [23] Durelli L, Verdun E, Barbero P, Bergui M, Versino E, Ghezzi A, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet 2002;359:1453–60.
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[24] Panitch H, Goodin DS, Francis G, et al, EVIDENCE Study Group. Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology 2002;59:1496 –1506. [25] Trojano M, Liguori M, Paolicelli D, et al. Interferon beta in relapsing– remitting multiple sclerosis: an independent postmarketing study in southern Italy. Mult Scler 2003;9:451–7. [26] Waubant E, Vukosic S, Gignoux L, et al. Clinical characteristics of responders to interferon therapy for relapsing MS. Neurology 2003;61:184–9. [27] Dubois BD, Keenan E, Porter BE, Kapoor R, Rudge P, Thompson AJ, et al. Interferon beta in multiple sclerosis: experience in a British specialist multiple sclerosis centre. J Neurol Neurosurg Psychiatry 2003;74:946–9. [28] Goodin DS. Interferons in relapsing remitting multiple sclerosis. Lancet 2003;361:1821. [29] Sturzebecher S, Wandinger KP, Rosenwald A, Sathyamoorthy M, Tzou A, Mattar P, et al. Expression profiling identifies responder and non-responder phenotypes to interferon-beta in multiple sclerosis. Brain 2003;126:1419–29. [30] Villoslada P, Oksenberg JR, Rio J, Montalban X. Clinical characteristics of responders to interferon therapy for relapsing MS. Neurology 2004;62:1653. [31] Wandinger KP, Lunemann JD, Wengert O, Bellmann-Strobl J, Aktas O, Weber A, et al. TNF-related apoptosis inducing ligand (TRAIL) as a potential response marker for interferon-beta treatment in multiple sclerosis. Lancet 2003;361:2036–43. [32] Waubant E, Vukosic S, Gignoux L, Dubief FD, Achiti I, Blanc S, et al. Clinical characteristics of responders to interferon therapy for relapsing MS. Neurology 2003;61:184–9. [33] Petzold A, Brassat D, Mas P, Rejdak K, Keir G, Giovannoni G, et al. Treatment response in relation to inflammatory and axonal surrogate marker in multiple sclerosis. Mult Scler 2004;10:281–3. [34] Rudick R, Lee J, Simon J, Ransohoff RM, Fisher E. Defining interferon β response status in multiple sclerosis patients. Ann Neurol 2004;56:548–55. [35] Baranzini SE, Mousavi P, Rio J, Caillier SJ, Stillman A, Villoslada P, et al. Transcription-based prediction of response to IFN beta using supervised computational methods. PloS Biol 2005;3(1):e2.
MS treatment: Postmarketing studies X. Montalban⁎ EUI planta 2, Unitat de Neuroimmunología Clínica, Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain Received 16 February 2006; accepted 10 October 2006 Available online 26 March 2007
Abstract Multiple sclerosis (MS) is an inflammatory chronic demyelinating disease. Nowadays, there are several registered drugs aimed to control the disease activity. Because these drugs are given parenterally for years, it is of utmost importance to attain maximum adherence to treatment through close and permanent care of patients. The efficacy of the different registered drugs has been compared against placebo. Observational and head-to-head studies have shown controverted results in the degree of efficacy between the products. Despite the efficacy reported, a high proportion of patients will have a lack of response to treatment. Early identification of these patients is therefore essential in order to attempt other therapeutic approaches. © 2007 Elsevier B.V. All rights reserved. Keywords: Multiple sclerosis; Interferon; Observational studies
1. Introduction Treatment of multiple sclerosis (MS) has experienced a radical change in the last decade. Nowadays, we have several formulations of immunomodulatory drugs (IMD) approved and registered for the treatment of the disease. Clinical trials with IMD in the past few years have demonstrated to exert a reduction of the disease activity [1–6]. Nevertheless, in most cases these data of efficacy emerge from clinical trials with durations under 4 years. Due to their short-term follow-up, clinical trials in RRMS can render erroneous clinical results [7,8]. Moreover, such results can be only partially reproducible in the daily clinical practice, because of the varying demographic backgrounds and clinical factors of the populations studied. Observational cohort studies bear the benefit of relatively easy long-term monitoring and can supply data on the behaviour of cohorts during extended treatment periods [9]. Although randomized, controlled trials must be considered the “gold standard” for research design,
⁎ Tel.: +34 932746202; fax: +34 932746084. E-mail address: [email protected]. 0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2006.10.022
agreement between their results and those from observational studies support the potential value of the latter. Several reviews approaching meta-analysis have shown that results from observational studies consistently match the data obtained in randomized, controlled trials [10–12]. Nevertheless, there are factors that may hinder the analysis of such observational studies, including the very lack of randomization, variation in duration of treatment, incomplete monitorization, dropouts and unaccounted drug switches [9]. 2. Factors related with dropouts and drug switches One of the problems that new IMD therapies pose is a relatively inconvenient administration procedure, side effects and the long periods on therapy. These factors can contribute to diminishing a patient's adherence to treatment. Bearing in mind that there is no efficacy in the event of IMD interruption and with the aim to obtain maximum benefit from the drug, it is paramount to help patients adhere to treatment. Awareness of the factors influencing discontinuation of IMD therapy in MS can help to find approaches to patient management with the aim to establish more specific indications and also to attain more optimal patient selection
X. Montalban / Journal of the Neurological Sciences 259 (2007) 42–45
in future clinical trials. Besides, the patients included in clinical trials are probably different from those in the daily clinical practice who receive less intensive monitoring. Reasons for interruption reported in clinical trials can hence be different from those in the clinical practice. A recent study including a long follow-up period and with a very low dropout rate, has demonstrated an overall discontinuation rate of 17%, one of the lowest reported in the literature [13]. Another recently published study shows that in a cohort of patients followed for at least 3 years, 61% stayed on treatment with IMD [14], although this proportion raises to about 80% in cohorts with thorough and careful follow-up. It has been suggested that the critical period for stopping IMD is set within the first 6 months of therapy and regular patient support during this time is paramount [14,15]. Other authors, however, found that a very small proportion of patients (1.7%) stopped IMD therapy during the first 6 months of follow-up [13], Nevertheless, half of the patients stop treatment within the first 2 years into therapy. Thus, care and support must be constantly available during the first few years of therapy. Probably, as other studies have shown, the implementation of a treatment protocol through expert and trained professionals who can explain the real treatment expectations and also give personalized healthcare services centered on the patient, allows for easy and quick contact with their neurologist and MS nurse resulting in a lower rate of patients discontinuing IMD [17]. The proportion of patients stopping IMD is significantly higher in the SPMS patient group than in the RRMS group. In a similar way, clinical trials report higher dropout rates and reduced efficacy for patients with SPMS [18,19]. Hence, IMD treatment should be accurately prescribed in the case of SPMS patients and the real expectations of the pros and cons of treatment clearly explained in order to avoid undesired dropouts. Patients with greater disability at therapy entry will also have a high risk to stop IMD. This probably points to a higher likelihood of short-term disability progression and the fact that they can become non-responders as shown in the natural history studies [8,20]. Recently published papers show that dropout patients have a worse response to treatment than patients who stay on treatment, thus favoring selective retention of responders to treatment [21]. In the light of this, it is paramount to follow up patients that become study dropouts after inclusion in therapeutic trials. Because they probably represent the group with poorer clinical evolution, the information provided by dropout patients is a cornerstone to result interpretation in clinical trials. Thus, quality care and thorough service given to patients initiating IMD is fundamental when aiming to attain low dropout rates. On the other hand, it needs to be pointed out that patients who stop IMD therapy are usually those who will develop higher disability in the short run. Thus, the early identification of this group of patients can aid clinicians when approaching other therapeutic strategies.
43
3. Post-marketing efficacy Recently, a study describing the behaviour of a large cohort of RRMS patients treated with different formulations of interferon beta has been published [22]. This is the study with the longest follow-up time reported to date. In this independent, open-label, non-randomized, observational study conducted to assess the efficacy and safety of IFNβ in a large cohort of RRMS patients representative of the general population on IFNβ therapy, the authors studied 495 RRMS patients. All patients initiated therapy with interferon because they had an active disease with two or more relapses in the previous 2 years with an EDSS score between 0 and 5.5. Patients were given information regarding the available therapies in RRMS including efficacy data from pivotal phase III studies as well as information regarding the safety profile of each agent. After a detailed discussion with the neurologist, patients made a final decision of selecting treatment: IFNβ-1b (Betaferon), IFNβ-1a (Avonex) or IFNβ-1a (Rebif). Clinical outcome measures of efficacy were the proportion of relapse-free patients at 2 and 4 years and those with confirmed and sustained disability progression at 2 and 4 years. Additionally, the changes in annualized relapse rate, proportion of decrease in relapse rate, proportion of patients reaching EDSS 6 at 4 years and number of patients who discontinued treatment due to inefficacy were also studied. The results of this study evaluating the effects of IFNβ-1b (Betaferon), IFNβ-1a (Avonex) and IFNβ-1a (Rebif) as used in the clinical practice, are in agreement with the efficacy and safety results of phase III trials of IFNβ in relapsing MS. The proportions of relapse-free patients during the first 2 and 4 years of follow-up were not statistically different among the three groups. Each treatment group showed a significant reduction in relapse rate after 24 and 48 months of treatment ( p b 0.0001). There were no differences in relapse rate within the first 2 years of treatment nor in the percentage change from baseline in relapse rate among the three IFN formulations. At 4 years of treatment, the three formulations were associated with significant reductions from baseline in relapse rates. The difference between groups in the percentage change in relapse rate induced by the three formulations at 4 years was not significant. The proportions of patients in the various groups with confirmed and sustained disability progression (increase of at least 1 EDSS point) after 2 years of follow-up were not different; all three products were safe and well tolerated, although skin reactions from subcutaneous IFNs were significantly more frequent. The adverse events profile for each IFNβ product in the present study is similar to that reported in each of the pivotal phase III trials [1–3]. No differences in the proportion of patients who dropped out because of adverse events were observed. In recent years, several head-to-head comparative studies with direct comparisons on the efficacy of IFNβ products in the treatment of relapsing–remitting MS have been published
44
X. Montalban / Journal of the Neurological Sciences 259 (2007) 42–45
[23–27]. The only two randomized studies, EVIDENCE for Interferon Dose-Effect: European North American Comparative Efficacy study and the INCOMIN, Independent Comparison of Interferon Study, showed significant differences in clinical efficacy between Rebif 44 mg versus Avonex and Betaferon versus Avonex, respectively [23,24]. However, other open label studies [25 26] have showed no differences in clinical efficacy between IFNβ products. Nevertheless, measures as relapse-free patients, used as primary end-points in EVIDENCE and INCOMIN, may be flawed mainly in the short-term studies. Moreover, because a measure as “attack free” will render the same type of information regardless of the actual number of relapses, the use of an outcome as “attack rate” that captures such clinically relevant information, might be preferable [28]. The choice of the appropriate medication for each patient remains an individual's decision since the effects of the different interferons seem to be similar. 4. Response definition The evaluation of a response to therapy relies on outcome measures that may directly or indirectly reflect the progression of a disease. At present, there is no clear definition for the lack of response to IFNβ in RRMS. In the absence of a cure and with a number of therapeutic options, it is sensible to have a framework for deciding when a given treatment is not producing the desired effect. A treatment failure definition requires setting the criteria so as to assess deterioration a priori, unequivocally. Relapses and disability progression are the two basic clinical phenomena of MS, and clinical response to IFNβ is based on these two measures. In the literature, different definitions of non-responders have been proposed [8,29–34], although none have been validated in the long-term follow-up. Long-term disability data are crucial in order to set the most clinically meaningful definition of non-response. Validated definitions to classify patients according to their response to therapy would facilitate rational evidence-based therapeutic decisions and would allow for improved design of future clinical trials, thus permitting to better correlate biomarkers with therapeutic response [34,35]. Definitions of response based on the reduction in the number of relapses are less sensitive to detect those patients with a higher disability after several years of follow-up. Nevertheless, the criteria based on the increase of disability have showed great sensitivity and specificity in predicting long-term disability. The criteria based only on the increase of disability already have shown in prior studies, with shorter time of follow-up, good sensitivity and specificity [8]. Some predictors of poor response to IFNβ have been pointed to in several studies [8,32]. These factors include a higher relapse rate and longer disease duration before and older age at IFNβ therapy initiation or ethnicity. However, these data remain preliminary and it's difficult at this time to implement them in our therapeutic practice.
5. Conclusions Treatment of multiple sclerosis has experienced a very important change in the last years. The appearance of new IMD can change the natural history of the disease. Nevertheless, these new drugs are not free from inconveniences and side effects. Taking into account that efficacy is related to staying on treatment, it is convenient to retain the patients on therapy for years. In this sense, the care and the attention given to patients can reduce the number of dropouts and, thus, help to optimize treatment. There are several available IMD for the treatment of MS, all of which have shown significant efficacy when compared against placebo. After several years of observational studies, there is no clear evidence on higher efficacy of one drug over another in the daily clinical practice. In spite of the efficacy shown by the IMD, there is a proportion of patients who still will not respond. The early identification of disability increase in these patients is crucial to avoid irreversible neurological impairment and to approach other therapeutic strategies. Long-term efficacy is essential in a chronic long-term disease such as MS. Major clinical parameters relevant in MS in the long-term are: disability progression, persistency and tolerability. References [1] The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:655–61. [2] Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, et al. Intramuscular interferon β-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996;39:285–94. [3] PRIMS Study Group. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing–remitting multiple sclerosis. Lancet 1998;352:1498–504. [4] Paty DW, Li DK, for the University of British Columbia MS/MRI Study Group and the IFN? Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing–remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebocontrolled trial. Neurology 1993;43:662–7. [5] Simon JH, Jacobs LD, Campion M, et al, for the Multiple Sclerosis Collaborative Research Group. Magnetic Resonance studies of intramuscular interferon β-1a for the relapsing multiple sclerosis. Ann Neurol 1998;43:79–87. [6] Li DK, Paty DW. Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-controlled study of interferon-β1a in relapsing–remitting multiple sclerosis. Ann Neurol 1999;46:197–206. [7] Noseworthy JH, O'Brien P, Erickson BJ, Lee D, Sneve D, Ebers GC, et al. The Mayo Clinic Canadian-Cooperative Trial of Sulfasalazine in active multiple sclerosis. Neurology 1998;51:1342–52. [8] Rio J, Nos C, Tintore M, Borras C, Galan I, Comabella M, et al. Assessment of different treatment failure criteria in a cohort of relapsing– remitting MS patients treated with interferon beta. Implications for clinical trials. Ann Neurol 2002;52: 400–6. [9] Wingerchuk DM, Noseworthy JH. Randomized controlled trials to assess therapies for multiple sclerosis. Neurology 2002;58(8 Suppl 4): S40–8. [10] Benson K, Arthur HJ. A comparison of observational studies and randomized controlled trials. N Engl J Med 2000;342:1878–86.
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