Economic Evaluation of Leflunomide in Patients with Rheumatoid Arthritis

Andreas Maetzel

A thesis submitted in conformity with the requirements

for the degree of Doctor of Philosophy,

Institute of Medical Science,

University of Toronto

O Copyright by Andreas Maetzel, 200 1

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Economic Evaluation of Leflunomide in the Treatment of Rheumatoid Arthritis. Andreas Maetzel,

Doctor of Philosophy, Institute of Medical Science. University of Toronto, 200 1

Abstract

Objective: To comprehensively evaluate the pharmacoeconomic properties of leflunomide, a novel

disease-modifymg anti-rheumatic drug (DMARD) to support reimbursement decisions by Canadian

provincial decisionmakers .

Methods: The evaluation was performed using two different analytical approaches. The first was based

on economic data collected prospectively in a Nonh American trial in patients with rheumatoid arthritis

(RA) randomized to placebo, leflunomide or methotrexate, and the second was based on a 5-year

simulation model comparing two treatment strategies, one including leflunomide. The model was

supported by an independently conducted survey of US and Canadian rheumatologists and a systematic

review of treatment withdrawals among patients on DMARDs.

Results: The survey confirmed methotrexate to be the treatment of choice without any clear alternative.

Analysis of the literature confirmed that patients stay significantly longest on methotrexate. Although the

economic consequences between Ieflunomide and methotrexate were similar, the higher drug costs of

leflunomide imply an extra 5 147,437 per QALY gained compared to placebo (methotrexate: 9 lZ,t26).

Methotrexate is both less expensive than leflunomide and produces higher utilities (non-significant), but

more patients on leflunomide achieve an American College of Rheumatology 20% response status at a

cost of $66,000 per responder gained compared to methotrexate. The model also showed that adding

leflunomide as a new option within a realistic sequence of DMARDs extends the time patients may

benefit from DMARD therapy at a reasonable cost-effectiveness of $10,682 per responder gained and

cost-utility of S18,474 per QALY gained.

Conclusion: This thesis shows that leflunomide has a place in the management of patients with RA and

that it comes with a reasonable economic profile.

Acknowledgments

I would like to express my deepest gratitude to my supervisor Dr. Claire Bombardier for her

continuing support, expert guidance and patience fkom the inception to the completion of this

project. I would also like to thank the thesis committee members Dr. Allan Detsky and Dr.

Murray Krahn for providing insightful and timely input throughout this research.

I would like to express my gratitude to Dr. Peter Tugwell, Dr. Vibeke Strand, Dr. George Wells,

Louise Lafortune, Dr. Anita Wong, Helena Sustackova, Nancy Ricard and Alison Baker for their

valuable assistance in part or all the projects that constitute this thesis.

The research was conducted within the Arthritis & Autoimmunity Research Centre at the

University Health Network Research Institute, which provided necessary resources and support

to make this research possible. As well, I am indebted to the Canadian Institute of Health

Research (formerly Medical Research Council) for providing the financial means through a PhD

fellowship for the last 3 years of this research.

Finally, I am indebted to my wife Simone, who has shown tremendous patience and tolerance by

bearing with me through three thesis-based degrees, and to my parents who worked hard to

provide their children with endless opportunities.

This research was supported by an unrestricted grant to the Arthritis and Autoimmunity Research

Centre om Aventis Canada hc. The terms of the contract stipulated that the authors should

retain the right to absolute control of the methods, conclusions and means of publication of the

research.

Table of Contents

Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

I . 1 Introduction , 1

1.2 Evaluation of Disease and Response to Treatment , 1

1.3 Epidemiology of Rheumatoid Arthritis , 2

1.4 Current Clinical Practice , 3

1.5 Economic Impact of RA in Canada, 5

1.6 Efficacy of Leflunomide . 6

1.7 Objective and Overview ,8

2. How US and Canadian rheumatologists treat moderate or aggressive rheumatoid arthritis:

Asurvey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

2.1 Preface , 10

2.2 Introduction,lO

2.3 Materials and Methods , 12

2.4 Results,14

2.5 Discussion , 21

3. *Meta-analysis of treatment termination rates among RA patients receiving disease-

modifying anti-rheumatic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

3.1 Preface,24

3.2 Introduction ,24

3.3 Methods , 25

3.4 Results ,27

3.5 Discussion,34

4. A 1-year randomized controlled trial-based economic evaluation of Leflunomide and

Methotrexate in Canadian patients with rheumatoid arthritis. . . . . . . . . . . . . . . . . . . . . . 38

4.1 Preface ,38

4.2 Introduction ,38

4.3 Materials and Methods ,39

4.4 Results ,43

4.5 Discussion ,49

An estimation of the 5-year cost effectiveness of adding Leflunomide to a strategy of

conventional disease modifying antirheumatic drugs in patients with RA . . . . . . . . . . . . . 51

5.1 Preface, 51

5.2 Introduction , 5 1

5.3 Methods,52

5.4 Results , 5 9

5.5 Discussion , 62

6. Epilogue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

List of Tables

Table 1.1: The American College of Rheumatology (ACR) Criteria for RA Diagnosis . . . . . . . 1

Table 1.2: Disease modifjmg anti-rheumatic drugs (DMARDs) used in the treatment of RA . . 4

Table 1.3: Efficacy of leflunomide in comparison to methotrexate and placebo in 482 patients

. . . . . with RA followed for 12 months. Results are presented on an intent-to-treat basis 7

. . . . . Table 2.1: Tabulation of results From surveys of rheurnatologists' treatment preferences 1 1

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 2.2: Number of respondents by province or region 15

Table 2.3: Percentage of Canadian physicians choosing slow-acting antirheumatic agents for

patients with aggressive RA and moderate RA as depicted in the scenarios of the survey16

Table 2.4: Percentage of US physicians choosing slow-acting antirheumatic agents for patients

. . . . . with aggressive RA and moderate RA as depicted in the scenarios of the survey. 18

Table 3.1: Number of patients at risk and duration of treatment in study arms From observational

studies and randomized clinical trials reported in the literature providing information on

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . treatment withdrawals of patients. . 28

. . . . . . . . . . . . Table 3.2: Statistical comparisons of treatment withdrawal rates between drugs 33

Table 4.1: Demographic and disease characteristics of the study patients at baseline . . . . . . . . 44

. . . . . . . . . . . . . . . . . . . . . Table 4.2: Standard gamble and rating scale values for 480 patients 45

. . . . . . . . . . . . . . . Table 4.3: Number of patients incurring costs in the three cost categories. .45

Table 4.4: Health Care Resource Utilization Items Incurred by patients over the 52 week study

. . . . . . . . . . . . . . . . . . . . . period, unadjusted, and adjusted by total time of follow up . 46

Table 4.5: Descriptive Statistics of annualized total, direct, indirect, non-medical costs and

estimated yearly drug acquisition and monitoring costs by treatment group . . . . . . . . . .46

Table 4.6: Statistical Evaluation of total costs, direct costs and direct costs trimmed by the

highest 1 %. Results of statistical tests on untransformed and log-transformed costs.

.....................*............*..................................47

Table 4.7:Calculation of cost per ACR2O responder and quality-adjusted life-year (QALY)

gained. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 8

Table 5.1: Probabilities of treatment withdrawals, overall and due to toxicity, adverse events in

continuing patients and ACR2O response rates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .59

Table 5.2: Average. minimum and maximum costs per type and incidence weighted adverse

event . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

Table 5.3: Costs of Monitoring DMARDs at baseline and during routine follow-up in a 6-month

period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

Table 5.4: Expected costs, numbers of cycles patients respond to therapy, time spent on active

therapy and cost per responder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . - 6 2

List of Figures

Figure 1.1: Intent-to-treat last observation carried fornard analysis of the percentage of patients

who met the American College of Rheumatology response criteria for improvement

. . . . . . . . of 20% or greater at month 1 and quarterly thereafter by treatment group. . 6

Figure 2.1: Scenarios and questions presented in both surveys. Items unique to the Canadian

......... survey are dark shaded; items unique to the US survey are light shaded. 13

Figure 2.2: Percentages of Canadian and US physicians choosing methotrexate (MTX),

parenteral gold (GST), hydroxychloroquine (HCQ), sulfasalazine (SSZ) or other

. . . . . . . . . . . . . . agents either alone or in combination (hatched parts of bargraph). 19

Figure 3.1: Survival curves representing the percentage of patients withdrawing From each agent

because of inelficacy, toxicity or other reasons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Figure 3.2: Survival curves representing the percentage of patients withdrawing from each agent

becauseofinefficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Figure 3.3: Survival curves representing the percentage of patients withdrawing from each agent

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . becausetoxicity 32

Figure 3.4: Percentage of patients withdrawing due to inefficacy, toxicity or other reasons,

separated by observational studies and randomized controlled trials. . . . . . . . . . . . . 34

Figure 5.1: Events occurring during a 6-month period as a consequence of taking a DMARD.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Figure 5.2: Sequence of DMARDs chosen for the strategies modelled in the analysis. One

strategy includes LEF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . - 5 4

6 . .

V l l l

List of Abbreviations

ACR

CRE'

DMARD

ESR

GNP

GST

HAQ IL-1 RA

LEF

MHAQ

MTX

NSAID

QALY

PBO

RA

RCT

RS

SG

ssz sTNFR

VAS

American College of Rheumatology

C-reactive Protein

Disease-modifying anti-rheumatic drug

Erythrocyte Sedimentation Rate

Gross National Product

Gold Sodium Aurothiomalate

Health Assessment Questionnaire

Interleukin- 1 Receptor Antagonists

Leflunomide

Modified Health Assessment Questionnaire

Methotrexate

Nonsteroidal Anti-Inflammatory Drug

Quali ty-adjusted Li fe-year

Placebo

Rheumatoid Arthritis

Randomized Controlled Trial

Rating Scale

Standard Gamble

Sulfasalazine

Soluble Tumour Necrosis Factor Receptor

Visual Analogue Scale

CHAPTER 1

1. Rheumatoid Arthritis

1.1 Introduction

Rheumatoid arthritis (RA) is a chronic disease that causes pain, stiffness, swelling and loss of

h c t i o n in the joints and inflammation in other body organs. The diagnosis of RA is made on the

basis of clinical, radiological and biological observations. The American College of

Rheumatology (ACR) has defined criteria for the diagnosis of RA (Table 1.1) which include

prolonged morning stifhess in the joints, characteristic nodules under the skin, joint erosions

apparent on X-ray tests, and blood tests of an antibody known as rheumatoid factor (1). Patients

may be suspected of having RA before all the diagnostic criteria are satisfied. Other diseases may

mimic RA as well, particularly at the onset of symptoms. The course of the disease may be

limited to a few months of discomfort, or develop into a progressive destruction of the joints

resulting in joint deformities requiring reconstructive surgery.

Table 1.1: The American College of Rhewtology (ACR) Criteria for RA Diagnosis -- - A - - - - - - - - - - - - - . - - - - - - - -

A patient is considered to have F U if at least 4 of these 7 criteria are satisfied: -- --- - - - . - - . - - -- -- -. -. - .

Morning stiffness for at least one hour and present for at least six weeks

0 Swelling of three or more joints for at least six weeks

Swelling of wrist, metacarpophalangeal or pro.uima1 interphalangeal joints for six or more weeks

Symmetric joint swelling present for at least six weeks

Hand roentgenogram changes typical of RA that must include erosions or unequivocal bony decalcification

Rheumatoid nodules

Serum rheumatoid factor by any positive method in less than 5% of n o m l subjects -.

1.2 Evaluation of Disease and Response to Treatment

There is not one single clinical measure with which to evaluate and document the

disease and its progression. Several measures taken together provide a more complete assessment

of the disease and, combined in composite measures of response, are recommended to be used

for the evaluation of new drugs. Various composite measures of response have been proposed,

the most frequently used are the criteria proposed by the ACR (2). A response, according to these

criteria, requires a predefined percentage change from baseline in both swollen and tender joint

counts, and improvement in at least three of the following five measures: 1) patient global

assessment of disease on a visual analogue scale, 2) physician global assessment of disease on a

visual analogue scale, 3) a Functional status measure, 4) patient global assessment of pain

intensity and 5) a laboratory measure of inflammation (either erythrocyte sedimentation rate

[ESR] or C-reactive protein [CRP]). The predefined percentage change may vary between 20%

(ACR 20), 50% (ACR 50) or 70% (ACR 70) improvement, with 20% showing the best

discriminatory power compared to placebo (3).

A typically used measure of fbnctional status is the Functional Disability Index of the

Stanford Health Assessment Questionnaire (HAQ) (4) and its validated shortened version, the

modified HAQ (MHAQ) (5). The MHAQ comprises questions relating to eight functional

dimensions (dressing, arising, eating, walking, hygiene, reach, grip and other activities) and the

total score is the average value which can vary between 0 (best) and 3 (worst).

Radiological measures are not part of standard response criteria, partially because

longer follow-up is needed to document changes in these measures. The Sharp and Lanen scores

are both derived fiom measuring damage of joints shown on X-ray. The Sharp score is the sum of

two sub-scores which evaluate the severity of erosions and the degree of joint space narrowing on

a scale of 0-3 for a total of 62 joints. By contrast, the Larsen score only evaluates joint erosions,

and results in a mean joint score.

1.3 Epidemiology of Rheumatoid Arthritis

It is difficult to estimate exactly how many Canadians are affected by the disease due

to the lack of an established etiologic agent and unique clinical and laboratory features that can

be used to define RA. Nevertheless, estimates based on accepted criteria indicate that in a

population of Caucasian origin approximately 1% of the population suffer fiom RA at any given

time, the incidence being lower at approximately 0.007% (6). The prevalence increases with age

in both men and women with a peak of onset in mid-working-life. The gender-ratio varies with

age, but is consistently higher in women (-70%).

RA leads to a decline in functional status as the disease progresses and can result in

premature mortality. Although patients with RA tend to die from the same type of causes as the

general population, studies suggest that patients with RA die earlier and more of cardiovascular

conditions when compared to similarly aged persons of the same gender (7).

1.4 Current Clinical Practice

Alleviating pain and preservation of function remain major therapeutic goals. This is

achieved by a combination of interventions that include rest, exercise and emotional support, and

pharmacological treatment, the choice of which is individualized and based upon such factors as

joint function, degree of disease activity, patient age, gender, occupation, family responsibilities,

and response to previous therapy. Most rheumatologists now agree that the inflammatory process

should be aggressively stopped in its beginnings, but remission-inducing therapies are not

available. Patients with RA therefore need uninterrupted therapeutic monitoring and often have

to adapt early to the specific circumstances of their disease.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually required as symptomatic

treatment to reduce joint pain and swelling, and to improve function. Analgesic effects are

prompt in onset, but reduction of inflammatory signs may take up to 1-2 weeks. There are few

significant differences in efficacy among NSAIDs, although there are more important differences

in the incidence of adverse events. Their adverse events are gastrointestinal intolerance and renal

toxicity, which sometimes lead to hospitalizations and deaths (8). The drugs traditionally

employed in the treatment of rheumatoid arthritis (&4) have rather incidentally found their way

into therapeutic usage. Common to these drugs, such as methotrexate, gold, hydroxychloroquine,

azathioprine, d-penicillarnine, sulfasalazine and others, is a slow acting therapeutic onset, the

reason for which they are sometimes called slow-acting antirheumatic drugs (Table 1.2).

However, previous classifications employed the term disease modifjmg antirheumatic drug

(DMARD) to differentiate them f?om symptomatic treatments such as NSAIDs. Hereinafter we

will refer to slow-acting antirheumatic drugs as DMARDs. Sulfasalazine was the first drug

specifically designed to treat rheumatoid arthritis but has not been shown to be more efficacious

than its competitors. Methotrexate, alone or in combination with other agents, is now

unanimously regarded as the first treatment option for patients with RA (9). With time, the

proportion of patients responding to treatment with any DMARD continuously declines, new

therapies need to be implemented or combinations of therapies are instituted to prolong the

therapeutic action.

The majority of patients with active RA are on combination therapy for the

above-mentioned reasons. They receive an NSAID and at least one DMARD, with or without

low-dose oral steroids. If disease remission is observed, regular NSAID or systemic steroid

treatment may no longer be needed. DMARDs control RA but usually do not cure the disease.

Therefore, even though remission or optimal control may be achieved, DMARDs should be

continued at maintenance dosage (10).

Hydroxychloroquine 2-4 months 200mg BID

Sulfasalazine 1-2 months Ig BID-TLD

Me tho trexa te 1-2 months 7.5- 15mg / wk

Injectable gold salts 3-6 months 25-50mg IM every 2-4 wk.

Oral gold 4-6 months 3mg DIE-BID

Azathioprine 2-3 months 50- 150mg DIE

D-penicillamine 3-6 months 250-750mg DIE

Infrequent rash, diarrhea, rare retina1 toxicity

Rash, ifiequent myelosuppression, GI intolerance

GI symptoms, stomatitis, rash, alopecia, infrequent myelosuppression. hepatotoxicity, rare but serious puimonary toxicity

Rash, stomatitis, myelosuppression, thrombocytopenia, proteinuria (monitoring prior each dose)

Same but less ftequent, more diarrhea

Myelosuppression, infrequent hepatotosicity, early flu-like illness with fever, GI symptoms

Rash, stomtitis, dysgeusia, proteinuria, myelosuppression, infrequent but serious autoimmune disease

Steroids may be used systemically or by joint injection in patients with active RA.

Oral steroids are usually given in low daily doses (prednisone 5 to 7.5mg) to patients with

inflammatory flares or as bridge therapy until DMARDs begin being efficacious. However, new

evidence indicates that low doses of prednisone could be used for longer time periods to stop

progression of the disease (1 1). Reservations will remain because the devastating consequences

of corticosteroid therapy will never be fully avoided, even with prescription of very low doses

(12;13). Furthermore, steroids (oral and parented) used in combination with other agents play a

potential role in serious toxicity, particularly liver and pulmonary toxicity. Intra-articular

injections are indicated when there is an acute local inflammation in one or several joints.

Better knowledge of the disease process in the recent decade has renewed the hope for

therapies that may, one day, have a more significant impact. More efficacious and safer RA

therapies are needed to reduce the burden of illness. The so-called biologics are a specific group

of recently emerged therapies. These drugs directly interfere into pathologic processes that have

been confirmed to be characteristic for RA. Drugs such as interleukin-l receptor antagonists

(IL-1 RA) (14; 1 9 , soluble Tumour Necrosis Factor receptors (sTNFR) (1 6; 17) and anti-TNFa

antibodies (1 8), are some of the agents currently under investigation and showing promising

results. These agents, however, are very expensive and, according to results presented so far,

etanercept as well as IL- l RA are only marginally superior to rnethotrexate (1 9).

1.5 Economic Impact of RA in Canada

The total economic impact of musculoskeletal conditions including arthritis and

rheumatism has been studied through analyses of Canadian national and provincial health survey

databases. An earlier 1986 estimate of the total economic impact of musculoskeletal conditions

measured the total costs of all musculoskeletal conditions to be approximately 8.2 billion

Canadian dollars in 1986 (10.8 billion in 1994 Cdn. 6) , which at the time represented 2% of GIW

and 10% of all health care expenditures (20). A more recent study of the total healthcare costs of

arthritis and rheumatism puts this figure to approximately 5.9 billion dollars (1994 Cdn.S) (21).

However, only one study provides information on the direct and indirect costs of RA collected

prospectively during the years 1983 to 1994 in a Quebec and Saskatchewan population of RA

patients (22). In this study, the total annual costs incurred by RA patients amounted to 95,953

dollars (1983 - 1989) and 56,253 (1990 - 1994). The direct costs were responsible for 64%

(53,788) and 74% ($4,656) of the total for the periods From 1983 to 1989 and 1990 to 1994

respectively. Roughly multiplying the $6,253 with the 1% of the Canadian population estimated

to be affected by RA would put the total healthcare costs of RA patients in Canada to

approximately 1.75 billion dollan (1 994 Cdn.). Therefore, RA constitutes a substantial problem

in Canada in terms of burden of illness, requiring concerted efforts to find new treatments that

lead to economic savings and to evaluate the economic benefit of existing therapies.

1.6 Efficacy of Leflunomide

Leflunornide is an antirheumatic drug whose metabolite inhibits a critical enzyme in

the synthesis of pyrimidine and impedes T-cell proliferation which plays a pivotal role in the

pathogenesis of RA. It has demonstrated an anti-inflammatory effect in both in vivo and in vitro

animal models. Following a loading dose (100 mg tablet per day for 3 days), a daily dosing of 20

mg is recommended for treatment of adult patients with RA.

The efficacy and safety of leflunomide in the treatment of RA was demonstrated in

two phase-ID, randomized and placebo-controlled clinical studies, one conducted in North

America (23) and one in Europe (24). The North American trial was conducted in 482 patients

with RA in the US and Canada. Patients in this trial were assigned to 1 of 3 treatment groups in a

3:2:3 randomization: leflunomide treatment (20mg/d), placebo or methotrexate (7.5mgwk).

Patients who were not classified as responders by week 16 or who othenvise did not tolerate

therapy up to this time were allowed to switch to alternate therapy, with methotrexate and

placebo patients being allowed to switch to leflunomide, and leflunornide patients to

methotrexate. Efficacy evaluation was performed in an intent-to treat analysis that included all

0 Leflunornide (n = 182) Placebo (n = 1 18)

A Metnotrexale (n= 180) . - - - - - .

-. -

0 3 6 9 1.2 No. of Months

Figure 1.1: Intent-to-treat last observation carried forward analysis of the percentage ofpatients who met the American CotIege of Rheumatology response criteria for improvement of 20% or greater at month 1 and quarterly thereafter by treatment group. (23)

Results of the North American study demonstrate that leflunomide is statistically

significantly superior to placebo in all efficacy measures including ACR response rate and all

individual components of the ACR response criteria (tender joint count, swollen joint count,

patient and physician global assessments, pain intensity assessment, HAQ or MHAQ, and ESR

or CRP) as well as morning stiffhess and rheumatoid factor levels (selection of results presented

in Table 1.3). The treatment effect of leflunomide was evident by 1 month, stabilizing by 3-6

months, and continuing throughout the course of treatment. A similar effect was seen for

methotrexate (Figure 1.1).

Both methotrexate and leflunomide achieved statistically equivalent ACR20 response

rates, with 35% and 41% respectively being considered successful responders, i.e. sustaining

response until study end at 52 weeks (Figure 1.1). Patients on leflunomide fared better than

methotrexate patients from a functional perspective, with statistically significant differences

favoring leflunomide in the HAQ disability index and 2 of 8 subscores of the SF-36 (Table 1.3).

Leflunomide is also statistically significantly superior to placebo in retarding disease progression

as measured by x-ray analysis of both erosions and joint space narrowing but no consistent

differences were noted between leflunomide and methotrexate on assessments of joint damage.

Table 13: Efficacy of leflunomide in comparison to methotrexate and placebo in 482 patients with RA followed for 12 months. Results are presented on an intent-to-treat basis

---- - - - - - - - -- -

Leflunornide Placebo Methotrexate - -- -- --- -

ACR response status (n=182) (n=118) (n=182) ACR success (>= 20%) 3 1% (33% - 48%) 19%(11% - 26%) 35% (29% - 42%)

ACR >= 20% improvement 52% (45% - 60%)$ 26% (18% - 34%) 46% (38% - 53%)5

ACR >= 50% improvement 34% (27% - 4 1 %)$ 8?4, (3% - 12%) 23% ( 17% - 29%)$

ACR >= 70% improvement 20% (14% - 26%)$ 3%(1%-8%) go/, (5% - 14%)$

Total Sharp Score (n=131) (n=83) (n=L38) Baseline (sd) 23.1 1 (34.0) 25.37 (3 I .3) 22.76 (39.0)

Change at endpoint (sd) 0.53 (4.5) : 7 2.16 (4.0) 0.88 (3.3) t 9 HAQ Disability Index (n= 164) (n=99) (n=168) BaseIme 1.3 1.3 1.3

Change at end point -0.45 $ * 0 -0.26

SF-36 physical component (n=157) (a=101) (n=162) Baseline 3 0 23.9 29.7

Change at endpoint 7-6 9 11 I 4.6

9 Leflunomide or methotrexate vs. placebo, p s= .001; fl Leflunomide vs. methoncxate, p = -05; $ Leflunomide vs. placebo, p r = .OO1: t Methotrexate vs. placebo , p = 0.02; 11 Leflunomide vs. methotrexate, p s= -001; * Leflunomide vs. methotrexate, p s= .O 1

The European trial was conducted in 358 patients with RA. Patients in this trial were

assigned to 1 of 3 treatment groups in a 3:2:3 randomization: leflunomide treatment (20mg/d),

placebo or sulfasalazine (2gId). Efficacy evaluation was performed at 24 weeks in an intent-to

treat analysis that included all patients who received drug and had at least one follow-up visit.

Results of the European Study are only briefly summarized here, as findings from this study will

not be fUrther utilized. ACR 20% response status was achieved by 55% of patients in the

leflunomide group (p = 0.0001 vs. placebo), 21% in the placebo group, and 56% in the

sulfasalazine group (p = 0.0001 vs. placebo). Leflunomide is thus a DMARD that is similar in

efficacy to methotrexate and sulfasalazine. Its increased drug acquisition costs require a

comprehensive assessment of its pharmacoeconomic properties to appropriately inform Canadian

decision makers about the value of this new DMARD.

1.7 Objective and Overview

?'he objective of the present thesis is to provide a comprehensive analysis of the

pharmacoeconomic characteristics of leflunomide versus potential comparators in the treatment

of RA for the purposes of reimbursement applications in Canadian jurisdictions.

This phmacoeconomic evaluation of leflunomide consists of five components. The

first component (Chapter 2) is a situational assessment, i.e. a study of the prescribing behaviour

of rheumatologists in Canada and the USA. The findings of this assessment assist in the planning

of the pharmacoeconomic evaluation by describing the type of choices physicians currently make

when treating patients with rheumatoid arthritis. The study allows to quantify the relative

importance of available S W s in the treatment of RA, when they are used, how often and in

what combinations.

The second component (Chapter 3) is a review of the clinical effectiveness of the

potential comparators of leflunomide: methotrexate, gold, hydroxychloroquine and sulfasalazine.

For economic purposes it is important to know how these drugs work in real life and also how

patients fare on these drugs over longer time periods. The review includes observational studies

and randomized clinical trials and has a special emphasis on summarizing how many patients are

able to maintain therapy over time, and their reasons for withdrawal fiom therapy. The findings

from all studies are presented as a combined "survival on therapy" curve for each comparator.

The summary withdrawal rates for specific time periods can thus be used in modelling

antirheumatic therapy over a longer time period in a simulation kamework.

The third component (Chapter 4) is a direct comparison of leflunomide to the "best"

alternative methotrexate and placebo. The data used for the direct comparison are taken from the

North-American randomized controlled trial comparing leflunomide to methotrexate and placebo

in 482 patients. Pharmacoeconomic data and outcomes relevant for pharmacoeconomic

evaluations were collected during the trial. All economic items collected as part of the trial were

costed in 1999 Canadian dollars to adapt the evaluation for a Canadian societal perspective (all

costs) and the perspective of the Ontario Health [nsurance Plan (direct medical costs). Cost-

effectiveness and cost-utility ratios are reported for leflunomide and methotrexate in comparison

to placebo and to each other.

The fourth component (Chapter 5) is an indirect evaluation of leflunomide within a

simulation framework and is modelled in a decision analysis tree with two treatment arms. One

arm consists of a sequence of DMARDs that includes leflunomide whereas the other arm

incorporates a sequence of DMARDs without leflunornide. The sequence of DMARDs

represents findings fiom the survey of rheumatologists (Chapter 2). Withdrawal rates and the

percentages of patients switching to new therapy are derived fiom the clinical review of the

effectiveness of DMARDs (Chapter 3). Costs for the management of adverse events are provided

by the results of a detailed adverse event questionnaire answered by five rheurnatologists.

Efficacy data are derived from meta-analyses of the literature. Extensive sensitivity analyses was

conducted over possible ranges for all variables used in the model. Results are reported as cost

per additional ACWO responder gained and per quality-adjusted life-year (QALY) gained.

CHAPTER 2

How US and Canadian rheumatologists treat moderate or aggressive

rheumatoid arthritis: A survey

2.1 Preface

The survey described in this chapter was published in 1998 (9). The purpose of this

survey was to identify, which primary DMARDs rheurnatologists would choose in the treatment

of patients with mild, moderate and severe RA and what the alternative would be in case of

efficacy failure. It was planned to use the findings to support the order of treatments in the

strategies for the model-based economic comparison of leflunomide.

2.2 Introduction

Current guidelines recommend treating most patients with active rheumatoid arthritis

(RA) aggressively and early, possibly before joint destruction begins (25;26). As a result,

slow-acting antirheumatic drugs once reserved for the later stages of disease are now being

prescribed in the early years. However, although many patients benefit from the use of these

often toxic agents, others do not. The selection of therapeutic strategies has therefore become a

challenge, particularly as patients with milder manifestations of RA generally require a different

approach to that taken in individuals with aggressive disease.

Hydroxychloroquine, gold sodium aurothiomalate (gold), methotrexate, and

sulfasalazine are the most frequently used slow-acting antirheumatic agents. Preferences between

them have shifted slowly over recent years, with s w e y s showing an increasing trend towards

methotrexate administration effectively replacing gold as the treatment of first choice. As

recently as 1985, gold was the initial drug of choice for patients with RA recruited in

rheumatology practices in Alberta (27). Methotrexate was seldom prescribed, either as the drug

of first choice or as consecutive treatment. By 1992, a survey mailed to Canadian physicians

revealed that gold and methotrexate were equally preferable in moderate RA, but that

methotrexate was preferable to gold in aggressive RA (Table 2.1) (28). An identical survey in

Australia showed that 44% of physicians favoured sulfasalazine for the treatment of moderate

RA, and 6 1% preferred methotrexate for severely aggressive disease (29).

Table 2.1: Tabulation of results tiom surveys of rheumatologists' treatment preferences

Canada - 1985 (27) Canada 1992 (28) Australia 1992 (29)

- Iritial Rx. Mod. RA Aggr. RA Mod. RA Aggr-RA

Methotrexate 0.0% 35.1% 44.5% 29.0% 6 1 .O%

I.M. Gold 39.6% 36.4% 3 1.6% 15.0% 2 1 .O%

Sulfasalazine 14.6% 5.8% 2.6% 44.0% 5 .O%

Aurano fin 25 -0% 0.0% 0.0% 1 .O% 1 .O%

Others 2 .O% 6.4% 5.2% t -0% 1 .O%

Rx. : Prescription; Mod.: moderate; Aggr.: aggressive

Many physicians in Canada or the US may consider methotrexate to be the treatment

of choice for both moderate and aggressive disease, although individual factors may affect the

strength of preference (30). Several observational studies support the superiority of methotrexate,

reporting that approximately 36% of patients continue drug treatment over a period of five years

(3 1-34). Unfortunately, however, all presently available antirheumatic agents, including

methotrexate, start to fail from day 1 and will eventually need to be discontinued, whether due to

immediate toxicity in the early phases or to lack of efficacy or some other reason later on. That

fact, and the paucity of alternatives, has led to considerable attention being paid to the

investigation of novel combination treatments and the development of new slow-acting

antirheumatic drugs.

Many of the latter are now under investigation in phase II and III trials and will

require economic assessment for formulary approval. Current guidelines for the economic

evaluation of health care interventions require new approaches to be compared to current

practice. In order to appropriately position a new agent it is therefore necessary to ascertain

existing treatment preferences among rheumatologists. The present paper reports two separate

s w e y s in which the views of Canadian and US rheumatologists, respectively, were elicited on

the treatment of moderate RA, aggressive RA, and aggressive RA that fails to improve in

response to high doses of methotrexate. As well as being necessary for the purposes of economic

evaluation, the infomation gathered may also be of interest to clinicians and policy makers.

2.3 Materials and Methods

The Canadian survey was initiated in September 1996. The Canadian Rheumatology

Association supplied the names of all 295 members; 32 who were not living in Canada or who

were known not to practice adult rheumatology were excluded, leaving 263 to whom the survey

was sent by fax (n=191) or mail (n=72).

The US survey was initiated in November 1996, at which time 3594 physicians were

registered with the American College of Rheumatology (ACR) and indicated that patient care

was part of their daily routine. A 10% random sample, weighted by region, was obtained from

the ACR mailing list. It consisted of 351 physicians: 102 from the Southeastern region, 1 16 From

the Central region, 58 From the Northern region, and 75 From the Western region. Thirty-one

physicians identified as paediatric rheumatologists or out of practice, or who had moved to an

unknown location, were excluded, giving a total of 320 who were sweyed either by fau (n=268)

or by mail (n=52) during April and May 1 997.

In both studies, the questionnaire consisted of a one-page document featuring an introductory

statement, three case scenarios and some questions (Figure 2.1).

SCLVARIO 1: [Iist second line agent(s) you would prescribe, either alone or in combination] Aggressive RA, ? 38 y 1st choice: DMARD-naive 26 activeIy inflamed joints 6 erosions 2nd choice:

ESR & RF markedly elevated

SCENARIO t : [list second line agent(s) you would prescribe, either alone or in combination] Moderately progressive RA, ? 32 y 1st Choice: DMARD-naive, NSALDs not helpful 6 act~vely inflamed joints -- - a - - .. - - - -- - - - -- -

no erosions 2nd Choice:

ESR & RF moderately elevated

-- - -- - . - . - - -. - --

What percentage of your population of RA patients similar to the ? Scenario 1 Scenario t

SCESARIO 0 3: Patient from scenario 1 1st Choice: initially bcner on MTX 25 rnglwcck now loss of efficacy - - - - - - - - - -- -- - - -- - - . . - --

a 22 actively inflamed joints 2nd Choice:

7 erosions

What percentage of your RA patients are in managed care?

What percentage have their drug prescriptions restricted by formularies?

What percentage require a refernl from their primary care physician to see you?

Was your choice of agents in this survey influenced by formulary restrictions?

LLLi "/. LLL1"/0 L U I 1% CI yes 0 no

Figure 2.1: Scenarios and questions presented in both surveys. Items unique to the Canadian survey are dark shaded; items unique to the US survey are light shaded.

The fint scenario described a patient with aggressive RA, 26 actively inflamed joints

and three erosions. The patient in the second scenario had moderately progressive RA, six

actively inflamed joints and no erosions. Finally, the third example described the same patient as

in scenario 1, but with an increase in inflamed joints and erosions despite treatment with

methotrexate 25 mg. Respondents were asked for their fint and second choice of second-line

agent in each case. They were invited to be f?ee in their therapeutic choices and to consider both

single and combination therapy. Respondents were also asked about the percentages of their

patients with moderate and aggressive RA who were receiving systemic corticosteroids.

The Canadian survey differed slightly from the US one in that it omitted a specific

invitation to consider combinatior? therapy in the three patient scenarios. Instead, Canadian

rheurnatologists were asked to indicate which therapy they would use if they had been asked to

combine agents, rather than to select a single second-iine treatment. In addition, three questions

addressed exclusively to US rheumatologists inquired about the proportions of patients who were

in managed care, who had their drug prescriptions restricted by formularies, and who had

required referral from a primary care physician. Finally, US physicians were asked whether their

choice of agents as reported in the survey was influenced by formulary restrictions.

Repeat faxes or mailings of both surveys were sent twice, with Cweek intervals. The

sample size was selected in order to obtain at least 200 usable responses From each country and

to permit estimation of percentages with a maximum error of 7%. Responses to all questions in

the survey were analysed using descriptive statistics, statistical tests were not performed as there

was no plan to test specific hypotheses.

2.4 Results

Choices of therapies

The Canadian survey was returned by 23 1 physicians (response rate, 87.8%), 17 who indicated

they were not practising adult rheumatology were excluded, leaving a total of214 eligible

respondents. Of 230 US physicians who returned the survey (response rate, 7 1.7%), 16 indicated

they were not practising adult rheumatology, again leaving 2 14 eligible respondents. The

majority of Canadians worked in Ontario or Quebec and most responding US rheurnatologists

had practices in the Central or southeastern regions (Table 2.2).

Table 2.2: Number of respondents by province or region * - Canada USA

Province Frequency Percent Region Frequency Percent - - - - - -- - - --

Ontario 96 44.9 Southeastern 5 8 27. I

Quebec 48 22.4 Central 7 8 36.4

British Columbia 22 10.3 Northern 35 16.4 Alberta 19 8.9 Western 43 20.1

Manitoba 7 3.3 - Saskatchewan 6 2.8

New Brunswick 6 2.8 Nova Scotia 5 2.3

Newfoundland 4 1.9 - Total: 213 99.5* 2 14 100.0 - - -. - - - - - -. - - - - - - - -. - - -. - . - . - - - - - . - - - -- . - - . - . - - . . - . - - -

* 1 Canadian respondent answered anonymously

Several major findings emerged From the Canadian survey (Table 2.3, following page):

Scenario 1 : Methotrexate was the drug of first choice of 68.7% of Canadian rheumatologists for

the treatment of patients with aggressive RA. Intramuscular gold was the first choice of 14.5%

and the second choice of 50%.

Scenario 1: More than 90% chose a single agent for the treatment of moderate RA: 47.2% opted

for hydroxychloroquine, 22.0% for methotrexate, 1 1.2% for gold, and 7.9% for sulfasalazine.

Sulfasalazine was the second choice of 27.6% of respondents.

Scenario 3: Over 50% of Canadian rheumatologists would continue their therapy with a single

agent, predominantly gold (34.6%). The preferred combination was methotrexate plus

hydroxychloroquine (40% of all combinations chosen).

TabIe 23: Percentage of Canadian physicians choosing slow-acting antirheumatic agents for patients with

aggressive RA and moderate RA as depicted in the scenarios of the survey. ---- --

Single Agents: Methotrexate I.M. Gold S ul fasalazine Hydroxychloroquine Azathioprine D-Penicillarnine

Cyc lo spo~e Chloroquine Autano fin Methotrexate I.M.

Combination: Methotrexate & Hydroxychloroquine Methotrexate & I.M. Gold Methotrexate & SuIfasalazine Methoaexate & Cyclosporine Methotrexate 8r Chloroquine Methotrexate & Azathioprine Methotrexate & D-Penicillarnine Hydroxychloroquine & I.M. Gold Hydroxychloroquine & Sulfasalazine Hydroxychloroquine & Azathioprine I.M. Gold & Sulfasafazine I.M. Gold & Azathioprine I.M. Gold & Chloroquine Methotrexate I.M. & Sulfasatazine

Methotrexate I.M. & Chloroquine Triple Therapy:

Methotrexate/Hydro;uyc~oroquineA.M. Gold Metho~exate/Hydroxychloroquine/Sulfasalazine

Methotrexate/Hydroxychloroquine/Azathioprine

Methotrexate I.M./HydroxychloroquineA.M. Gold 1.M. ~o~d/Hydroxych~oroquine/Azathiop~e

Aggressive RA Moderate RA 1st 2nd 1st 2nd

Choice Choice Choice Choice

--

No answer provided: 0.0

MTX ineff. 1st 2nd

Choic Choic

. --

- numbers may not add to 100% due to rounding)

The responses of the US physicians were somewhat different (Table 2.4 - following

page):

Scenario 1 : 78.5% of physicians reported that methotrexate was their drug of first choice for the

treatment of patients with aggressive RA as depicted. Intramuscular gold predominated as a

second choice (24.8%), followed by sulfasalazine (1 4.O%), azathioprine (1 2.6%) and

hydroxychloroquine (8.4%).

Scenario 2: 90% of respondents reported preferring single agents for the treatment of moderate

RA as depicted. Hydroxychloroquine (39.3%) and methotrexate (38.8%) were equally widely

used. Sulfasalazine was given as a second choice by 25.7%.

Scenario 3: Only 37% of US rheumatologists chose single therapy for patients with aggressive

RA failing methotrexate, and no clearly preferred agent emerged. Although the majority of

respondents indicated that they would use combination (38.3%) or triple (23.8%) therapy, most

combinations included methotrexate plus either sulfasalazine or hydroxychloroquine. The same

agents also dominated triple therapy, with 2 1.5% of respondents nominating methotrexate plus

hydroxychloroquine and sulfasalazine.

Table 2.4: Percentage of US physicians choosing slow-acting antirheumatic agents for patients with aggressive

RA and moderate RA as depicted in the scenarios of the survey.*. --

Aggressive RA Moderate RA MTX ineff. 1 s t 2nd 1 s t 2nd 1st 2nd

Choice Choice Choice Choice Choice Choice Single Agents:

Methotrexate 1.M. Gold Sul fasalazine Hydroxychloroquine Aza thioprine D-Penicillamine Cyclosporine Aurano fin Minocyctine Cyclophosphamide

Combination: Methotrexate & Hydroxychloroquine Methotrexate & I M . Gold Methotrexate & Sulfasalazine Methotrexate & Cyclosporine Methotrexate & Auranofin Methotrexate & Aza th iop~e Methotrexate & Minocycline Methotrexate & Cyclophosphamide Hydroxychloroquine & I.M. Gold HydroxychIoroquine & Sulfasalazine Hydroxychloroquine & Azathioprine Hydroxychloroquine & Minocycline 1.M. Gold & Azathioprine Azathloprine & Sulfasalazine Cyclosporine & D-Penicillamine

Triple Therapy: Methotrexiitem ydroxyc h1oroquineA.M. Gold Methotrexate/HydroxychloroquineiSulfasalazine Methotrexate/Hydroxychloroquine/Azathioprine Methotrexate /HydroxychIoroquine~inocycIine Methotrexate/Hydroxychloroquine/CycIosporine Methonexate/l.M. GoId/Azathioprine Meth0trexateA.M. GoId/Sulfasalrtzine

No answer provided: * numbers may not add to 100% due to rounding

Looking only at the first

choices of single or combination

therapy (Figure 2.2 ) both Canadian

and US rheumatoIogists reported

relying primarily on methotrexate

when treating patients with

aggressive RA and

hydroxychloroquine or methotrexate

in patients with moderate RA.

Canadian rheumatologists also

favoured gold in aggressive or

moderate RA, thereby slightly

reducing the strength of their

preference for methotrexate. In

particular, Canadians said they liked

to prescribe gold to patients who fail

adequate doses of methotrexate,

whereas no leader emerged from the

choices of US rheumatologists. Most

combinations chosen by either group

of rheumatoIogists included

methotrexate plus

hydroxychloroquine with or without

sulfasalazine; 2 1.5% of US

rheumatologists preferred a triple

combination of all three, compared

to only 3.3% of the Canadian

sample.

MTX GST HCQ SSZ Chhcn 5 ( m GST HCQ 552 Olhcn

C3n3& US

10006 Scenario 2 - Moderate RA

MTX GST HCQ SSZ Wrn 5tTS GST HCQ SSZ Othm Cam& US

Scenario 3 - Aggressive RA failing 25mg MTX

W R G!X HCQ SSZ Ochcn M I 3 GSf HCQ SSZ Men Canada US

Figure 2.2: Percentages of Canadian and US physicians choosing methotrexate (MTX), parented gold (GST), hydroxychloroquine (HCQ), sulfasalazine (SSZ) or other agents either done or in combination (hatched parts of bargraph).

US rheumatologists indicated that, on average, 66.7% of patients with RA similar to that

described in scenario 1 would receive steroids (SD: 30.5%; median: 75%; inter-quartile range:

50% - 90%; missing: 11). In comparison, the Canadian figure was 44.5% (SD: 32.2%; median:

40%; inter-quartile range: 1575%; missing: 13). For patients with moderate RA similar to

scenario 2, US rheumatologists estimated that 38.9% would receive systemic steroids (SD:

29.1 %; median: 30%; inter-quartile range: 1 O-SO%; missing: 13), compared to 16.1 % in the

Canadian survey (SD: 20.3%; median: 10%; inter-quartile range: 045%; missing: 16).

Answers to the additional questions in the US survey showed that, on average, 36.9% of

patients were estimated to be in managed care (SD: 30.4%; median: 30%; interquartile range:

1040%; missing: 16), 35.1% were estimated to have formulary restrictions (SD: 33.2%; median:

25%; interquartile range: 10-60%; missing: 19) and 43.8% were estimated to require referral for

rheumatologic care (SD: 33.1 %; median: 40%; interquartile range: 1 WO%; missing: 17).

2.5 Discussion

The results of the present surveys confirm methotrexate as the primary choice in the

treatment of aggressive RA. Most Canadian and US rheumatologists preferred it, although some

Canadians also favoured gold. Most preferred combinations were also based on methotrexate,

usually plus hydroxychloroquine with or without sulfasalazine. The triple combination of

rnethotrexate, hydroxychloroquine and sulfasalazine was primarily favoured by US

rheumatologists treating patients who fail methotrexate 25 mg. Both sets of findings also

demonstrate that there is no clear single agent alternative to methotrexate: respondents were

divided between competing single agents or tended to use methotrexate-containing combination

therapy.

Comparison of the Canadian results to reports in the literature indicates that methotrexate

is increasingly preferred by rheumatologists for the treatment of moderate or aggressive RA.

However, when compared to the findings of the survey by Collins and associates (28), these

results suggest little change in the preference among Canadian rheumatologists to reserve

combination therapy for later in the treatment process, even in patients with aggressive RA.

Historical comparisons were not possible with the US information because of a lack of published

surveys of the prescription choices of American rheurnatologists.

Because physicians were asked to indicate two therapeutic choices for patients with either

moderate or aggressive RA, additional conclusions became evident - not least that there is an

obvious scarcity of treatment options. US rheumatologists reported using methotrexate to treat

patients with aggressive disease. Canadians said they would prescribe either rnethotrexate or

gold. However, there is no agreement about alternatives to methotrexate. In patients with

aggressive RA who fail methotrexate, agents such as cyclosporine and azathioprine were

favoured by only a few respondents, indicating that expectations of their therapeutic potential are

limited. For most Canadian and US rheurnatologists, the next step after methotrexate appears to

be to add an additional drug such as hydroxychloroquine or sulfasalazine. The strong preference

for triple therapy among US rheumatologists (2 1.5%) was probably influenced by the

encouraging results published by O'Dell and associates (35).

The study also showed wide variation between rheumatologists in their estimates of how

many of their patients with aggressive or moderate RA would receive steroids. Compared to US

rheurnatologists, Canadian rheumatolo$sts estimated that fewer of their patients with aggressive

or moderate RA would receive steroids, but these differences were smaller than the variations

between individual rheumatologists.

The questions in the present study, unlike those generally used in surveys, were designed

to elicit open answers that needed to be spelled out instead of being checked off fiom a list. This

reduced the likelihood of bias due to respondents being cued towards particular answers, and

increased the probability that the type of treatment selected would reflect that chosen in a real-life

situation. It is well known that answers of physicians to written case simulations do not fully

coincide with the reasoning and actions they adopt in real life (36;37). The few studies using

written case scenarios in patients with rheumatoid arthritis (38;39) and osteoarthritis (40),

although not evaluating therapeutic strategies, have demonstrated acceptable agreement. The

validity of the US survey is supported by data fiom an inception cohort of 750 US RA patients

with disease of less than 1 year. Wolfe et al. (41) showed that alone or in combination

methotrexate represented 47% of the prescriptions (46.2% in the US survey for patients with

moderate RA), hydroxychloroquine 56% (48.6% in the US survey) and sulfasalazine 10%

( 1 1.2% in the US survey).

Our surveys achieved response rates that were high - 87.8% response rate in a census of

Canadian rheurnatologists and 71.7% in a scientific random sample of US rheumatologists - and

compare favourably with the 44% response rate obtained by Prashker and Meenan on a random

sample of 300 board-certified US rheumatologists (42), and the 29% response rate achieved by

Moreland et al. in a survey of 4032 US rheurnatologists (43) . An equally high response rate of

68% was achieved by O'Dell and associates in a survey of a random sample i.f 200 US

rheumatologists (44). A recent literature review revealed that only 20% of 68 published mail

surveys using physicians as respondents achieved response rates exceeding 70% (45).

Both surveys were conducted within the 9-month period between September 1996 and

June 1997. The Canadian study differed slightly in structure kom the US one. Canadian

physicians were asked to indicate the type of second-line agents they would prescribe to the

patients in the three scenarios, but no reference was made to the prescription of combination

therapy. Nevertheless, 6% to 30% reported that they would administer combination therapy,

depending on the scenario. These percentages are similar to those derived from Canadian

physicians' responses to a previous survey (28). Only at the end of the questionnaire were

rheumatologists specifically asked about combination therapy. Many referred to their answers to

scenario I , for which they had already chosen combination treatment. In the US s w e y , the

combination question was eliminated as redundant. Nonetheless, rheumatologists were

specifically asked to record their treatment choices, whether single agent or combination therapy.

In conclusion, the responses of Canadian and US rheumatologists to the present survey

illustrate the paucity of treatment options for patients with RA and confirm that there is no clear

preference of choice between the alternatives to rnethotrexate. New agents are therefore needed

to increase the therapeutic options for aggressive disease. There is also a need for more

information about patient preferences.

CHAPTER 3

Meta-analysis of treatment termination rates among RA patients receiving disease-

modifying anti-rheumatic drugs

3.1 Preface

The meta-analysis presented in this chapter was conducted to summarize experience from

observational studies of the potential comparators for leflunomide. The study was published in

2000 (46). Observational studies report on the effectiveness of DMARDs under routine care

conditions, thus providing more realistic estimates of withdrawal rates than those reported in

randomized controlled trials. These withdrawal rates are essential to build a realistic decision

analysis model for the comparison of DMARDs.

3.2 Introduction

Given the chronic nature of rheumatoid arthritis (RA), it is important to obtain long-term

evidence of the success of therapy with disease modifjmg anti-rheumatic drugs (DMARDs). This

may be provided by the findings of observational studies or randomized controlled trials (RCTs).

Compared with observational studies, RCTs generate more detailed and standardized data

concerning therapeutic response (47), but are generally conducted over time periods that rarely

exceed one year. The therapeutic potential of the study drugs must therefore often be extrapolated

beyond the period of investigation. Furthemore, patient populations in RCTs are highly selected,

and monitoring is intense. Some investigators have argued that observational studies, which

typically document treatment failure as the proportion of patients who withdraw from therapy

due to lack of efficacy, treatment toxicity, or reasons unrelated to therapy, provide more realistic

estimates of how patients respond to therapy (48-53).

Observational studies of drug therapy often use survival analysis to assess treatment

withdrawal rates. For outcomes such as time to treatment failure, the product limit method is a

fundamental part of this approach, allowing for the estimation of withdrawal rates even when

patients enter a study at different times and are therefore observed for varying periods (54).

However, because estimates of s w i v d become unstable at follow-up periods reached by only a

few patients, such analyses are usually stopped when too few subjects remain on treatment for

reasonable inferences to be drawn. It is therefore advantageous to combine data from several

observational studies in order to increase sample size, particularly at the tail end of the s w i v a l

curve.

A number of observational studies of DMARD therapy in RA have now been published,

creating an important opportunity to summarize their findings in combination with those of

RCTs. Agents considered in the present meta-analysis are parenteral gold (GST),

hydroxychloroquine (HCQ), methotrexate (MTX), and sulfasalazine (SSZ). The primary

objective is to determine overall treatment withdrawal rates, and to look at how they break down

according to lack of efficacy and toxicity. A secondary objective is to compare treatment

withdrawal rates fiom observational studies with those fiom RCTs.

3.3 Methods

Selection of references

The Medline database fiom 1966 to August 1997 was searched by combining the

keyword 'rheumatoid arthritis' with textwords and keywords for GST, SSZ, MTX, and HCQ,

including common synonyms. Letters, editorials and comments were excluded, as were articles

written in languages other than English, French, German or Spanish. The resulting references

were reduced to a set of' 1387 by excluding all those that did not address efficacy or toxicity. A

further 1035 references derived fkom a broader search conducted by the RA subgroup of the

Cochrane Musculoskeletal Review Group were added, to give a total of 2422. The Cochrane set

of references was retrieved from the Excerpta Medica and Medline electronic databases, using

keywords and textwords for 1) randomized clinical trial, 2) clinical trial, 3) comparative study, 4)

evaluation study, 5) follow-up study, 6 ) prospective study, combined with all references indexed

under 7) arthritis, rheumatoid.

Screening and assessment of references

Based on information in titles and abstracts, the 2422 references resulting from both

searches were classified according to the four agents of interest and the design of the study.

Eligible designs were RCTs, and observational studies including case series, case control and

cohorts, and case reports. Paper copies were obtained of all clearly relevant papers, plus those

with uninformative titles and/or abstracts. A total of 445 investigations were found that provided

original information. These were then assessed by two authors according to the following

criteria: (1) Does the study document the experience of patients from the day therapy was

initiated? (2) Does the study provide data for one of the four therapies of interest? (3) Does the

study provide information on treatment withdrawal rates? (4) Do all included patients have a

documented diagnosis of RA? Investigations meeting all four criteria were retained as the set of

studies providing withdrawal information. Of those, only those studies disclosing the actual

number of patients withdrawing fiom the study drug were used for the meta-analysis. Authors of

four large excluded studies were approached with a request to provide additional information but

were either unable to provide the data or declined to collaborate.

All observational studies were further appraised according to the following criteria:

(1) Was reporting of termination rates a primary or secondary objective?

(2) Was outcome ascertainment prospective or retrospective?

(3) Was clinical response specifically defined?

(4) With regard to follow-up, were:

a) all patients followed over a fixed interval independent of treatment status

(no censoring); or were

b) patients followed over intervals varying from a few months to several

years depending on study entry and treatment termination (with

censoring)?

( 5 ) Were lifetable or Kaplan Meier swiva l analysis techniques applied?

(6) Did the study provide information about the numbers ofpatients at risk, censored

and terminating treatment at each interval?

Data extraction

Numbers of patients reported to have withdrawn from treatment with each DMARD were

abstracted independently by two of the authors, whose findings were checked for agreement and

corrected where necessary. The dataset was then constructed. Take for example the treatment arm

of a study of 6 months' duration in which five of 20 patients had withdrawn fiom treatment by 6

months. Those five patients were coded as one observation and classified as treatment failures at

the midpoint of the interval (month 3), whereas the 15 patients who continued treatment were

coded as a second observation and classified as censored at study end (month 6). Each

observation was weighted by the number of patients, such that the first counted as contributing

five patients, and the second 15. Observations from a few studies conducted over long time

periods without providing detailed interval information were modified by apportioning

withdrawals to 6-month intervals assuming a constant failure rate.

Analvsis

Survival analysis and statistical comparisons were then performed. Actuarial survival

curves stratified by DMARD were plotted for all studies entered into the database using four

different definitions of failure: I) withdrawal due to lack of efficacy, toxicity or other reason; 2)

withdrawal due to lack of efftcacy or toxicity; 3) withdrawal due to lack of efficacy; and 4)

withdrawal due to toxicity. For the purposes of analyses 2, 3 and 4, withdrawals not defined as

treatment failure were coded as treatment continuations up to the midpoint of the interval.

Statistical comparisons were undertaken in two steps: first, the cumulative survival

probabilities for treatment with each of the four DMARDs were compared pairwise using log-

rank and Wilcoxon statistics; second, withdrawal rates for each agent were compared using Cox's

proportional hazards model (proc PHREG in SAS) with adjustment for study type and year of

publication. As many treatment failures occurred at the same timepo int, the exact algorithm for

tied events was used. HCQ treatment was excluded From the comparisons due to the limited

amount of data available and because it is generally prescribed in mild RA, although survival

c w e s are presented. Three statistical comparisons were performed within each of the four

groups: 1) MTX vs GST; 2) MTX vs SSZ; and 3) SSZ vs GST. Further subgroup analyses

compared the effect of study type on treatment withdrawal rates for MTX, SSZ and GST

separately. A time limit of 24 months was set and the same statistical approaches used.

3.4 Results

Of the initial 445 studies, 1 59 satisfied all four screening criteria; 7 1 were RCTs and 88

observational studies. Reasons for the 286 exclusions were as follows: 132 (46.2%) did not

evaluate an inception cohort, 220 (76.9%) did not provide information on treatment withdrawal,

32 (1 1.2%) studied diagnoses other than RA, and 45 (1 5.7%) evaluated drugs other than MTX,

GST, HCQ or SSZ (some studies were excluded for more than one reason). Included in the

present meta-analysis were 1 10 of the 159 studies which provided detailed withdrawal

information.

Further assessment of the observational studies for methodological characteristics showed

that provision of information on treatment termination rates was a primary objective in 42 (48%),

and outcome ascertainment was prospective in 62 (70%); treatment success or failure was

defined by explicit criteria in 2 1 (24%). Follow-up over a fixed interval independent of treatment

status was documented in 38 (43%), and of the remaining 50 observational studies that reported a

variable follow-up, 26 presented the data using Kaplan Meier survival analysis techniques. Raw

numbers of patients at risk, censored, and terminating treatment at within-study intervals were

reported in only 13, four and seven papers, respectively.

The 1 10 studies included in the meta-analysis contributed 142 arms, the majority of them

reporting results with GST or MTX administration. Only three observational study arms provided

withdrawal information for HCQ (Table 3.1). The maximum observation time on HCQ treatment

was only 24 months, whereas data for GST, MTX and SSZ were reported for as long as 72

months.

Table 3.1: Number of patients at risk and duration of treatment in study arms From observational studies and

randomized clinical trials reported in the literature providing information - . -- - - - on - treatment withdrawals of patients. - -- -

Gold Hydrorychloroquine Methotrexate Sulfasalazine

Length OBS RCT OBS RCT OBS RCT OBS RCT (months) N Pat. N Pat. N Pat. N Pat. N Pat. N Pat. N Pat. N Pat. -- PA a - - - - -- - - - - - . - - - .

[O* 61 3 647 14 387 2 5 6 9 4 194 2 523 14 404 2 181 9 469

(6, 121 9 366 I8 689 - 8 327 7 191 1 1 616 2 103 5 163

(12,243 5 349 2 149 1 2 3 1 18 3 198 2 88 2 180 - (24,361 2 127 - - 3 171 1 185 (36,481 1 49 - - 2 174 - (48,601 2 392 - - 2 247 - 1 222 1 100

(60,721 - 1 78 - Total: 22 1930 34 1225 3 592 13 539 20 1582 28 1293 7 686 15 732

RCT = randomized controlled trial, OBS = Observational Study, N = Number of treatment arms, Pat. = Number of

patients in treatment arms

Sunrivalsn-therapy curves including all types of withdrawals indicate that 36%, 23% and

22% of the patients continued MTX, GST and SSZ, respectively, for 60 months (Figure 3.1) with

median swiva l times of 4 1 months, 24 months and 18 months respectively. The combined

29

number of patients at risk at baseline for each of the three drugs was 2875 (MTX), 3155 (GST)

and 14 1 8 (SSZ). When considering only withdrawals for lack of efficacy or toxicity (excluding

administrative reasons or relocation), the percentage of patients estimated to continue MTX as

compared with GST or SSZ increased to 5 1%, indicating that a considerable proportion failed to

continue MTX for reasons other than lack of efficacy or toxicity (data now shown as figure).

Data on withdrawals for lack of efficacy only (Figure 3.2) indicate that 75%, 73% and

53% of patients receiving MTX, GST and SSZ, respectively, would continue therapy for 60

months. For this subgroup analysis, the combined number of patients at risk at baseline for each

of the three drugs was 201 3 (MTX), 2233 (GST) and 1392 (SSZ). Analysis of withdrawals due to

toxicity (treating all other withdrawals as non-informative) revealed that 65%, 36% and 48% of

the patients continued MTX, GST and SSZ, respectively, for 60 months (Figure 3.3).

Percentage of Patients remaining on treatment Withdrawals are for inefficacy, toxicity or other reasons

Months Adiusted Sam~Ie Size GST 3128 2186 977 623 404 33 1 252 23 5 181 172 HCQ 1131 640 129 29 1 1 MTX 2813 2084 1029 749 578 393 254 214 159 151 SSZ 1399 870 392 316 217 186 140 I40 1 1 1 1 1 1

- -- - - - - . - - - - - -- - - - - - -- - - -- - - - - - - - - - - - - - - - - - --

Figure 3.1: Survival curves representing the percentage of patients withdrawing From each agent because of inefficacy, toxicity or other reasons. Six-month interval data were generated from studies providing withdrawal information for intervals larger than 12 months. The data are from observational studies and randomized controlled trials.

Percentage of Patients remaining on treatment Withdrawals are for inefficacy

\------ I ----__-_-_ L \ 80% 1 ).,. \ . - _ _ _ _ _ _ . . _ _ _ _ _ _ _ - - - . - - . _ _ _ _ MTX

' \---.- \, -

! \ \. ', \.

'. GST

, I \ HCQ k

'- - . 60% - '..-.. ssz

0% . 42 48 54 60

Months Adiusted Sample Size GST 2055 1512 857 509 338 244 HCQ 495 330 96 12 4 AMTX 1903 1426 805 561 462 288 SSZ 1261 812 399 316 224 1 SO

- -- -- -- - A A -- - -- - - - --- - - - - PA - - - - - - -- -

Figure 3.2: Survival curves representing the percentage of patients withdrawing from each agent because of inefficacy. Six-month interval data were generated from studies providing withdrawal information for intervals larger than 12 months. The data are from observational studies and randomized controlled trials.

Percentage of Patients remaining on treatment Withdrawals are for toxicity

Adiusted Sample Size GST 2171 1638 860 53 1 338 255 193 171 133 120 HCQ 504 33 1 99 10 4 MTX 1930 1462 807 563 465 29 2 19 1 149 128 122

-- SSZ 1326 811 399 3 14 224 181 149 139 t 15 108

- --- A - - - -- - - - - -

Figure 3.3: Survival curves representing the percentage of patients withdrawing from each agent because toxicity. Six-month interval data were generated from studies providing withdrawal information for intervals larger than 12 months. The data are from observational studies and randomized controlled trials.

Combined data from all published studies indicate that, after adjusting for study type and

year of publication, patients treated with SSZ are up to 1.9 times more likely to fail therapy than

patients treated with MTX (Table 3.2). Patients treated with GST are up to 2.3 times more likely

to fail therapy compared to patients treated with MTX, however when looking at failures for lack

of efficacy only, it turns out that patients treated with GST are significantly less likely to

discontinue therapy compared to patients on MTX. This finding is significant only after adjusting

for type of study and year of publication. Overall, more patients withdrew from SSZ than GST

and, compared to GST, twice as many patients withdrew from SSZ due to lack of efficacy.

However, less patients withdrew from SSZ due to toxicity.

Table 3.2: Statistical comparisons of treatment withdrawal rates between drugs by

means of the Log-Rank, Wilcoxon, and Cox's proportional hazards regression. -

- - . . . . - - - - - - - .

All reasons Log-Rank Wilcoxon

Cox's Proportional Hazard

Toxicityflnefficacy Log-Rank Wilcoxon

Cox's Proportions[ Hazard

inefficacy Log- Rank Wilcoxon

Cox's Proportional Hazard

Toxicity Log-Rank

Wilcoxon Cox's Proportional Hazard

GST vs. hITX

P .- .- - -

< .0001 c .0001

< .0001 1.40

< .0001 < -000 I < .000f 1.68

0.36

0.02

0.0077 0.73

< .ooo 1

< ,000 1

< .0001 2.28

SSZvs. MTX SSZ vs. GST

HR = h a r d ratio (see text for explanation)

The comparison of withdrawal rates between observational studies and RCTs involving

MTX, GST and SSZ revealed no statistically significant differences for up to 24 months (Figure

3.4).

GST

Obs. Studies ~ Obs. Studies . - . . ._ - _.

RCTs RCTs - Figure 3.4: Percentage of patients withdrawing due to inefficacy, toxicity or other reasons, separated by observational studies and randomized controlled trials. The comparison was limited to 24 months duration and showed no statistically significant difference in withdrawal rates between observational studies and randomized controlled trials for all three agents.

3.5 Discussion

The present study summarises rates of treatment withdrawal in published observational

studies and RCTs of MTX, GST, SSZ and HCQ. Analysis of the combined data shows that

patients stayed longest on single DMARD therapy with MTX. However, nearly two thirds of all

subjects started another therapy within 5 yean because of lack of efficacy, treatment-associated

adverse events, or other factors. When withdrawals due to lack of efficacy alone were considered,

there were more patients withdrawing £kom MTX than GST, and it was noted that a large

proportion of patients who withdrew from MTX did so for reasons other than inefficacy or

toxicity.

This is not the first investigation to make a formal attempt to review withdrawals from

treatment with selected DMARDs (48;55;56), but it is the first to combine data from

observational studies and RCTs, and to specifically compare rates of withdrawal due to lack of

efficacy, toxicity and other reasons. Wolfe noted in a review that estimates of 5-year treatment

withdrawal vary considerably, with those for MTX ranging kom 30% to 75% (57). Wolfe

combined the 5-year estimates of MTX therapy, weighting them according to the sample size of

patients at risk at baseline; however, this may not be appropriate as the precision of the survival

estimates is determined by the number of patients at risk not only at baseline but throughout the

study period. Felson et al. compared withdrawal rates between DMARDs but restricted their

review to RCTs (56). Furthermore, they compared overall withdrawal rates and those due to

toxicity, but did not calculate combined survival curves.

Some investigations that were not included in the present meta-analysis - because they

did not disclose the actual number of patients withdrawing - documented higher rates of MTX

maintenance at the 5-year interval. For example, Wolfe et al. estimated that -45% of subjects

remained on MTX at 5 years (3 l), and Pincus et al. put the figure at -65% beyond 5 years (32).

Inclusion of these data would have slightly increased the combined percentage of patients

continuing MTX for up to 5 years. In fact, the year of publication independently contributed to

survival differences for MTX and SSZ. Withdrawal rates on MTX and SSZ have therefore

declined in recent years. Year of publication was insignificant for HCQ and GST, documenting

no change in survival on therapy For these drugs over the years. This is confirmed by the

similarity of the present 5-year treatment survival estimate of 23% to those by Wolfe et al. (3 1)

and Pincus et al. (32) who noted, respectively, that 20% and 28% of patients continued GST

therapy for up to 5 years.

Even though the combined rates of survival on therapy here are obtained from several

studies, only two treatment arms each for GST (58;59) and SSZ (59;60), and three for MTX (6 1 -

63), contributed information for up to 60 months. However, survival-on-therapy curves for the

combined studies reveal a consistent pattern within the first two years and most are parallel,

suggesting that additional studies of the same agents would be unlikely to make a considerable

difference. More detailed information concerning the disease status and demographic

characteristics of patient populations would probably facilitate analysis of subgroups exhibiting

different rates of survival on therapy, but that level of detail could not, unfortunately, be

achieved. Thus, this meta-analysis can offer only a rough guide to physicians who want to know

how long a particular patient is likely to continue treatment with an individual DMARD.

A M e r limitation of the present study is the lack of adjustment for meaninghl

covariables in the statistical comparisons. Although information was sought on common

variables such as joint count, rheumatoid factor status, disease duration, and the number of prior

DMARDs, it had too seldom been collected by investigators to allow for a more detailed

analysis. Earlier studies might have included patients with more severe disease, leading to lower

treatment survival rates - particular with GST.

Examination of the underlying reasons for treatment withdrawal in the present meta-

analysis indicated that, after adjustment for year of publication, patients on GST were

significantly less likely to withdraw from therapy due to lack of efficacy than MTX patients.

These data do not reveal how many patients achieved remission or significant clinical

improvement during treatment with these two agents, but they do encourage us to take a closer

look. GST is one of the least favoured DMARDs (9), despite efficacy comparable to MTX

having been demonstrated by RCTs (64;65), on large databases (66;67), and in the meta-analysis

by Felson et al. (56) The present results suggest that toxicity is the main reason for GST being

out of favour. It is likely that most of the problems relate to the cutaneous rash that, it has been

speculated, occurs more often in patients slated for remission (55). However, GST-associated

adverse events can be managed in such a way as to avoid discontinuation of therapy (68) or

promote initiation of a second course (68-70). Furthermore, withdrawal rates reported in the

literature may obscure the true efficacy of GST, as it has been observed that patients who

withdraw from GST are more likely to experience a sustained improvement compared to patients

withdrawing fkom MTX (71). This finding may be a direct consequence of using implicit

judgment to classify patients as toxicity or inefficacy withdrawals. h this meta-analysis we had

to rely on the original author's classification of withdrawals which is often performed without

clear guidance by specific criteria, which in turn leaves the possibility for classification biases

that may artificially favour one drug over others.

It is encouraging that, contrary to current opinion, there is no apparent difference in

withdrawal rates between observational studies and RCTs. Theoretically, withdrawal rates in

RCTs could be either higher (due to protocol-mandated withdrawals or patients fearing that they

are taking placebo) or lower (because subjects participating in RCTs receive more care and

attention than is usual in a real world setting). However, although the present results show that

equal trust can be placed in reported withdrawal rates, whether they originate from RCTs or

observational studies, the relevant comparison was possible for only up to 24 months of follow-

UP*

The product limit calculation of treatment survival probabilities is a routine method

employed in the reporting of treatment success of various DMARDs. However, it is possible that

the method is often applied to data which violate some basic assumptions for its use (72). For

example, survival estimates in many older studies may be biased downwards, as these patients

generally received their first DMARD late in the disease course, but also because survival on a

specific treatment may improve as rheumatologists gain experience with it (72). This better

survival for patients will not be given its due respect when all patients are grouped together for

the purpose of the survival analysis. The results presented here will only repeat the same

potential biases that may afflict the underlying studies, unless these biases cancel each other out.

The decision to withdraw therapy is oflen implicitly made in observational studies. Those

that adopt explicit definitions of clinical response and follow common methodological reporting

standards will enhance the short-term results provided by RCTs and supply valuable information

on the long-term performance of antirheumatic therapies to physicians, patients and researchers.

CHAPTER 4

A 1-year randomized controlled triabbased economic evaluation of Leflunomide

and Methotrexate in Canadian patients with rheumatoid arthritis.

4.1 Preface

This chapter reports the economic comparison of leflunomide and methotrexate based on

data that were prospectively collected alongside the North-American phase ID randomized

controlled trial comparing leflunomide to methotrexate and placebo during a 52-week period.

4.2 introduction

The last decade has seen an intense debate about appropriate treatment strategies in the

management of patients with rheumatoid arthritis (RA). A consensus seems to have emerged that

patients with moderate or aggressive RA should be treated early and aggressively, with some

experts arguing for combination of disease modifying anti-rheumatic drugs @MARDs) as initial

therapy. However, these recommendations were made in the absence of potent therapeutic

alternatives, thus necessitating a recurrence to combination of presently available, but less potent

drugs such as sulfasalazine or hydroxychloroquine. Fortunately, in the last few years several new

medications were approved for the treatment of patients with RA. In 1998, leflunomide was the

first disease modi fylng drug approved in over a decade by the US Food and Drug Administration

(FDA). Soluble TNFa receptor and monoclonal anti-TNFa antibodies followed. These drugs add

new and powefil options to the management of RA. Compared to available therapies which may

cost as low as USS300 per year, these new agents cost between USS3,500 and USS 13,000 per

year. Thus, their therapeutic potential needs to be measured not only by their ability to slow or

halt disease progression, but also by their share in decreasing the healthcare costs incurred by

patients with RA. Reimbursement approval for these new agents will likely depend on their

demonstrated cost-effectiveness.

RA is a costly disease due to its chronic nature and sometimes severe progression that can

require hospitalization and intense medical and surgical treatment. Published estimates of the

yearly costs of RA were recently summarized by Cooper, who estimated that RA patients incur

yearly costs of US$8,416 per patient in 1996 dollan. This estimate was shared to equal parts by

direct medical and nonmedical costs and indirect costs, such as losses in productivity. The

authors documented wide variation around the cost-estimates translating into standard deviations

of nearly 53,000. Only one cost of illness study was conducted in Canada, so far. In this study the

annual costs incurred by RA patients were calculated to average CADS6,253 (1994 dollars) in

the period extending from 1990 to 1994 (22). Direct costs were responsible for 74% ($4,656) of

the total costs and prescription drugs for - 20% of the direct costs. Extrapolating these costs to

the 0.5% to 1% of the Canadian population estimated to be affected by RA leads to an estimate

of the total healthcare costs of RA patients in Canada between 0.9 and 1.75 billion dollan (1994

Cdn.).

There are few published economic evaluations of DMARDs (73-75) and only one

collected data prospectively alongside a clinical trial (75). Traditionally, economic evaluations

are made by combining information From various sources into a modelling Framework, however

most current ongoing trials incorporate economic outcomes such as healthcare and productivity

costs into their protocols. The present study reports the results of an economic comparison of

leflunornide, methotrexate and placebo based on economic outcomes measured prospectively

alongside a North American phase EI trial comparing leflunomide to methotrexate and placebo in

482 patients with RA followed for one year (76). Costs for all economic outcomes were

calculated in Camdim dollars from the perspective of the Ontario Health Insurance Plan.

4.3 Materials and Methods

The material analysed in the present study was collected as part of a 1-year randomized

double blind comparison of leflunomide, methotrexate and placebo in 482 US patients with

rheumatoid arthritis (76). Patients with active RA aged 18 years or older were eligible for

treatment if they met the American College of Rheumatology (ACR) criteria for having RA for 6

months or longer. Patients could not have previously received methotrexate, other DMARDs had

to be discontinued for at least 30 days. Patients were assigned to 1 of 3 treatment groups in a

3:2:3 randomization: leflunomide treatment (20 mg/d), placebo, or methobexate treatment (up to

15 mglwk). Patients identified on or after week 16 as non-responders according to ACR response

criteria (2) were allowed to switch to alternate therapy: methotrexate and placebo patients

switched to leflunornide and leflunomide patients to methotrexate.

Clinical data and information on costs were collected biweekly from weeks 4 to 12 and

monthly thereafter. Questionnaires examining health related quality of life and interviews

eliciting patients' utilities were applied at baseline, week 24 and 52, or at study exit. The intent-

to treat analysis included all patients who received drug and had at least one follow-up visit.

Clinical study results have been published elsewhere (76).

Utilities

Patients' utilities for their current health status at baseline, week 24, 52 or at study exit

were elicited through rating scale and standard gamble (SG) measurements. Patients were

initially asked to rate their health on a rating scale anchored by perfect health (1 00) and

immediate death (0). In the SG interview, patients were asked to make a choice between their

current health as a certain outcome or a gamble involving death and perfect health as the

uncertain outcomes. Patients were then told to imagine a treatment leading to either death or

perfect health. The chances of treatment success, i.e. perfect health, were varied systematically

from 100% downwards, and the chance of perfect health that made patients insecure as to

whether they preferred their current health state or the gamble was then recorded as the SG utility

for the patient's current health state. Utilities for patients who rated their own health worse than

death were considered 0 for the purpose of this analysis.

Costs

Treatment or disease related costs were quantified by asking the patient about: 1) any

health resources used that were not specified by the clinical protocol and that were associated

with an adverse event; 2) any expenses incurred by the patient out of her own pocket because of

the disease or treatment related adverse events; and 3) any loss in the patient or her caregiver's

productivity or the performance of social or leisure activities including costs resulting as a

consequence of a loss in productivity.

Health resource utilization questions inquired about 1) the number and duration of

hospital, intensive care unit (ICU) or nursing home stays, 2) the number of office or emergency

room visits to health professionals, 3) the number and type of outpatient diagnostic tests and

laboratory tests received and 4) the number and type of outpatient procedures performed.

Personal expense questions asked for any out of pocket costs for health services, transportation

costs, costs for meals on wheels and the type and costs of equipment purchased in order to cope

with the disease or adverse events related to the study drug. Finally, patients were asked about

the amount of work time they or their caregivers lost, the extra time incurred through performing

additional chores, the amount of lost leisure time and the costs incurred by hiring extra help to

perform daily chores.

Canadian costs were estimated for all resource utilization and cost items. Hospitalizations

were coded into case mix group (CMG) codes according to the C M G ~ 1998 Directory for use

with ~lx". Average 1998 daily hospitalization costs by CMG were then derived From a mid-size

inner-city teaching hospital's database of hospitalization costs for over 18,000 patient encounters.

These were multiplied by the patient's length of stay in order to obtain the full hospitalization

costs. Average daily hospitalization costs across all CMGs were used for three patients whose

CMG codes did not appear in the hospital's database. The physician component of the

hospitalization costs were obtained from the Ontario Health Insurance Plan (OHIP) Schedule of

Benefits (SOB), 1999 version. All hospitalizations were classified by the study physicians on

whether they were not, possibly or probably related to the drugs under investigation. All

hospitalizations rated by the study physicians as possibly or probably related were considered

related for the purpose of this analysis.

Costs of office or emergency room visits to health professionals and costs for imaging

procedures were obtained from the OHIP SOB. Costs for laboratory tests were derived &om the

Ontario Schedule of Benefits for Laboratory Services, 1999 version. A standard request including

CBC, transaminases, creatinine, BUN was used to cost performance of laboratory tests

independent of the number indicated by the patient. The OHIP SOB was also used to cost

outpatient procedures such as endoscopy, skin biopsy or pulmonary function test, assuming the

assessment conducted most frequently under routine conditions. Personal expenses incurred by

patients during the trial were converted from US to Canadian dollars using 1997 Purchasing

Power Parities published for 1997 by the Organization for Economic Cooperation and

Development. Costs for productivity time lost to the patient by age and gender were derived from

1996 Canadian Census data using the average 1995 yearly income for each age and gender group.

Costs for productivity time lost to the caregiver were calculated using the average 1995 yearly

income of the total population, as age and gender information was not provided for the caregiver.

Costs for lost leisure time were not calculated.

Costs for the routine monitoring of patients on leflunomide or methotrexate were

calculated according to monitoring guidelines published in the product monograph of each drug

in the Compendium of Pharmaceuticals and Specialties. Wholesale costs of drugs were increased

by the 10% maximum allowable markup and a prescription fee of 56.1 1 was added for each 6-

month prescription. All costs were updated to 1999 levels using the the respective portions of the

Canadian Consumer Price Index.

Analysis

Patient's utilities derived from the Feeling Thermometer and Standard Gamble

questionnaire for the baseline, week 24 and week 52 or study exit measurement were weighted

by the time period covered, according to the trapezoidal rule, and divided by the total time of

observation in order to obtain a utility per person-year of observation. Utilities between study

groups were compared using analysis of variance, with Tukey'studentized range test for painvise

comparisons.

Costs for medical procedures and visits unrelated to the disease, such as dental visit were

excluded from hrther analysis. Costs for services, tests, procedures and hospital visits (medical

costs) and patients' out of pocket costs (non-medical costs) formed the direct cost component,

patient time and productivity costs, excluding leisure time, the indirect medical cost component.

Each individual patient's direct medical costs and indirect costs were then added over the study

period and further adjusted by the total time of follow-up in order to obtain an annualized cost

estimate.

The statistical analysis of cost data is being debated in the literature, with some experts

arguing for non-parametric tests on often transformed costs, due to the heavily skewed

distributions of cost values (77), and others for parametric tests, which are thought to be

sufficiently robust with larger sample sizes (78). Several statistical comparisons were made thus

in the absence of a consensus on the appropriate statistical tests to be used in cost-comparisons

(79): 1) Student's t-test on untransformed costs to compare means between two groups; 2)

Student's t-test on untransformed costs with reference to 200 bootstrap samples; 3) Wilcoxon test

on log-transformed cost data; 4) Student's t-test on log-transformed costs; 5) a 2-Score test

statistic, proposed by Zhou et al. (80) was calculated to adjust for possible inequalities of

variances; and 6) an analysis of log-transformed costs in an ordinary least squares regression

model with adjustment for age and gender. Expected values, still on a log-transformed scale,

were then back transformed, using a nonparametric smearing estimate that takes into account the

residuals remaining from the least squares estimation (8 1).

Statistical comparisons were performed on: 1) all costs, to form a societal perspective, 2)

direct healthcare costs only and 3) direct healthcare costs excluding, arbitrarily, the top 1%

extreme outliers to perform the cost comparison

4.4 Results

01485 patients enrolled, 482 received at least one dose of a study drug or placebo and

were evaluated for safety; 480 had at least one follow-up visit to evaluate efficacy (1 82 patients

received leflunomide therapy, 180 received methotrexate therapy and 1 18 received placebo). All

patients were similar in the measured demographic and prognostic variables (Table 4.1). The

efficacy results, published elsewhere (76), are briefly recaptured here: Both leflunomide and

methotrexate achieved statistically equivalent response rates with 52% and 46%, respectively

being considered successful responders as defined by the American College of Rheumatology

preliminary criteria for 20% improvement (ACR20) (2). Furthermore, 41 % and 35% of

leflunomide and methotrexate patients sustained ACR20 response status until study end at 52

weeks. Patients on leflunomide fared better than methotrexate patients from a functional

perspective, with statistically significant differences favouring leflunomide in the HAQ disability

index and 2 of 8 subscores of the SF-36. Leflunomide is also statistically significantly superior to

placebo in retarding disease progression as measured by x-ray analysis of both erosions and joint

space narrowing but no consistent differences were noted between leflunomide and methotrexate

on assessments of joint damage.

Table 4.1: Demographic and disease chiuacteristics of the study patients at baseline (76).

Leflunomide Placebo Methotrexate

-- --- - (n= 182) (n=118) (n= 1 82) -- -

Female, % 72.5 70.3 75.3

Age, years ' 54.1 k 12.0 54.6 10.7 53.3 k 1 1.8

Rheumatoid Arthritis, duration, y ' 7.0 5 8.6 6.9 k 8.0 6.5 * 8.1

Rheumatoid Anhritis, s 2 years, % 3 9 33.3 40.1

Rheumatoid factor positive, % 64.8 60.2 59.4

No. of DMARDs that failed ' 0.8 5 1.0 0.9 i 0.9 0.9 -C 1 .O

No prior DMARD treatment, O/o 44.5 39.8 44

Taking concomitant NSAIDs, % 75.2 65.2 69.7

Taking concomitant steroids, % 53.8 55.1 52.7

No. of tender joints (range, 0-28) 15.5 k 6.4 16.5 = 6.3 15.8 i 6.9

Patients' global assessment of 5.6 * 2.2 5.8 i 2.2 5.4 i 2.3 disease activity (10 point VAS)

Modified health assessment 0.8 k 0.6 0.9 = 0.5 0.8 * 0.5 questionnaire scores

ESR, mm/hr 38.4 2 26.8 - - - - - -- - - -

37.3 i 28.7 -

33.8 = 25.4 -- - - --

.t Values are mean * Standard Deviation

DMARD: Disease modifying anti-rheumatic drug; VAS: Visual analogue scale; ESR: Erythrocyte sedimentation

Utilities

Rating scale values were missing for 19, 1 1, and 1 1 patients in the leflunomide,

methotrexate and placebo group respectively, and SG utilities were missing for 2 1, 12, and 1 1

patients, respectively. Missing values exclusively occurred in patients who were considered non-

responders, with the exception of l patient in the leflunomide group and 1 in the rnethotrexate

group who were responders. Analysis of variance showed no statistically significant differences

between leflunomide and methotrexate (Table 4.2). Rating scale values for both leflunomide

(67.7) and methotrexate (64.8) were significantly different fiom placebo (57.5) [p < .05]. In

addition, standard gamble results were statistically significantly different between methotrexate

(83.2) and placebo (77.0) [p < .05], but not between leflunomide (80.2) and placebo (Table 4.2).

Table 4.2: Standard gamble and rating scale values for 480 patients participating in a 12-month randomized controlled trial comparing leflunornide to methotrexate and placebo.

Leflunomide Placebo Methotrexate

n = I63 (RS) and 16 1 (SG) N = 107 (RS and SG) N = 169 (RS) and 168 (SG)

Mean Med. IQR Mean bled. IQR Mean Med. IQR -- -

Rating Scale 67.7 4 70.3 57.5 - 80.4 57.5 57.5 44.0 72.5 64.8 67.9 55.0- 78.1

Standard Gamble 80.2 86.3 72.5 - 96.5 77 83.5 65.0 - 92.7 83.2 ' 89 75.5 -96.3 -- - - -- - - - - - - - - - - - - - --

IQR: Inter-quartile range; $5: statistically significantly different from placebo, p < .05 RS: Rating Scale SG: Standard Gamble

Costs

Among the 480 trial participants there were 234 (48.8%) patients who incurred direct medical

costs, including hospitalizations, related to the study drugs or the underlying disease (Table 4.3).

Hospitalizations judged to be related to the drug or RA occurred in 2, 3 and 2 patients in the

leflunomide, methotrexate and placebo groups, respectively.

Table 43: Number of patients incurring costs in the three cost categories. -- - - - - .- -- . - - - - - -- - - - - - - -- - - - - - - - -- - - - - -- A . -

-- - - - - - - LEF (N= 182) hlTX (N= 180) PBO (N=118) . - - - - - - - - - . - - -- - - - - - - - -- - -. - -

Direct medicaI costs 95 52.2% 93 51.7% 45 38.1%

Hospitalizations Cj udged related by study physicians) 2 1.1% 3 1.7% 2 1.7%

Direct nonmedical costs (out of pocket) 13 7.1% 5 2.8% 8 6.8%

Indirect costs (patient time 1 productivity) - -- . 55 30.2% 50 27.8% - . - - - -- - - -- --

42 35.6% -- --- - - A

LEF: leflunomide; MTX: methotrexate; PBO: placebo

Resource utilization episodes, such as the number of hospitalizations (all), outpatient physician

visits and the number of separately ordered laboratory tests, occurred more frequently in the

leflunomide group, while the number of outpatient diagnostic imaging tests and the number of

outpatient procedures were similar in the leflunomide, methotrexate and placebo groups (Table

4.4). These observations also hold when resource utilization episodes are annualized. The

annualized direct costs and indirect costs exhibit markedly skewed distributions: almost 50% of

patients incurred no costs, and a few patients incurred extremely high costs (Table 4.5).

Table 4.4: Health Care Resource Utilization Items Incurred by patients over the 52 week study period, unadjusted, and adjusted by total time of follow up as number of events per person-year

- - - - - -

Leflunomide .Methotrexate PIacebo Items Unadj. per person- Unadj. per person- Unadj. per person-

-- -- - -- year year year Total person-years of observation 126.1 135.1 65.8

Hospital or Nursing Home Stays 3 5 0.28 6 0.04 10 0.15

Outpatient Physician Visits 288 2.28 209 1.55 110 1.67

Outpatient Diagnostic Imaging 94 0.75 90 0.67 5 7 0.87

Lab tests (No. separately ordered) 205 1.63 67 0.50 45 0.68

Outpatient Procedures - - - - -- - 42 0.33 50 0.37 26 0.39 -- - - -- -- - - - -

# 1 10' py : Number of events per 1000 person-years of observation

Table 4.5: Descriptive Statistics of annualized total, direct, indirect, non-medical costs and estimated yearly drug acquisition and monitoring costs by treatment group - - - - - - -- - - -- - - - - - - - - - - - - -

Leflunomide Methotrexate Placebo

-- - - - - - - - - - - Mean Median M iMean Median Max Mean Median Max - - - - - - - - - - - - - -. -- - - - - - - -. - - - - -. - - . -- - -

Totalcosts(excl.drugand $1,761 5171 $54,216 $1,280 $107 $78,925 $1,324 9132 520,315 monitoring costs) Direct costs $753 $54 $49,566 $620 $51 $78,925 S336 S167 37.31 1

Direct costs (excl. top 1%) $420 S53 $9,885 $173 550 $1,654 5227 SO $4,218

Direct non-medical costs $22 $0 $1,030 S2 SO $170 $66 SO $3,181 Indirect costs $986 SO $33,474 $660 $0 $39,553 $921 SO $20,147

Monitoring costs $483 - $599 - $55 - Drug acquisition costs $3,853 5258 - - - -- - - - - - -- - - - - - - - - - - -- - * -- - - - - - - -- - - - - - - - - -- - - -

Statistical analyses of the annualized total costs, representing the societal perspective, revealed

no statistically significant differences between leflunomide and methotrexate, or in comparison

of these two agents with placebo (Table 4.6 - Following page). Analysis of direct medical costs

only, representing the perspective of the Provincial Health Insurance Plan, also revealed an

absence of a statistically significant difference between leflunomide and methotrexate. However,

direct annualized medical costs associated with leflunornide were statistically significantly higher

than placebo in the statistical comparisons of the log-transformed costs: Wilcoxon Rank Sum, t-

test and regression on log-transformed costs. Direct annualized medical costs associated with

methotrexate were significantly higher than placebo in the regression analysis on log transformed

cost data. The differences in direct costs between leflunomide and placebo persisted after

arbitrarily trimming all costs by the top 1%.

Table 4.6: Statistical Evaluation of total costs, direct costs and direct costs trimmed by the highest 1%. Results of statistical tests on untransformed and Iog- transfomed costs.

LEF vs. MTX LEF vs. PBO MTX vs. PBO

Total Costs

t-test

Bootstrap

Wilcoxon Rank Sum

T-test (log S + 1 )

Z-score (log $ + 1 .)

Regression (log $ + 1 )

Direct Costs

t- tes t

Bootstrap

Wilcoxon Rank Sum

T-test (log S + I )

Z-score (log S + 1 )

Regression (log $ + 1 )

Direct Costs (1% trim)

Wilcoxon Rank Sum

T-test (log $ + 1)

Z-score (log S + 1 )

$9: with adjustment for age and gender

LEF: leflunornide; MTX: methotrexate; PBO: placebo

Mean costs adjusted for age and gender were calculated by "back-transforming" the

regression analysis results. The "back-transformed costs" demonstrate only a slight difference to

the original costs, suggesting that age and gender have marginal influence on total or direct costs

(results not shown).

Incremental cost-effectiveness and cost-utility ratios were calculated using the total costs

provided in Table 4.5, the previously reported ACR20 response rates and the SG utilities

reported in Table 4.2. The marginal societal benefit of LEF in comparison to placebo was valued

at $21,445 per ACR.20 responder gained and S 147,438 per quality-adjusted life-year (QALY)

gained (Table 4.7). The marginal benefit of MTX was 54,738 per A C E 0 responder gained and

f 12,226 per QALY gained. While MTX was associated with less costs and higher utilities, LEF

achieved a higher percentage of AC R20 responders, leading to a cost-effectiveness ratio of

$66,000 per ACE220 responder gained in comparison to MTX. Cost-effectiveness and cost-utility

ratios were similar when calculated £?om the provincial payer's perspective.

Table 4.7:Calculation of cost per ACR.20 responder and quality-adjusted life-year (QALY) gained. - - -. - - -- .- . .

Costs Costs % A 0 QALYs Cost per ACR Cost per QALY

-- --- - -. - - --- - - -- -- - - - - - - - - 20 responder

Le flunomide $6,097 S5,089 41% 0.80

Methotreme $2,137 $1,477 35% 0.83

Societal Perspective

~Methotrexate vs. Placebo $4,738 S 12,226

Leflunomide vs. Placebo $2 1,445 S 147,437

Leflunomide vs. Methotrexate $66,000 MTX dominates

Payer's Perspective

Methotrexate vs. Placebo S6,788 S 17.5 16

Leflunomide vs. Placebo $21,355 $146,812

Leflunomide vs. Methotrexate --

$60,200 MTX dominates -

ACR20: Response status by American College of Rheumatology Criteria for Improvement of at least 20%

4.5 Discussion

[n this investigation we compared, from the perspective of a Canadian health insurance

plan, the economic consequences and health utilities of RA patients treated with leflunornide,

methotrexate or placebo. All data were collected during the first 12 months of a North American

randomized controlled trial which was conducted in 482 patients with rheumatoid arthritis. The

results of this analysis demonstrate that, when excluding drug monitoring and acquisition costs,

leflunomide has an othenvise similar economic profile compared to the best alternative

methotrexate. In comparison to placebo, leflunomide costs an extra $147,437 per QALY gained

and methotrexate S12,226. Although no statistically significant differences were found in health

state utilities between leflunomide and methotrexate, methotrexate is both less expensive than

leflunomide and produces higher utilities. However, more patients on leflunomide achieved an

ACMO response status at a cost of $66,000 per responder gained in comparison to methotrexate.

This is one of the few economic evaluations in rheumatology, where economic data were

collected concurrently to a randomized controlled trial. Both patient and investigator were

blinded to treatment assignment and data collection procedures were identical in each treatment

arm, which lends support to the conclusion that the economic consequences were similar

between the two active treatments. It is unclear, however, how high the economic consequences

would have been, had this study been performed under routine treatment conditions similar to the

daily practice of the rheumatologists in the study.

Because a portion of medical resource consumption was mandated by the protocol, it was

not possible to determine the full costs that would have occurred in the absence of protocol-

related monitoring. Treatment or disease-related resource consumption was collected in a fairly

detailed way, but no attempt was made at collecting resource utilization data at a micro level.

Additionally, the use of healthcare resources unrelated to the treatment of RA was not

documented and thus not included in the costing process. Even though some unrelated costs

might have been documented due to judgmental errors on part of the investigator, these are

probably distributed fairly evenly and unlikely to influence the final comparison.

Consumption of medical resources, in the present study, occurred to US patients in a US

healthcare setting but these resources were costed in Canadian dollars. There is sufficient

evidence from other diseases that US utilization of healthcare may be up to twice as intense as

that in Canada (82). Overall direct costs are thus inflated compared to potential Canadian costs

and the already non-significant difference between leflunomide and methotrexate would have

been smaller than the one observed had this study been conducted in a Canadian setting. A

differential effect on the direct costs in both treatment arms is unlikely given the fact that these

data were collected in a randomized controlled trial.

Methotrexate is considered the standard therapy in the management of RA and, among

DMARD monotherapies, patients on methotrexate achieve the highest relative response. Thus

the requirement of regulatory agencies to use methotrexate as the active comparator in clinical

trials of new therapies. In Canada, methotrexate is also one of the least expensive DMARDs,

which makes it one appropriate comparator for a direct economic comparison. Other comparators

could have been conceivable as well, particularly those DMARDs that are chosen if a patient

fails or presents adverse events to methotrexate. Because methotrexate is considered both the

least expensive and most effective DMARD, the cost-effectiveness and cost-utility ratios of

leflunomide in comparison to other DMARDs are likely to be more favourable than the present

values in comparison to methotrexate.

There are only few studies to which we can compare the results of the present study. The

closest, and most recent study is the one by Verhoeven and associates (83) who compared the

cost-effectiveness and cost-utility of combined step-down prednisolone, methotrexate and

sulphasalazine, to sulphasalazine alone in a Dutch setting. The authors found a not statistically

significantly better economic profile and a significantly better clinical profile in favour of

combination therapy. Measurement of costs in this study were comprehensive, including costs

unrelated to the disease. This explains the higher total costs oFUS$5,500 - US$6,500 incurred by

the study patients. Even though the combination therapy arm was clinically superior to the

sulfasalazine arm, the economic consequences were not statistically significantly different.

Althoug it is unknown, how much clinically superior a new therapy has to be, in order to produce

more favourable economic consequences in comparison to methotrexate, it is likely that this is

difficult to achieve given the low costs of this drug and its high effectiveness.

Before the approval of leflunomide by the FDA in 1998, there was a decade without new

treatments that physicians could offer to patients with RA. Recently, several new drugs have

been approved and rheumatologists face better treatment choices than before. Our study showed

that leflunomide has an economic profile that is similar to methotrexate and that the extra costs

faced by policymakers are fixed treatment costs that, however, are higher than the costs of

generic drugs, such as methotrexate. From an economic perspective, leflunomide imposes itself

as an alternative once methotrexate fails, due to its equally high efficacy. But leflunomide might

also be a drug of first choice, provided that drug acquisition costs are covered.

CHAPTER 5

An estimation of the i y e a r cost effectiveness of adding Leflunomide to a strategy of

conventional disease modifying antirheumatic drugs in patients with RA

5.1 Preface

This chapter reports the results of the model-based economic evaluation of leflunomide as

an element of a typical treatment strategy for patients with more aggressive rheumatoid arthritis.

Data that were collected in the surveys (Chapter 2), the meta-analysis (Chapter 3) and the

randomized clinical trial (Chapter 4) were used to support a decision-analysis-model. The model

runs over 5 years with cycles of 6 months duration and evaluates the cost-effectiveness and cost-

utility of adding leflunomide to a typical DMARD-strategy.

5.2 Introduction

The last decade has seen an intense debate about appropriate treatment strategies in the

management of patients with RA. A consensus seems to have emerged that patients with

moderate or aggressive RA should be treated early and aggressively, if possible by combining

several disease modifying anti-rheumatic drugs (DMARDs). However, these recommendations

were made in the absence of potent therapeutic alternatives. Fortunately, several new therapies

were recently approved for the treatment of patients with RA, which now add powerfbl options

to the management of RA. In 1998, leflunomide (LEF) was the first disease modifying drug

approved in over a decade by the US Food and Drug Administration (FDA), soluble TNFa

receptor and monoclonal anti-TNFa antibodies followed. However, compared to existing

therapies, which may cost as low as USS300 per year, these new agents cost between US$3,500

and US$13,000 per year. Thus, their therapeutic potential needs to be measured not only by their

ability to slow or halt disease progression, but also by their share in decreasing the healthcare

costs incurred by patients with RA. Reimbursement approval for these new agents will likely

depend on their demonstrated cost-effectiveness.

The costs of illness associated with RA are compounded by a disease that often starts

early in life, that can lead to severe disability and frequently requires hospitalization and intense

medical and surgical treatment. The yearly costs of RA vary, but have been estimated to be

approximately US$8,416 per patient in 1996 dollan. Direct medical and non-medical costs and

indirect costs, such as losses in productivity, share equal parts of this sum. In Canada, the annual

costs incurred by RA patients were calculated to average CAD$6,253 (1 994 dollars) (22), with

direct costs responsible for 74% ($4,656) of the total and prescription drugs for - 20% of the

direct costs. Extrapolating these costs to the 0.5% to 1% of the Canadian population estimated to

be affected by RA would leads to an estimate of the total healthcare costs of RA patients in

Canada between 0.9 and 1.75 billion dollars (1994 Cdn.).

The relationship between costs and effectiveness of old or new anti-rheumatic therapies

has been examined in only very few economic evaluations (73-79, and all of these compared one

therapy to another over a short time-period. There have been two attempts to model the disease

over longer time horizons (84;85) but without the required efficacy data to study the costs and

benefits within a therapeutic framework. The present study is an attempt to examine the

incremental cost-effectiveness and cost-utility of LEF, a novel disease modifying antirheumatic

drug, within a realistic sequence of DMARDs modelled over a 5-year time horizon in patients

with active RA, from a Canadian payer's perspective.

5.3 Methods

Decision Analysis Model

A decision analysis model was developed to represent the events that occur as a

consequence of taking DMARDs (Figure 5.1 - following page). Several models were available

from the literature (73;74), but none of the models allowed for a combination of data from

observational studies - which primarily report on the proportion of patients maintaining therapy

and randomized controlled trials (RCTs) - which primarily report on the degree of treatment

response, e.g. the American College of Rheumatology composite criteria for 20% improvement

(ACR20) (2).

Adverse Event -.: Sty tnew DhMRD

I tack o f Efficacy .'. Stan new DMARD

Minor Adverse Event Clinical Response I --. : Continue same D W R D (ACUO)

i 1 1 1 No Adverse Event

- ' Continue same D W R D !

Minor Adverse Event 1 No Clinical Response ; - - ' Continue same DMARD I (ACR2O) P

'4 No Advcne Event : Continue same D M R D

6 Months - _ _ _ _ _ ___--__. . _ _ _ _ _ _ .___

Figure 5.1: Events occurring during a 6-month period as a consequence of taking a DMARD. Patients who stop one DMARD start a new one and repeat the cycle with the new DMARD.

To conform with available data from observational studies and RCTs, the decision tree is

designed so that patients may experience three types of events during a 6-month treatment period

(Figure 5.1): 1) they continue therapy, 2) they stop therapy because of adverse events or 3) they

stop therapy because it is lacking or losing efficacy. Furthermore, continuing patients may be

classified clinically with regard to the quality of the response to treatment - here defined as

meeting the A C E 0 criteria - and whether they experience minor adverse events. Because this

analysis is limited by the type of data available from the literature, a more detailed classification

of adverse events by type and severity could not be utilized.

Overall, two DMARD strategies were compared, one including LEF and the other

excluding it (Figure 5.2). Both strategies try to emulate treatment as it happens in real life, which

means that patients cycle through different treatment regimens when they encounter toxicity or

lack or loss of efficacy. A new treatment regimen is chosen for those patients who fail the

previous regimen.

Lack of Egicocy +

Methotrexate

Strategy with /"\ Strategy without leflunomide ,I leflunomide

/

Leflunomide Gold

Toxicity / i Lack of Eflcacyf

v Gold

Toxicity / Lack of Eflcad

v Cyclosporine

Methotrexate/ Sulfasalazine/ H ydroxychloroquine

/ Toxicity / Lack of Eflcacy

Toxicity / Lack of Eflcacy

v Cyclosporine

- - -.A- - - - - - -- - - - - -- - - - - - - - - - - - . - - - . --

Figure 5.2: Sequence of DMARDs chosen for the strategies modeIled in the analysis. One strategy includes LEF.

The choice of treatment strategies is supported by results of a mailed survey using case

scenarios of patients with RA (9). The treatment strategy ercklding LEF is modelled to start with

methotrexate (MTX) followed by combinations of MTX and sulfasalazine (SSZ), and MTX, SSZ

and hydroxychloroquine (HCQ) in case of efficacy failure, while patients developing toxicity to

MTX are modelled to take gold afterwards. Patients failing gold then receive cyclosporine

(CYA) as a last alternative (Figure 5.2). The treatment strategy including LEF is modeled to

allow the patient to take LEF before gold when they can no longer take MTX because of toxicity

or lack of efficacy. In technical terms this representation of the treatment strategies is considered

a Markov model, which covers a 5-year time horizon and is split into 10 intervals of 6 months

duration.

Probabilities

Outcome information for each DMARD was derived from a systematic review of

observational studies and RCTs of DMARDs, the detailed results of which are reported

elsewhere (46). A systematic search of the Medline database was performed Erom t 966 to August

1997 by combining the keyword 'rheumatoid arthritis' with textwords and keywords for MTX,

gold, auranofin, HCQ, chloroquine, CYA and azathioprine. Synonyms of these agents were

included as well. All abstracts were scanned for relevance and resulted in a set of 1387 references

which was further complemented by 1035 references from a broader literature search conducted

by the RA subgroup of the Cochrane Musculoskeletal Review Group. Both searches gave a total

of 2422 references.

Outcome information to be abstracted £?om these references included:

1) Maintenance of DMARDs: percentage of patients maintaining DMARDs and reasons for

withdrawal including adverse events and lack or loss of efficacy,

2) ACR20 response status: percentage of patients meeting ACR preliminary criteria for 20%

improvement (2) , and

3) Percentage of patients suffering one or more adverse events and the type of adverse event.

Maintenance of DMARDs

Of the 2422 references, a total of 445 investigations were found that provided information

on treatment withdrawal. Studies that documented the experience of patients from the day

therapy was initiated, and that provided withdrawal information for one of the four therapies in

patients with RA were included in the published meta-analysis. References for CYA and various

combinations of DMARDs were searched according to the same criteria for the purpose of this

economic evaluation. Studies published after 1997 and reporting withdrawals with the

above-mentioned drugs were added on an ongoing basis. Information on treatment withdrawals

was abstracted according to a standardized questionnaire. Combined withdrawal rates and 95%

confidence intervals were obtained using parametric regression assuming an exponential hazard

function. Withdrawal rates were converted to 6-month treatment withdrawal probabilities for use

in the decision analysis model.

ACWO response status

All 2422 references were further searched for observational studies and RCTs that were

published after 1990 and used explicit response criteria. Possible response criteria included the

ACR preliminary criteria for 20%, 50% and 70% improvement (2), the Paulus criteria for 20%,

50% and 70% improvement (86)and the European League for Rheumatism (EULAR) criteria for

good response (87) which are based on the disease activity score (DAS). The cut-off date was

chosen because it coincided with the publication of the Paulus response criteria. Papen reporting

any one of the above-mentioned criteria were retained and the respective values were abstracted

for the therapies of interest.

Percentage of ~atients suffering one or more adverse events

All studies which provided withdrawal information were also screened for the reporting

of adverse events, in particular the number and percentage of patients suffering one or more

adverse events. The frequency or percentage of patients suffering one or more adverse events

were then abstracted and combined for all studies of each respective DMARD or combination of

DMARDs.

Utilities

Standard gamble (SG) utilities for responder and non-responder status were obtained From the

MTX and LEF treatment groups of the North American study of LEF (76). Utilities were

collected at baseline, week 24 and week 52 or at discontinuation of the study. Utilities obtained

from all patients on LEF or MTX, and who were classified as a treatment success or failure by

ACR20 response criteria at the end of the study period, were used as utilities for DMARD

treatment success or failure in the model. This was considered justified, since the quality of

response to the other comparators could be assumed to be similar to the quality of response

achieved with MTX or LEF.

Costs

Costs of Manaeine Adverse Events

Costs of managing averse events occurring in patients on DMARDs had to be estimated

by gathering information on how rheumatologists would typically manage these events. A

questionnaire was developed, inquiring about rheumatologists' typical management of adverse

events occurring on MTX, gold, SSZ, HCQ and CYA. The type and frequency (per 1000

person-years) of these advene events were derived from the observational studies and RCTs

included in the database. Where possible, adverse events were collapsed into a common category.

In the questionnaire, advene events were categorized into two classes of severity: 1)

severe enough to cause treatment withdrawal or 2) mild adverse event, not necessitating

treatment withdrawal. The questionnaire consisted of a total of 2 19 adverse event management

sections (MTX: 28 withdrawal events/ 38 continuations; gold: 27/23; SSZ 23/18; HCQ 7/20;

CYA: 17/19). The questionnaire was sent to five rheurnatologists in Toronto: two community

rheumatologists and three with academic affiliations. Specifically, they were asked to indicate

whether they would deal with each type of adverse event over the phone, see the patient in the

office or recommend immediate hospitalization. They were also asked to indicate how they

would typically manage this type of adverse event, i.e.: 1) what type of instructions they would

give to the patient including prescriptions of medications and change of anti-rheumatic

medication; 2) which investigations or tests they would order, and 3) whether they would refer to

other specialists, or plan follow up and how often in their own practice

Data from all completed questionnaires were entered into a database to carry out the

costing of all management items. Costs of physician visits, procedures and laboratory tests were

derived from the Ontario Schedule of Physician and Laboratory Benefits, September 1999

version (88). Costs of prescription and over the counter medications were obtained from the

catalogue of a large wholesaler providing the majority of hospital pharmacies in Toronto. A

maximum mark-up of 10% allowable for patients insured under the Ontario Drug Benefit Plan

was added to the price of each drug (prescription and over the counter). A prescription fee of

$6.1 1 was W e r added to the price of each prescription. Costs of hospitalizations were provided

by the Ontario Case Cost Project database based on the ICD9-CM code for the respective adverse

event.

A single cost estimate for the management of each advene event was obtained by

averaging the five respondents' costs for each event. Furthermore, a cost per generic adverse

event episode associated with each treatment was then obtained by weighting each adverse

event's associated cost by the fraction of its incidence relative to the overall incidence of adverse

events, and adding these weighted costs. The same procedure was repeated with the lowest and

highest management costs for each advene event to obtain confidence limits. Costs for the

management of advene events associated with DMARD-combinations were calculated by

assuming that physicians' management of an adverse event on DMARD combination would be

identical to the same adverse event reported for single drugs.

Costs of Monitoring

Costs of monitoring patients on DMARDs were derived from the Canadian Compendium

of Pharmaceuticals and Specialties (CPS) by costing all management steps required when

fo1lowing monitoring directions issued under precautions for each drug. Monitoring costs were

divided into baseline monitoring, i.e. one-time investigations necessary to implement the

medication and check for absence of contraindications. Routine monitoring costs were calculated

separately as these do not change over time. Costs of physician services, procedures and

laboratory services were derived from the Ontario Schedules of Benefit for physician and

laboratory services (88). Monitoring for combinations of DMARDs were combined and all

overlapping monitoring items were eliminated.

Costs of Drugs

Costs of drugs were derived £iom the wholesale price catalogue of a supplier to the

majority of hospital-based pharmacies in Toronto. A mark-up of 10% was added to the price of

each drug and a prescription fee of $6.1 1. The average price per month was based on the

recommended dosage to be given to patients. High and low drug costs were calculated depending

on the maximally and minimally therapeutic dosage for each drug.

Un certainiy

Uncertainty was dealt with by employing second order Monte Carlo simulations. A cohort

of 5000 patients was simulated to go through each DMARD sequence for the full 5-year period.

Costs and utilities were discounted by 3%. Values for the probabilities and costs incorporated

into the model were randomly chosen at each cycle from realistic distributions specified

beforehand. Distributions for cost items were specified to be triangular in shape with the mean

value to be the most likeliest and the minimum and maximum values to be the least likely.

Distributions for probabilities and utilities were assumed to approximate the normal distribution

shaped by the standard deviation For each respective value. The Monte Carlo method then

proceeds such that a value is picked from the distributions whereby values around the average are

picked more frequently than values at the extremes of the distributions, with the probability of

being picked determined by the shape of each distribution. A confidence interval for the resulting

cost-effectiveness ratio was arbitrarily set as the cost effectiveness ratio of each values mean plus

or minus its standard deviation (89).

5.4 Results

Pro babiiities

Detailed withdrawal information for the comparators was provided by 119 studies entered

into the original meta-analysis (46) . Findings From 7 studies published after 1997 were added

later for the purpose of this economic evaluation. Thus, a total of 126 studies provided

information on single agent therapy with MTX, gold, SSZ, HCQ, CYA and LEF, and

combination therapy MTX and SSZ, and MTX, HCQ and SSZ. All 126 studies contributed 158

treatment arms, of which 141 arms were contributing information for the therapeutic strategies

used in the model. Probabilities of withdrawal From therapy and the subset of toxicity

withdrawals were combined across studies for each drug (Table 5.1). The conditional probability

of failing due to toxicity (Table 5.1) was derived by dividing the toxicity failure rate by the

general failure rate. Percent response was obtained and combined across studies from the intent

to treat findings of relevant RCTs of the respective therapies.

Table 5.1: Probabilities of treatment withdrawals, overall and due to toxicity, adverse events in continuing

patients and ACWO response rates. - - -- - - -- - -

Toxicity Withdrawals Adverse Events Drug as percentage of all among patients AC wo response

(%) withdrawals continuing therapy

MTX (SE) 13.5 (2.8) 49.2 (1.6) 18 74.2 (3.2)

MTX & SSZ (SE) 12.5 (4.0) 68 (3.1) 92.9 79.3 (4.5)

MTxlSSZJHCQ (SE) 3.6 ( I .3) 23.5 (6) 72.1 80.9 (4.2)

LEF (SE) 3 1.6 (7.3) 52 (4.5) 29.6 72.9 (2.8)

Gold (SE) 26 (4.3) 71 (3.5) 27 59.4 (6.0)

CY A (SE) 19.3 (4.4) 47.5 (2.6) 46.4 41.3 (5.6)

MTX: methotrexate; SSZ: sulfasalazine; HCQ: hydroxychloroquine; ACR.20: American College of

Rheurnatology criteria of 20% improvement ; SE: standard error

The values obtained for the percentage of patients experiencing one or more adverse

events that do not lead to treatment withdrawal, are only approximate estimates without

confidence intervals, due to the special reporting of adverse events. In RCTs, adverse events are

generally reported as the number of events which makes it impossible to know how many

patients had one or more events. Furthermore, advene events are not reported on a

time-dependent basis, obscuring whether they occurred simultaneously or not. These findings

have management implications, and it was thus assumed that all events receive separate

management, which likely overestimates the costs of managing advene events.

Costs

Questionnaires collecting data on the management of advene events with gold, MTX,

SSZ, HCQ and CYA were completed by all five rheumatologists (Table 5.2). Costs are presented

separately for advene events, mild enough not to lead to treatment withdrawal. and for severe

adverse events that cause treatment withdrawal.

Table 5.2: Average, minimum and maximum costs per type and incidence weighted adverse event.

Severe adverse events are those that cause treatment withdrawals, while events that let patients

continue on therapy are considered mild*. - - .. . . - . - - -

Continuations Withdrawals

Average Minimum Maximum Average Minimum Maximum

LEF $83.69 $69.34 S 101 2 2 $253.00 S 199.65 $296.47

Gold $62.88 $16.98 $107.99 $146.18 547.50 $23 1.59

CYA $100.87 $30.86 $208.62 $265.04 $68.07 S400.49

* as determined by answers of five rheurnatologists to a detailed questionnaire

Costs for baseline and routine monitoring were derived from specifications accompanying

the product monographs in the Canadian Compendium of Pharmaceuticals and Specialties (Table

5.3 - following page); no minimum and maximum was calculated for the baseline monitoring as

there were no ranges provided for the numbers of test and investigations to be done at baseline.

Costs of drugs were calculated £iom the perspective of the Ontario Drug Benefit Plan (Table 5.3).

Tabte 53: Costs of Monitoring DMARDs at baseline and during routine follow-up in a 6-

month period. -

- -- - - - - . - - - -- Baseline Routine (Average & Range) Drug costs

MTX 9 137.06 $230.72 ($156.45 - $304.99) $ 129.22

MTXfHCQtSSZ $266.39 $266.76 (S 159.04 - $374.47) $642.85

LEF $ 140.50 $171.33 ($125.16-5217.50) $1,926.36

Gold 562.68 $419.24 ($384.06-5454-41) $518.62

Ut if it ies

Of 364 patients in the active treatment arms in the North American study of LEF, there

were 329 patients who participated at the utility interviews; 135 were defined as treatment

success, and 195 as not a treatment success by ACR20 criteria. SG utilities for success were

8 1-62 * 22.79 (mean * standard deviation) and 82.37 * 27.99 for patients considered not a

success (difference of 0.75 no statistically significant).

Cost-effectiveness and cost -141 ility rest clts including sensitivity analysis

Results of the cost-effectiveness analysis over a 5 year period, i.e. ten 6-month cycles,

show that the strategy including LEF would cost approximately 37,675 dollars per 5-year period

and a strategy excluding LEF would cost approximately $6,6 10, a difference of 5 1,065 over the 5

year period (Table 5.4). Patients in the sequence of DMARDs that includes LEF would, on

average, be in a state of response for 3.04 years over the 5-year period, gaining an extra 36.5 days

compared to patients in the sequence that excludes LEF, who would be in a state of response for

2.94 years. These findings translate into a cost-effectiveness ratio of $10,682 for each additional

year of response. Confidence intervals for the cost-effectiveness ratio were calculated from the

output of the simulations as ratios of the costs and effects plus/minus one standard deviation.

Adding or subtracting one standard deviation provided a range of $3,380 to $21,018 per year of

response. This cost-utility analysis shows that patients in the strategy including LEF gain 0.058

quality adjusted life-years (3.636 QALYs vs. 3.578 QALYs) which with the above mentioned

costs per strategy would provide a cost-utility ratio of S 18,474 per QALY gained (Confidence

interval i I standard deviation: 54,178 - $83,6 14).

Table 5.4: Expected costs, numbers of cycles patients respond to therapy, time spent on active therapy and cost per responder. Table shows point estimates and mean +/- one standard deviation as determined by Monte Carlo simulations with 5000 runs.

-- - -- - - - - - - - - -- - . -

Mean SD Minus SD Plus SD -- -- - -- - - - - - - -- -

Costs

Inc. Lef

Excl. Lef

Years in ACR2O response

Inc. Lef Excl. Lef

QALYs

Inc. Lef.

Exc. Lef

Cost per responder

fnc. vs. ExcI.

Cost per QALY

Inc. vs. Excl.

5.5 Discussion

In this investigation we compared, from the perspective of a Canadian health insurance

plan, the cost-effectiveness and cost-utility of adding LEF to a realistic treatment strategy in the

management of patients with active RA, as supported by data gathered through a systematic

review of the literature and surveys of Canadian rheumatologists. Evaluation over a 5-year period

shows that adding LEF as a therapeutic option increases the management costs by S 1,085

compared to the strategy without LEF with a cost-effectiveness ratio of $10,682 per additional

year of response to treatment gained, and a cost-utility ratio of $18,474 per QALY gained.

The model-based cost effectiveness approach was selected to demonstrate the added

value of LEF when introduced in a management approach adopted by Canadian rheumatologists

in their usual management of patients with active RA. This approach emulates the management

of EL4 patients in real life where they cycIe through different treatment regimens upon

experiencing toxicity or lack of efficacy. There are several advantages to this type of analysis.

The modelling approach allows estimation of the expected performance of the drug in the real

world and theoretically provides a better estimate of the cost-effectiveness of new interventions.

Furthermore, the impact of LEF can be assessed over a time horizon that exceeds the limited

time-horizons adopted in clinical trials. Within that more realistic framework, the addition of

LEF as a new treatment alternative for patients requiring a new therapy extends the time patients

may benefit from DMARDs.

The strategy modelled in this investigation was identified by means of a survey of

Canadian rheumatologists, which showed that MTX discontinuation is followed by prescriptions

of MTX combinations, gold, or immunosuppressants such as CYA (9) These treatment choices

were therefore incorporated into the model-based cost effectiveness analysis. The choice of

sequence was limited, on one hand by technical considerations, imposed by the type of model

used, and on the other hand by the availability of information which needed to be retrieved from

a systematic review of the literature. Even though it is clear that different rheumatologists will

opt for different treatment sequences, only the sequence thought to be most representative of

rheumatologists' treatment choices for patients with more aggressive RA was chosen for the

comparison. In addition, the choice of sequence was limited by the availability of emcacy data,

i.e. ACR.20 response, in the literature. For example, the survey of Canadian rheumatologists

identified the combination of MTX and HCQ to be more frequently used than that of MTX and

SSZ. However, the combination of MTX and HCQ could not be modeled, as there is no study

reporting ACWO response rates for this treatment strategy. Because the MTX-HCQ combination

is perceived in practice to be equally efficacious to the methotraxate-sulphasaiazine combination,

the substitution of one for the other in the model was not expected to change the conclusions of

the analysis.

The advantage of choosing a sequence of DMARDs was that the results could be

presented in a setting that is more realistic than single-agent comparisons of LEF to other

DMARDs or DMARD-combinations. Furthermore, the incremental cost-effectiveness of single

agent comparisons, for example LEF vs. CYA or gold would be lower than the cost-effectiveness

resulting from a comparison of treatment sequences. This is because the costs and efEects of each

treatment sequence were proportionally influenced by the time patients spend on the drugs in

each sequence. Indeed, given the relatively lower discontinuation rate, MTX and MTX

combinations were contributing more to the costs and effects than drugs that appear later in the

sequence, such as gold and CYA.

The analysis was conducted over a five-year time-horizon based on the 2-year

information available for LEF and information available in the literature for the other DMARDs.

Having to extrapolate from the 2-year data is a limitation of the model that does not Favor LEF.

For example, long-time experience with MTX showed that approximately 14% of patients

discontinue during a 6-month period. When referring to the North American trial comparing LEF

to MTX, the clinical trial setting points to a discontinuation rate of 32% with no difference in

discontinuation rates between the two agents (76).

Other outcomes, such as improvement in ACR criteria by 50%, would also have been

plausible choices for the model. This is especially important as the newer DMARDs may be

more potent and probably qualitatively superior to existing therapies, however, very few studies

in the literature report on ACRSO outcomes. Although here is little reason to suspect qualitatively

superior responses among the comparators used in the present study, this cannot be entirely

excluded, and would likely bias against leflunornide.

While it is likely that, with more exposure to the drug, discontinuation rates in real life

will fall to the level observed For MTX, the model used a 32% discontinuation rate for LEF

because of lack of other values. This also implies an underestimation of the time patients spend

on LEF and thus a possible overestimation of the cost-effectiveness ratio (i.e. overestimation of

the cost per additional year of response gained and cost per QALY) given the higher costs and

lower response rates of the following DMARDs.

Direct medical costs estimated for the purpose of the model-based comparison are only an

approximation of the costs likely to be encountered in real life. It is conceivable, that costs will

be lower in real life. First, monitoring costs were derived from monitoring recommendations

provided in the product monographs. In real life, physicians will likely monitor less, the more

they gain experience with each drug. Similarly, costs of managing adverse events were derived

kom a literature-based survey of 5 Toronto rheumatologists. Costing of the adverse events was

based on the answers provided in the swey , which may deviate from physicians' behaviour in

real practice. Physicians responding to the questionnaire may have adopted a more cautious

approach, not knowing the precise clinical circumstances accompanying the adverse event.

The majority of data supporting the model-based comparison were derived from the

literature. The literature, however, is sparse for much of the data needed. For example, only 35%

of the observational studies studying maintenance of DMARDs provide data needed for the

model. Similarly, only approximately 30% of RCTs or observational studies provide information

on the number of patients suffering one or more adverse events. Explicit response criteria have

only recently been used in RCTs and are seldom used in observational studies. For these reasons,

the data used in our model do not represent all studies that were conducted with the respective

drugs.

Research into the economics of DMARDs is complicated by the chronic nature of RA.

There is not one drug to treat RA, but a multitude and all of them are failing with time. This

makes modeling more complicated, in particular if combinations of drugs are used. Of Further

importance for modeling RA is the severity and stage of the disease, as a differential response

may be expected from patients with mild RA or those who try MTX as first drug or after

previous failure of other drugs, such as SSZ or HCQ. These details were impossible to consider

in the present modeling framework.

The results of this study confirm that leflunomide has a place in the management of

patients with RA and that its integration into the therapeutic armamentarium comes at reasonable

cost. The exact therapeutic value of leflunomide in the routine management of patients with RA

needs to be Further established. As rheumatologists gain more experience with leflunomide, the

drug's effectiveness will likely improve and further enhance its economic profile.

CHAPTER 6

Epilogue

Pharmacoeconomic evaluations of pharmaceuticals often depend on information that needs to be

collected in routine care settings, and often country-specific. Data from randomized controlled

trials, observational studies and administrative databases, and those collected from experts need

to be integrated in an appropriate way to adequately estimate the pharmacoeconomic

characteristics of a given drug in a country-specific setting. The methods of economic evaluation

are inexact and often leave sufficient room for specific decisions or assumptions to influence the

final findings. Consequently, results of economic evaluations are preferably seen as supporting

reimbursement decisions rather than guiding them.

This thesis presents a comprehensive assessment of the pharmacoeconomic properties of

leflunomide, a novel disease-modifying anti-rheumatic drug. Several studies, surveys and rneta-

analyses were undertaken to put this economic evaluation on a more stable foundation. The

physician survey was necessary to understand treatment preferences and their sequences in

patients who are similar to those receiving leflunomide. Furthennore, to not just provide head to

head comparisons to methotrexate or other DMARDs, an understanding of the long-term

behaviour of patients on these DMARDs was required. The meta-analysis of DMARDs provided

this quantitative information from published studies of these DMARDs under clinical trial and

routine care conditions. These data made it possible to model the management of patients with

RA in the long-term and to align treatments in a sequence that is close to what physicians would

do in their routine care of patients with RA. Review of these published studies also provided

sufficient information about the incidence and severity of adverse events under routine care

conditions.

However, the information derived fkom observational studies needed to be supplemented by data

collected in randomized controlled trial settings. For example the standard gamble utilities

measured in the randomized controlled trial of leflunomide, methotrexate and placebo were

required to assess the cost-effectiveness of leflunomide in terms of cost per quality adjusted life-

year gained. Equally important were the ACR response rates. Therefore, this combination of trial

data, data derived fiom systematic reviews and separately conducted surveys corroborated the

treatment model underlying this economic evaluation fiom various perspectives, that of the

routine care setting and that of a clinical trial setting.

The separately conducted analysis of the immediate economic consequences of methotrexate,

leflunomide and placebo, as collected alongside the randomized controlled trial, provided a

further understanding of the pharmaco-economic properties of leflunomide. The results showed

that decision makers can count on economic consequences that are similar to methotrexate and

therefore assist decision maken in gaining a better understanding about the costs of leflunomide,

should they opt for Full or restricted reimbursement.

Leflunomide is a much needed DMARD that enables patients to delay the need for much more

aggressive therapies or even surgery. Its overall profile, including efficacy and adverse events, is

equal to that of rnethotrexate, at present the standard treatment for patients with rheumatoid

arthritis. It comes at an extra costs that decision makers need to assess in their particular

circumstances. The results of this thesis may provide helpful assistance.

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