A medicoeconomic review of early intervention with biologic agents in the treatment of inflammatory bowel diseases

Figures & data

Table 1 Common biologic treatments for inflammatory bowel diseases

Class	Drugs	Current indications
Anti-TNF-α monoclonal antibodies	Infliximab	CD, UC
	Adalimumab	CD, UC
	Golimumab	UC, CD*
	Certolizumab	CD
Inhibition of leukocyte trafficking	Natalizumab	CD
	Vedolizumab	UC, CD
	Etrolizumab*	UC
T-cell depletion	Ustekinumab*	CD

Notes:

* In trials, not yet approved for general use. Biosimilars of infliximab are not considered in this review.

Abbreviations: TNF, tumor necrosis factor; CD, Crohn’s disease; UC, ulcerative colitis.

Table 2 Remission rates for biologic therapy in CD and UC patients in a short timeframe

Disease	Intervention	Cohort size	Timeframe (weeks)	Remission (%)	P	Reference
CD	ADA	76	4	36	0.001	Hanauer et al^Citation13
	Placebo	74		12
CD	ADA	159	4	21	0.001	Sandborn et al^Citation14
	Placebo	166		7
CD	CZP	215	6	32	0.174	Sandborn et al^Citation15
	Placebo	223		25
CD	CZP various	23	4	47.1	0.041	Winter et al^Citation16
	Placebo	24		16
CD (with fistula)	CZP	24	6	12	NS	Schreiber et al^Citation17
	Placebo	15		10
CD	IFX	169	6	29.6	<0.001 vs AZA	Colombel et al^Citation18
	IFX + AZA	169		32.5	<0.001 vs AZA
	AZA	170		14.1
CD	IFX	27	4	33	0.002	Targan et al^Citation19
	Placebo	25		4
CD	IFX + AZA	67	14	64	0.001	D’Haens et al^Citation20
	Step-up to IFX	66		34
CD	Natalizumab	259	8	26	0.002	Targan et al^Citation21
	Placebo	280		16
CD (with raised CRP)	Natalizumab	526	10	40	<0.05	Sandborn et al^Citation22
	Placebo	134		28
UC	IFX	121	8	33.9	<0.001	Rutgeerts et al^Citation23
	Placebo	123		5.7
UC	ADA	130	8	18.5	<0.03	Reinisch et al^Citation24
	Placebo	130		9.2
UC	ADA	142	8	15.6	0.019	Sandborn et al^Citation25
	Placebo	152		9.3
UC	Golimumab 400mg/200mg	257	6	17.9	<0.001 vs placebo	Sandborn et al^Citation26
	Golimumab 200mg/100mg	253		17.8	<0.001 vs placebo
	Placebo	251		6.4

Abbreviations: CD, Crohn’s disease; UC, ulcerative colitis; ADA, adalimumab; CZP, certolizumab pegol; NS, not significant; IFX, infliximab; AZA, azathioprine; CRP, C-reactive protein; vs, versus.

Table 3 Paradigm: use of biologics in inflammatory bowel disease

Clinical scenario	Step-up first-line therapy	Step-up second-line therapy	Early biologic therapy	Stopping rule (possible)
Mild first attack, CD or UC	Standard*	Immunosuppression**	Usually not indicated	Single attack with remission and mucosal healing in patient unwilling to continue medication
Severe first or subsequent attack, CD or UC	Accelerated standard	Rapid introduction of biologic	Indicated in high-risk patients***	None
Fistulous and perianal CD	Standard, biologic in selected cases	Biologic	Indicated	None
CD, short strictures	Endoscopic/surgical dilatation	Requires maintenance therapy (likely azathioprine)	Indicated if there is evidence of acute inflammation	None
UC, strictures	Surgery	None	Not indicated	After panproctocolectomy in absence of pouchitis
Postoperative CD	Continue the immunomodulator or biologic used preoperatively	Biologic (of same or another class)		Not advised

* 5-aminosalicylic acid (in UC), corticosteroids (consider budesonide in CD), consider MMX preparations;

** azathioprine or 6-mercaptopurine preferred;

*** refers to factors indicating a poor prognosis, such as onset in children or young adults, extensive disease and/or extraintestinal manifestations at presentation, terminal ileum location, stricturing and/or penetrating behavior, genetic/serological markers, and family history of inflammatory bowel disease. In every case, it is necessary to fit the treatment paradigm to the specific needs of the particular patient, including patient preferences and the availability and cost of medications.

Abbreviations: CD, Crohn’s disease; MMX, Multi-Matrix System; UC, ulcerative colitis.

Table 4 Cost-effectiveness analyses of biologic agents for CD

Intervention, comparator, and target population	Country	Time horizon	Study perspective	ICER ($/QALY)	Reference
Combination therapy with IFX + AZA at 2.5 mg/kg daily versus IFX monotherapy (IV infusion 5 mg/kg at weeks 0, 2, 6, and every 8 weeks thereafter) in men aged 25 years with biologically naïve CD refractory to conventional non-anti-TNF-α therapy	UK	1 year	Health care payer	50,000	Saito et al^Citation58
Top-down strategy: induction treatment of combined immunosuppressive therapy with IFX (2.5 mg/kg/day) and if symptom exacerbation occurred, additional IFX infusions and methylprednisone (32 mg/day for 3 weeks followed by 4 mg/week dose tapering) prescribed versus step-up strategy: induction treatment of methylprednisone and if symptom exacerbation or relapse occurred, AZA and IFX were added to treatment in newly diagnosed patients with luminal CD	Italy	5 years	Health care payer	Cost-saving	Marchetti et al^Citation59
ADA versus CZP in US adult patients aged 35 years with moderate-to-severe CD who failed to respond to standard therapy	US	54 weeks	Health care payer	Cost-saving	Tang et al^Citation60
Natalizumab versus CZP in US adult patients aged 35 years with moderate-to-severe CD who failed to respond to standard therapy	US	54 weeks	Health care payer	300,000	Tang et al^Citation60
ADA versus natalizumab in US adult patients aged 35 years with moderate-to-severe CD who failed to respond to standard therapy	US	54 weeks	Health care payer	Cost-saving	Tang et al^Citation60
IFX versus natalizumab in US adult patients aged 35 years with moderate-to-severe CD who failed to respond to standard therapy	US	54 weeks	Health care payer	Cost-saving	Tang et al^Citation60
IFX versus CZP in US adult patients aged 35 years with moderate-to-severe CD who failed to respond to standard therapy	US	54 weeks	Health care payer	Cost-saving	Tang et al^Citation60
Induction therapy of IFX (5 mg/kg) infusions followed by maintenance therapy of IFX (5 mg/kg) infusions every 8 weeks versus induction therapy of ADA (160 mg) subcutaneous injections followed by maintenance therapy of ADA (40 mg) subcutaneous injections every 2 weeks in Canadian patients aged 37 years and weighing 73 kg	Canada	5 years	Health care payer	470,000	Blackhouse et al^Citation61
Induction therapy of IFX (5 mg/kg) infusions followed by maintenance therapy of IFX (5 mg/kg) infusions every 8 weeks versus usual care: variety of conventional non-anti-TNF-α treatments including corticosteroids and other immunosuppressants in Canadian patients aged 37 years with refractory CD	Canada	5 years	Health care payer	230,000	Blackhouse et al^Citation61
Induction therapy of ADA (160 mg) subcutaneous injections followed by maintenance therapy of ADA (40 mg) subcutaneous injections every 2 weeks versus usual care: variety of conventional non-anti-TNF-α treatments including corticosteroids and other immunosuppressants in Canadian patients aged 37 years and weighing 73 kg	Canada	5 years	Health care payer	200,000	Blackhouse et al^Citation61
CZP (400 mg) subcutaneously and continued on monthly maintenance therapy versus natalizumab (300 mg) intravenously every month in US patients aged 35 years with moderate-to-severe CD unresponsive to prior TNF-α antagonists	US	1 year	Health care payer	590,000	Ananthakrishnan et al^Citation62
ADA versus IFX in US patients with moderately to severely active CD	US	56 weeks	Health care payer	Cost-saving	Yu et al^Citation63
ADA 2 years of treatment versus standard care in moderate to severely active CD patients in the UK	UK	60 years	Health care payer	23,000	Bodger et al^Citation64
ADA 1 year of treatment versus standard care in moderate to severely active CD patients in the UK	UK	60 years	Health care payer	16,000	Bodger et al^Citation64
IFX 2 years of treatment versus standard care in moderate to severely active CD patients in the UK	UK	60 years	Health care payer	48,000	Bodger et al^Citation64
IFX 1 year of treatment versus standard care in moderate to severely active CD patients in the UK	UK	60 years	Health care payer	51,000	Bodger et al^Citation64
ADA (every other week) maintenance treatment versus nonbiologic treatment, placebo (also doses of conventional, nonbiologic medications) in CD patients (in two randomized, double-blind placebo-controlled trails, CHARM and CLASSIC, lifetime model duration) (severe disease groups)	UK	1 year	Health care payer	14,000	Loftus et al^Citation65
ADA (every other week) maintenance treatment versus nonbiologic treatment, placebo (also doses of conventional, nonbiologic medications) in CD patients (in two randomized, double-blind placebo-controlled trails, CHARM and CLASSIC, lifetime model duration) (moderately severe disease groups)	UK	1 year	Health care payer	38,000	Loftus et al^Citation65
ADA (every other week) maintenance treatment versus nonbiologic treatment, placebo (also doses of conventional, nonbiologic medications) in CD patients (in two randomized, double-blind placebo-controlled trails, CHARM and CLASSIC, 56-week model duration) (moderately severe disease groups)	UK	1 year	Health care payer	72,000	Loftus et al^Citation65
ADA (every other week) maintenance treatment versus nonbiologic treatment, placebo (also doses of conventional, nonbiologic medications) in CD patients (in two randomized, double-blind placebo-controlled trails, CHARM and CLASSIC, 56-week base case model) (severe disease group)	UK	1 year	Health care payer	34,000	Loftus et al^Citation65
ADA (every other week) maintenance treatment versus nonbiologic treatment, placebo (also doses of conventional, nonbiologic medications) in CD patients (in two randomized, double-blind placebo-controlled trails, CHARM and CLASSIC, 56-week base case model) (severe disease group)	UK	1 year	Health care payer	34,000	Loftus et al^Citation65
Maintenance therapy with IFX (5 mg/kg) versus standard care without IFX in adult patients with fistulizing CD in the UK	UK	5 years	Health care payer	63,000	Linsday et al^Citation66
Maintenance therapy with IFX (5 mg/kg) versus standard care without IFX in adult patients with active luminal CD in the UK	UK	5 years	Health care payer	56,000	Linsday et al^Citation66
Dose escalation of IFX to 10 mg/kg versus IFX discontinued and ADA initiated with a 160 mg injection followed by a 80 mg dose 2 weeks later, maintenance of 40 mg every other week in CD patients who have lost response to standard dose (5 mg/kg) IFX therapy	US	1 year	Health care payer	380,000	Kaplan et al^Citation67

Notes: Study perspective: The study perspective is the viewpoint from which costs and benefits are calculated. All studies included in our review were conducted from a health care payer perspective and include only direct costs incurred by insurance companies (private or national health care service). Time horizon: The time horizon is the length of time in which resource use (eg, drug use, hospital admissions) are measured. ICER is calculated by dividing the incremental cost by the incremental QALYs gained of an intervention over the examined comparator. An ICER is not calculated when the intervention costs less (cost-saving) and is at least as effective as the comparator. In many of these cases, the intervention is considered “dominant” over the comparator, suggesting that it is both cost-saving and more effective.

Abbreviations: CD, Crohn’s disease; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year; IFX, infliximab; AZA, azathioprine; IV, intravenous; TNF, tumor necrosis factor; ADA, adalimumab; CZP, certolizumab pegol; CHARM, Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance; CLASSIC, CLinical assessment of Adalimumab Safety and efficacy Studied as Induction therapy in Crohn’s disease.

Table 5 Cost-effectiveness analyses of biologic agents for UC

Intervention, comparator, and target population	Country	Time horizon	Study perspective	ICER ($/QALY)	Reference
IFX, includes first infusion of 5 mg/kg on the 4th day, with concomitant standard care comprising IV therapy for an additional 7 days during the hospital stay versus cyclosporine, includes infusion of 4 mg/kg on the 4th to 11th days, with concomitant standard care comprising IV therapy for an additional 7 days during the hospital stay in acute severe UC patients not responding to 72 hours of IV steroid therapy	UK	1 year	Health care payer	41,000	Punekar et al^Citation68
5 mg/kg and 10 mg/kg IFX + ADA versus usual care in Canadian patients diagnosed with refractory UC	Canada	5 years	Health care payer	590,000	Xie et al^Citation69
5 mg/kg IFX + ADA versus usual care in Canadian patients diagnosed with refractory UC	Canada	5 years	Health care payer	370,000	Xie et al^Citation69
IFX treatment 5 mg/kg, remission strategy versus standard care in patients with moderate-to-severe UC in the UK	UK	10 years	Health care payer	44,000	Tsai et al^Citation70
IFX treatment 5 mg/kg, responder strategy versus standard care in patients with moderate-to-severe UC in the UK	UK	10 years	Health care payer	62,000	Tsai et al^Citation70

Notes: Study perspective: The study perspective is the viewpoint from which costs and benefits are calculated. All studies included in our review were conducted from a health care payer perspective and include only direct costs incurred by insurance companies (private or national health care service). Time horizon: The time horizon is the length of time in which resource use (eg, drug use, hospital admissions) are measured. ICER is calculated by dividing the incremental cost by the incremental QALYs gained of an intervention over the examined comparator. An ICER is not calculated when the intervention costs less (cost-saving) and is at least as effective as the comparator. In many of these cases, the intervention is considered “dominant” over the comparator, suggesting that it is both cost-saving and more effective.

Abbreviations: UC, ulcerative colitis; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year; IFX, infliximab; IV, intravenous; ADA, adalimumab.

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