TECHNOLOGY OVERVIEW: PHARMACEUTICALS

Transcription

1 TECHNOLOGY OVERVIEW: PHARMACEUTICALS ISSUE 5.0 DECEMBER 1996 INTERFERON BETA 1-B AND MULTIPLE SCLEROSIS prepared by Nicolaas Otten, Pharm D. Coordinator, Pharmaceutical Assessment, CCOHTA This overview has been prepared by staff at the (CCOHTA) and is based in part on a study commissioned by CCOHTA: A Therapeutic and Economic Assessment of Betaseron7 in Multiple Sclerosis conducted by Dr. Murray G. Brown (Dalhousie University, Halifax, Nova Scotia), Dr. T. Jock Murray (Dalhousie University, Halifax, Nova Scotia), Dr. John D. Fisk (Dalhousie University, Halifax, Nova Scotia), Dr. Ingrida S. Sketris (Dalhousie University, Halifax, Nova Scotia), Dr. Carolyn E. Schwartz (Frontier Science and Technology Research Foundation Inc., Brookline, Massachusetts), Dr. John C. LeBlanc (Dalhousie University, Halifax, Nova Scotia). Cost/Effectiveness Modelling & Implementation Murray G. Brown (Dalhousie University, Halifax, Nova Scotia) & Mr. Chris D. Skedgel (Dalhousie University, Halifax, Nova Scotia). The overview has been reviewed and accepted by CCOHTA's Scientific Advisory Panel. It does not necessarily reflect the opinions of the Panel, the Board of CCOHTA or the investigators.

2 Additional copies of Interferon Beta 1-b and Multiple Sclerosis are available from CCOHTA. Vous pouvez aussi vous procurer la version française à l=occets. Reproduction of this document for non-commercial purposes is permitted provided appropriate credit is given to CCOHTA. Legal Deposit National Library of Canada ISSN Multiple sclerosis (MS) is the most common progressive neurological disorder in young people. Age of onset is usually in the 30's with females affected more than males. The clinical course is unpredictable, with recurrent attacks (exacerbations) that may or may not be followed by progressive deterioration. Symptoms include disturbances of sensation, movement and cognition. The most common disease course is called relapsing-

3 remitting (rr) where acute attacks last from weeks to months followed by complete recovery or with sequela and residual deficit. Eventually most patients develop a progressive form of the disease. Some develop a progressive form from onset while a small percentage have a benign course. The most common tool to assess stage of disease progression and patient physical disability is called the Expanded Disability Status Scale (EDSS). The scale ranges from zero (normal) to 10 (death from MS) in 0.5 step intervals. A value of 6 depicts an individual unable to walk without an aid (eg. cane). This scale does not consider cognitive dysfunction, fatigue, or pain all of which commonly increase disability and reduce quality of life in MS. Recently, magnetic resonance imaging (MRI) findings have been shown to be correlated not only with burden of disease but also disease progression. Until the release of interferon beta 1-b (Betaseron 7 ) no therapy affected either the frequency of attacks or the rate of disease progression. Clinical trials have demonstrated the drug significantly decreases the relative frequency of acute attacks (24-33%). There was a trend to slowing the progression of the disease as measured by EDSS. However the cost of therapy is high ($16,685 CDN annually). CCOHTA was asked to conduct an economic and clinical evaluation of interferon beta 1-b in MS. The report below is primarily based on the two major clinical reports of the same study 1,2, a study commissioned by CCOHTA 3 (which assessed the cost effectiveness of the drug on the rate of disease progression), and cost data provided by one MS treatment centre in Calgary 4 (which was used to determine the cost effectiveness of treating acute exacerbations). CONCLUSIONS Clinical trials 1. Interferon beta 1-b (Betaseron 7 ) reduced the relative risk of acute attacks by 28 to 33% in the first two years of treatment. This rate was maintained in years 3 to 5 but failed to reach statistical significance. 2. A high percentage of patients developed neutralizing antibodies to the drug by year 3 (38%) which appeared to attenuate the effect on reducing acute exacerbations. On the other hand, if the patients who developed neutralizing antibodies are removed from the analysis, Betaseron 7 has an even greater treatment effect. 3. Although the drug displays a high incidence of side effects (eg. flu-like symptoms, pain on injection), most are seen on initiation of therapy, are mild, and are usually manageable. Dropout rates were similar between placebo and treatment over 4 years (approximately 38%). The most common causes for dropout were excessive use of steroids and adverse effects respectively. 4. The clinical trial 2 failed to establish an effect of Betaseron 7 in limiting progression of disability (p = 0.096). However it seems reasonable to expect an impact of interferon beta-1b on progression based on the trends demonstrated in the clinical trial, the magnetic resonance scanning (MRI) findings, and the demonstration of a significant effect on disability with a similar drug (interferon beta-1a) 5. Lesion size was shown to be significantly smaller on MRI in the Betaseron 7 group. A significant correlation was also found between increasing burden of disease as measured by MRI and increasing disability. 5. Further trials have begun on the drug including evaluating interferon beta-lb in secondary progressive multiple sclerosis. 2

4 2. Economic Evaluations (i) Avoiding acute exacerbations The cost effectiveness of avoiding acute attacks (exacerbations) is dependent upon three factors: the frequency of acute attacks, whether the attacks are severe enough to be treated, and how the attacks are treated. The frequency of acute attacks tends to decline over time and is highly variable between patients. If approximately 50% of attacks normally require pharmacologic treatment, the cost for avoiding one acute exacerbation annually would range from $48,146 to $67,196 based on the frequency reported in the clinical trial 2 and the treatment costs at one MS centre 4. However since 27% of attacks are severe or moderate while on Betaseron 7 compared to 35% with no treatment then the range would be $37,072 to $51,741. These estimates by CCOHTA staff bracket the estimate of $48,800 reported in the commissioned study 3. (ii) Disability model 6 The commissioned study model found that the cost-effectiveness of using Betaseron 7 was $219,061 (undiscounted) and $325,760 (discounted) per >normalized EDSS disability year avoided= (equivalent to a full year of being without the worst level of the disease) for females with relapsing- remitting MS 3. The model took into account the average life time of an MS patient and treating the patient until s/he reached an EDSS score of 6 or greater through a two step process. This model also assumes that interferon beta-1b delays the progression from a >mild= to a >severe= disability category by about 15%. Sensitivity analysis indicates that C/E estimates and total program costs are particularly dependent upon how MS natural history is modelled, treatment efficacy and cost, patient demand and compliance, and discount rate. (iii) Limitations There are a number of limitations to the data available that could have a major impact on the results (an extensive discussion of the limitations of the commissioned report are contained within the technical document): (i) (ii) The drug has not been proven to have an effect on ameliorating progression of the disease as measured by the EDSS. Further, the model in the commissioned study evaluated the impact on progressive MS as one of the scenarios. No clinical trials have been completed in this type of MS. The cost of treatment ($16,685 annually) greatly exceeds any direct savings to the public health care system. However the analysis uses a third party public payor perspective which incorporates only the third party payor portion of MS societal costs when estimating foregone costs due to treatment. Direct medical costs may represent only 10% of the total cost to society. 6 3

5 (iii) Estimates of EDSS-weighted disability years avoided assume each step on the EDSS scale is equal; eg. deteriorating from 2 to 3 is equivalent to going from 5 to 6 which is unlikely. Unlike quality of life scales, EDSS focuses on loss of mobility not other dimensions of general health. (iv) >Normalized EDSS disability year avoided= is not equivalent to a quality adjusted life year. (v) The epidemiology of MS was extrapolated to 40 years from Swedish data published on 25 years experience. (vi) Estimates of QALYs gained due to reduced exacerbations or disability progression were not available. (vii) The MS clinic data used in the CCOHTA staff analysis of the cost of treating acute exacerbations used unweighted average cost of a hospital day in Alberta. Further, it did not incorporate physician fees or any rehabilitation costs other than what a nurse might provide. (viii) The evaluation on avoiding an acute exacerbation did not take into account permanent sequelae that may follow from an acute attack. For example 36% of patients have some level of disability following an initial acute exacerbation. Further, it is assumed that treatment costs are equal for moderate and severe exacerbations. 4

6 INTRODUCTION INTERFERON BETA 1-B AND MULTIPLE SCLEROSIS Multiple sclerosis (MS) is the most common progressive neurological disorder in young people. The prevalence of the disease in Canada ranges from 50 to 200 per 100,000 population. Onset of the disease is usually in the third or fourth decade of life with females affected more than males (from 3:2 to 2:1). Many patients have a normal lifespan and live with some degree of disability over a prolonged period. Multiple sclerosis is a disease of the central nervous system caused by damage to the myelin sheath around nerve bundles. This damage occurs in a variety of areas including the brain, spinal cord and optic nerve. Scars or plaques develop which interrupt nerve impulses and produce various neurological disturbances. The clinical course is unpredictable, with recurrent attacks (exacerbations) that may or may not be followed by progressive physical impairment. Relapses typically occur earlier in the course of the disease and usually decrease in frequency over the years. The most common neurological symptoms include disturbances of vision (diplopia and nystagmus), coordination, sensation, gait, speech, and endurance (fatigue), and of bowel (constipation), bladder (failure to store and/or void urine), sexual function and disturbances of cognition including memory and attention. Most clinical trials have used the Expanded Disability Status Scale (EDSS) as the standard tool to measure disability in MS. The EDSS rates a patient=s level of function from zero (normal neurological exam) to 10 (death) with every half-point increase on the scale representing a progressive deterioration of disability. Mobility is a prominent element in this scale. A score of 6 is associated with a requirement for walking aids. There are several different classification systems for MS. Generally, the majority of patients fall initially into the relapsing-remitting (rr) type. Initial exacerbations have been shown to be followed by complete or near complete remissions in approximately 64% of patients. 7 This may take several weeks to months. Usually they will eventually develop a progressive form (50% in 10 and 14 years in men and women respectively). 7 However, once progression begins, the median time to EDSS of 6 is about 5 years. 7 A smaller group of patients will present with a progressive form without any acute exacerbations (males more than females). These patients tend to have a faster and more turbulent course. The economic costs to society are substantial for this disease. Most studies have shown that direct medical costs are less than indirect costs (lost productivity, caregiver time, etc). 8 Acute exacerbations may cause lost work time, while increasing disability reduces employment opportunities and increases dependence upon others. Direct medical costs include treatment for acute exacerbations (many patients are now treated in outpatient settings), physician time, hospitalization (relatively infrequent), drugs (increases over time due to therapy of MS complications), and physiotherapy. 5

7 TREATMENT There are few treatment options available that have a significant impact on the course of the disease. Until the last few years, steroid therapy, for decreasing relapse severity or for delaying the onset of MS after an episode of optic neuritis (optic neuritis often precedes development of MS), was the only intervention that influenced disease status. No therapy has proven to be effective at slowing the rate of disability as measured by the EDSS nor the frequency of acute exacerbations until the publications of the trial on interferon beta - 1b (Betaseron 7 ) 1,2. Betaseron 7 reduced the frequency of acute exacerbations over 2 years which was maintained over a further 3 years but statistical significance at the 5% confidence level was achieved only in years 1 and 2. It also decreased the rate of disability progression at only the 10% confidence level. Since then two other drugs have been found to affect the natural history of the disease. Copolymer I (Copaxone 7 ) was also found to have a significant impact on exacerbation rates 9. Interferon beta-1a (Avonex 7 ) was found to not only have a significant effect on exacerbation rate but also to significantly reduce clinical progression of the disease. 5 This latter drug differs in source and slightly in chemical structure in comparison to Betaseron 7. What this means clinically has yet to be determined as no head to head trials have been conducted. INTERFERON BETA-1B (INFB) (BETASERON 7 ) In a three year randomized, controlled study, patients with relapsing-remitting MS were randomized to one of three groups: interferon beta-1b in doses of 1.6 million I.U. (0.05 mg) subcutaneously (SC) every other day, 8 million I.U. (0.25 mg) SC every other day, and placebo. 1,2 The 8 million I.U. dose appeared to be more efficacious. Since it is also the currently recommended dose most of the data below relates to this dosage regimen. A total of 372 ambulatory patients with relapsing remitting MS who had an EDSS of 5.5 or less and at least 2 exacerbations within the previous 24 months were admitted into the trial. Significant findings in the first 2 years included a decrease in exacerbation rate from 1.27 to 0.84 per person per year as well as a 23% relative risk reduction in moderate and severe exacerbations. The percent free of exacerbations and the median time to first exacerbation following randomization were also significantly in favour of interferon beta - 1b. In a continuation study patients were given the option of withdrawing from the protocol at year 2 and 3. Those patients remaining in the trial continued to be blinded as to which treatment they were receiving. The median time on the continuation trial was 45 months. During the first 2 years 25/123 patients on Betaseron 7 withdrew (10/25 due to adverse reactions). A further 5 patients opted not to continue the active drug at year 2. The decline in exacerbation rates appeared to be maintained over 5 years and a trend toward an effect on disability progression was also seen. The most common adverse effect was a flu-like illness that was usually managed by a nonsteroidal anti-inflammatory agent. Most of these problems dissipated within a few months of treatment. 6

8 PARAMETERS OF THE EVALUATIONS A. Product Description and Study Population/Criteria Interferon beta 1-b (Betaseron 7 ) is administered subcutaneously at a dose of 8 Million I.U. every other day. In the commissioned study 3, the impact of the drug on disability is initially evaluated by determining the change in probability of reaching an EDSS of 6. Separate evaluations are conducted on the following patient populations (i) relapsing-remitting (rr) MS only (includes those going on to a progressive course), (ii) progressive MS, and (iii) combined rr/progressive MS. The analysis is further divided into male and female patients. The cost-effectiveness (C/E) model assumes the patient receives the drug 2 years after onset, once diagnosis is confirmed, and discontinues the drug 2 years after EDSS 6 is reached. Initial C/E estimates were derived from modelling a treatment effect which reduced the cumulative probabilities of reaching endpoint EDSS 6. Revised C/E estimates, considered more realistic, model a treatment effect which reduces the cumulative probabilities of reaching endpoints EDSS 3 and EDSS 6. For purposes of comparing various C/E estimates found in the commissioned study, the revised C/E estimate (undiscounted) for Betaseron 7 treatment of females diagnosed as relapsing-remitting at onset is adopted as a reference case. For the evaluation of the effectiveness of the drug in treating acute exacerbations, only the patient population with acute exacerbations is considered. Estimates of acute exacerbations are taken from the five year follow up of the interferon beta 1-b study 3. B. Target Audience/Perspective The results of this study will be helpful to provincial/territorial ministries of health in their evaluation of this medication for formulary purposes. The evaluation of foregone costs is restricted to the impact on the health care system (direct health care costs paid by a ministry of health in a Canadian province or territory). Because direct private sector costs and indirect costs were not included, and these are often greater than public sector direct costs, this analysis of foregone costs has a very limited perspective. C. Treatment Comparators Since no proven effective therapy is marketed for either the reduction in the frequency of acute exacerbations or on progressive disability, Betaseron 7 is compared with no therapy. D. Type of Analysis The study is a cost-effectiveness analysis based on efficacy information obtained from one clinical trial 1 and a follow up report 2 as well as a 25 year epidemiologic study conducted on MS patients 7. 7

9 E. Outcome of Interest INTERFERON BETA 1-B AND MULTIPLE SCLEROSIS For disability, it is normalized disability years avoided based on the EDSS scale. Thus one normalized disability year avoided (nedss-dya) is equivalent to avoiding a year of the full EDSS scale. eg. a patient with an EDSS of 2 would require 5 years at this state to have the equivalent of one disability year (years of disability x EDSS score equalling the maximum EDSS of 10). Following this same example, if treatment delays disability progression from an EDSS of 2 to an EDSS of 4 for five years a total of one disability year avoided (nedss-dya) is attained. The model is based on the impact of treatment on the cumulative probability of attaining two disability progression endpoints of EDSS 3 and EDSS 6. For acute exacerbations the outcome of interest is the annual rate of acute exacerbations. F. Time Horizon The evaluation of the drug on disability is modelled over a 40 year natural history of MS taken from a Swedish epidemiological study describing the natural history over 25 years 7. This is extrapolated to 40 years for the purpose of modelling a life-time with the disease. For the evaluation of acute exacerbations, a one year time horizon is taken. G. Cost Elements of Interest (i) (ii) Commissioned study Direct costs accruing to the health care system are used. For the study evaluating the drug=s impact on disability, public sector health care costs measured in Nova Scotia linked to their MS patient data base are used. These included physician services, hospital services (inpatient and day surgery) and Seniors= Pharmacare services for persons 65 years old or more. Calgary MS clinic costs For the CCOHTA staff study evaluating the impact of the drug on acute exacerbations, direct medical costs for the management of acute exacerbations in hospital or clinic are taken from the Calgary MS clinic 4. 8

10 RESULTS 1. Impact on Disability Progression: Cost Effectiveness (Commissioned Study) Reference Case: Seven criteria constituted the reference case: (a) relapsing/remitting female MS population (b) all patients start therapy in year 3 after initial diagnosis and complete therapy two years after reaching EDSS of 6 (c) cumulative probability of reaching EDSS of 3 and 6 is reduced by 15% in those patients receiving Betaseron 7 (d) 100% compliance The cost-effectiveness ratio for the reference case was $219,061 (not discounted) per normalized EDSS disability year avoided.: The expected number of disability years avoided per female classified as relapsing-remitting at onset is 1.4 over the course of the disease until an EDSS of 6 is reached. Impact of varying elements of the analysis Table I below shows the results of varying single parameters (while keeping the other parameters the same as the reference case). The results are shown as % change from the reference case. TABLE 1: Percentage Change in Cost-Effectiveness (C/E) Ratio From Reference Case of Females with RR MS Variable Impact On C/E % Change Variable Impact On C/E % Change compliance 9 to 45 % annually compliance 9 to 20% annually 2%[* discount costs & 2.5% 25%[ 3%[ discount costs and 7.5% 97%[ progressive** patients only 60%\ double health care costs to treat ms +1%\ male only 17%\ health care costs half of baseline +1%[ user copay of 20% 1%[ reduce price of interferon by 25% 25 %\ treatment effect only 7.5% 91%[ treat patients for complete lifespan 45%[ treatment effect 22.5% 31%\ all ms patients RR & progressives** 5%\ discount 5% 57%[ * Arrow up or down mean less attractive or more attractive cost-effectiveness ratio respectively. ** An identical treatment effect size is assumed for persons classified as progressive from onset even though no clinical evidence currently exists for this. 9

11 2. Impact on Acute Exacerbations (CCOHTA staff study) TABLE 2: Calgary MS clinic costs used (Cost of Treating Acute Exacerbations) Treatment Description of Service/Supplies Cost Inpatient 9 days $570/day ($5,130 total) Outpatient Drug: $ (parenteral and oral steroids) Supplies: $76.00 Nursing time: 10 hours ($275.00) $ total TABLE 3: Differences in Annual Acute Exacerbation Rates/Patient on Placebo versus Interferon Beta 1-b Year Placebo Rate (A)* Interferon Rate (B)* Difference (A - B) * From reference 2 Cost-effectiveness analysis TABLE 4: Cost-effectiveness of Avoiding One Acute Exacerbation Annually * Where Treated (TX) Year TX * * Inpatient+ $24,073 $35,015 $44,442 $55,023 $48,146 Outpatient+ $33,598 $48,870 $62,027 $76,795 $67,196 * Calculated as: (annual cost of drug ($16,685) - cost avoided for one attack) Difference in annual acute exacerbation rates * * Rates based on reference 2 and costs based on reference 4 + Assumes all patients would be treated as inpatients or outpatients respectively 10

12 Thus in year one, based on the acute exacerbation rates reported in the clinical trial, the cost for avoiding an acute exacerbation is $29,575 or $34,147 in patients treated in the outpatient or inpatient setting respectively. The cost for avoiding an acute exacerbation increases due to the declining rate of acute exacerbations over time and the decrease in absolute difference between treatment with Betaseron7 and placebo. Not all patients require pharmacological treatment for acute exacerbations. Table V below indicates that the cost effectiveness of acute exacerbations is very sensitive to this factor. TABLE 5: Cost-effectiveness ratio: Impact of changes in the percent of acute exacerbations treated in the health care system* Percent of Acute Exacerbations Requiring Treatment Where Treated 25% 50% 75% 100% inpatient $ 96,292 $48,146 $32,097 $24,073 outpatient $134,392 $67,196 $44,797 $33,598 * Using first year rates (best case scenario) from reference 2 and costs from the Calgary MS clinic 4. Note: There was evidence in the clinical trial 1 that the prevalence of moderate and severe attacks was reduced as well (27% of attacks while on Betaseron 7 vs. 35% on placebo 1 or a 23% difference). Therefore the costeffectiveness in Table V would also be reduced by 23%. For example if 50% of attacks (approximately equivalent to the % of patients exhibiting moderate or severe exacerbations) had to be treated, the cost-effectiveness would be $37,072 to $51,741 per acute exacerbation avoided instead of $48,146 to $67,196. DISCUSSION Although the clinical evidence for the effect of interferon beta - 1b on acute exacerbations is stronger than the impact on disability, most clinicians and patients are more concerned about the latter. The model presented of the drug=s effect on progressive disability attempts to incorporate natural history of the disease with the RCT efficacy results and data obtained in a large MS patient population. It relies on the use of the EDSS scale in measuring the outcome over a lifespan. However this assumes the scale is linear which it is not. Further work in mapping out various stages with a quality of life scale would be necessary to properly model the impact of the drug. All of the limitations aside, the public sector health care costs of treating MS patients (at least until the later stages of the disease) tend to be much less than the cost of the drug. These evaluations take the perspective of government payor. Surveys conducted in the MS population indicate that additional societal costs such as loss of employment exceed direct health care costs. Finally, this is a two-stage model of MS natural history of disability progression. If a societal perspective were taken and one had the ability to measure more endpoints associated with different costs between the start of the disease and EDSS of 6 the cost-effectiveness ratios would probably improve. This assumes that the drug would have an impact on societal costs. 11

13 In the cost for avoiding acute exacerbations analysis by CCOHTA staff, the costs quoted are from 1992/93. Limitations include the fact that no physicians fees are included and an unweighted hospital day. However the costs for nursing time and hospital costs have changed marginally since then. The cost of treating an acute exacerbation includes the use of intravenous methylprednisolone 1 gram given for 5 days followed by oral prednisone treatment. Although the cost of parenteral methylprednisolone is higher now some clinicians use only oral prednisone or a shorter course of methylprednisolone which would result in lower costs. Although a Canadian consensus guideline on patient selection for interferon beta - 1b treatment was reported in a letter to the editor in further work is needed to determine which patients are more likely to benefit. Additional pharmacoeconomic studies using a societal perspective with better clinical outcomes are needed. 12

14 REFERENCES 1 The IFNB Multiple Sclerosis Study Group. (1993). Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology, 43, The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. (1995). Interferon beta-1b in the treatment of multiple sclerosis: Final outcome of the randomized controlled trial. Neurology, 45, Brown, M.G., Murray, T.J., Fisk, J.D., Sketris, I.S., Schwartz, C.E., LeBlanc, J.C. (1996). A therapeutic and economic assessment of Betaseron 7 in multiple sclerosis. Ottawa: Canadian Coordinating Office for Health Technology Assessment (CCOHTA). 4 Harris C.,Metz, L. (1993). Home intravenous Solu-Medrol program for multiple sclerosis patients. (abstract). Proceedings of the Multiple Sclerosis Satellite Symposium to the World Congress of Neurology, September, 1993, Vancouver, British Columbia, pp Jacobs, L.D., Cookfair, D.L., Rudick, R.A., et al. (1996). Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Annals of Neurology, 39, Blumhardt, L.D., Wood, C. (1996). The economics of multiple sclerosis: A cost of illness study. British Journal of Medical Economics, 10, Runmarker, B., Andersen, O. (1993). Prognostic factors in multiple sclerosis incidence cohort with twenty-five years of follow-up. Brain, 116, McGown, L., McWhinnie, L. (1996). MS patient survey: Cost and reimbursement of treatment. The cost of multiple sclerosis. Montreal: Concordia University Pharmaceutical Management Centre. 9 M c Donald, W.I. (1995). New treatments for multiple sclerosis. BMJ, 310, Oger, J. (1995). [Consensus statement about indication for treatment of multiple sclerosis patients with interferon beta 1B.] Canadian Journal of Neurological Sciences, 22,

15 Previous drafts of the technical document A Therapeutic and Economic Assessment of Betaseron7 in Multiple Sclerosis were reviewed by the Scientific Advisory Panel of CCOHTA: Dr. Andreas Laupacis Dr. David Feeny Dr. Lawrence Joseph Dr. Roy West Dr. Raisa Deber Dr. Heather Bryant Ottawa Civic Hospital McMaster University McGill University Memorial University University of Toronto University of Calgary Comments were also received from: Dr. Luanne Metz Dr. Anthony Auty Mr. Kevin Wilson Ms. Christina Wolfson Berlex Canada University of Calgary Winnipeg, Manitoba Saskatchewan Health McGill University CCOHTA would like to thank the above for their contributions. The complete report A Therapeutic and Economic Assessment of Betaseron7 in Multiple Sclerosis is available by contacting CCOHTA. Please address all enquiries and correspondence to: Publications, CCOHTA, Green Valley Crescent, Ottawa, Ontario, Canada, K2C 3V4. Tel.: (613) ; Fax: (613) ; pubs@ccohta.ca 14