Economic evaluation of linaclotide for the treatment of adult patients with irritable bowel syndrome with constipation in the United States

Figures & data

Figure 1. Model tree.

Table 1. Base-case and sensitivity analysis model inputs.

Parameter	Value	Range
		Low	High
Treatment response
Lubiprostone response (8 mcg BID)
Based on IBS-QoL^a	57.2%	N/A	N/A
Based on global assessment of symptom relief^b	13.0%	N/A	N/A
OR linaclotide 290 mcg once daily vs lubiprostone 8 mcg BID  (indirect comparison using placebo)
Based on IBS-QoL^c	1.21	1.00	1.41
Based on global assessment of symptom relief^d	1.60	1.09	2.11
Discontinuation^e
Linaclotide 290 mcg once daily	0.0%	N/A	30.1%
Lubiprostone 8 mcg BID	0.0%	N/A	23.1%
Costs
Drug (daily)
Linaclotide 290 mcg once daily^f	$7.70	$6.93	$8.47
Lubiprostone 8 mcg BID^g	$9.16	N/A	N/A
Treatment failure (per patient)^h	$825	$314	$1781
Indirect cost (per patient)^i
Based on IBS-QoL	$38.21	$28.66	$47.76
Based on global assessment of symptom relief	$76.29	$57.22	$95.36
Utilities^j
Based on IBS-QoL
Response	0.85	0.84	0.86
Non-response/discontinued	0.81	0.81	0.83
Based on global assessment of symptom relief
Response	0.91	0.89	0.92
Non-response/discontinued	0.81	0.80	0.82

BID, twice daily; IBS-C, irritable bowel syndrome with constipation; IBS-QoL, Irritable Bowel Syndrome Quality-of-Life; SBM, spontaneous bowel movement.

^aResponse rate (≥14-point increase from baseline) derived through fitting to a normal distribution based on ITT results from Table 12 in FDA 2008 Medical Review10.

^bResponse rate (‘moderately’ or ‘significantly’ relieved) obtained from pooled data based on Tables 64 and 71 in FDA 2008 Medical Review, ITT population10.

^cPlacebo-adjusted odds ratios derived from response rate (≥14-point increase from baseline) of linaclotide (post-hoc analysis of Phase 3 clinical trial data) vs lubiprostone. Lubiprostone response calculated as described above in Source 1. Low and high estimates were derived from bootstrapping results.

^dPlacebo-adjusted odds ratios derived from response rate (‘considerably’ or ‘completely’ relived) of linaclotide (post-hoc analysis of Phase 3 clinical trial data) vs lubiprostone. Lubiprostone response calculated as described above in Source 2. Low and high estimates were derived from bootstrapping results.

^eDiscontinuation assumed to be zero in the base-case; discontinuation rate for ‘any reason’ used for sensitivity analysis from the linaclotide (post-hoc analysis of Phase 3 clinical trial data) and lubiprostone.) clinical trials10.

^fTruven Health Analytics Red Book™ 2014 WAC price for linaclotide. Low and high estimates only used for probabilistic sensitivity analysis; assumed to be ±10% of the base-case value.

^gTruven Health Analytics Red Book™ 2013 WAC price for lubiprostone.

^hDerived from the findings from a one-time, web-based survey of physicians on treatment patterns and resource use for patients with IBS-C who had/did not have a response to a recent treatment course18. The low bounds of the interquartile range (IQR) of the estimated base-case costs were used as the low estimates. The high estimates were taken from a retrospective database analysis of Medicaid administrative claims7.

ⁱDerived from data collected from the Work Productivity and Activity Impairment (WPAI) Questionnaire in the Phase 3 clinical trials for linaclotide19. Low and high estimates were calculated as ±25% of the base-case value.

^jDerived from the EQ-5D scores from Phase 3 clinical trials for linaclotide19.

Table 2. Model results for 1000 patients with irritable bowel syndrome with constipation (direct costs only).

	Definition of response
	IBS-QoL responder^a			Global assessment of symptom relief responder^b
Comparator arms	Direct cost per patient	Responders (%)	QALYs per patient	Direct cost per patient	Number of responders	QALYs per patient
Lubiprostone 8 mcg BID	$911	57.2%	0.1917	$1056	13.0%	0.1894
Linaclotide 290 mcg once daily	$803	61.8%	0.1921	$977	19.3%	0.1909
Incremental (linaclotide-lubiprostone)	−$108	4.6%	0.0004	−$80	6.3%	0.0014

IBS-C, irritable bowel syndrome with constipation; IBS-QoL, Irritable Bowel Syndrome Quality-of-Life; QALY, quality-adjusted life year.

^aIBS-QoL responder at least a 14-point increase in IBS-QoL from baseline to the end of 12 weeks of treatment.

^bGlobal assessment of symptom relief responder: Monthly responder for at least 2 out of 3 months (‘moderately’ or ‘significantly’ relieved of symptoms).

Figure 2. Probabilistic sensitivity analysis results for cost per patient and probability of response; (a) response based on IBS-QoL, and (b) response based on global assessment. Each point on graph represents the result of one of a thousand iterations of a second order Monte Carlo simulation.

Table A1. Odds of response by definition of irritable bowel syndrome with constipation response to treatment.

Response rate	Pooled results for lubiprostone			Pooled results for linaclotide			OR linaclotide vs lubiprostone
	Lubiprostone 8 mcg BID	Placebo	OR	Linaclotide 290 mcg once daily	Placebo	OR
IBS-QoL^a ≥14-points increase	0.57	0.51	1.29	0.59	0.48	1.56	1.21
Based on global assessment of symptom relief^b	0.13	0.07	2.06	0.20	0.07	3.28	1.60

Notes: Results are intent-to-treat (ITT) results, at the end of week 12.

^aResults for lubiprostone are based on data from Table 12 in FDA 2008 Medical Review and pooled linaclotide trial data. Results for linaclotide are from pooled trial data on ITT population.

^bResults for lubiprostone are based on Tables 64 and 71 in FDA 2008 Medical Review, ITT population. Results for linaclotide are from pooled trial data on ITT population.

IBS-QoL, Irritable Bowel Syndrome Quality-of-Life; OR, odds ratio.

Table A2. Actual and fitted distribution of irritable bowel syndrome with constipation quality-of-life responders.

	Fitted distribution
	Mean	SD	Calculated percentage*	Actual*
Linaclotide
Placebo	13.0	17.1	47.6%	39.0%
Linaclotide 290 mcg once daily	17.9	17.8	58.6%	53.8%
Lubiprostone
Placebo	14.4	19.0	50.8%	N/A
Lubiprostone 8 mcg twice daily	17.1	17.0	57.2%	N/A

*Percentage of patients with at least a 14-point increase from baseline in IBS-QoL.

Table A3. Physician survey results for the practice patterns of patients with irritable bowel syndrome with constipation.

	Primary care physician (%)	Gastroenterologist (%)
Physicians ordering test for patients with non-response	75	50
Tests ordered
Thyroid Function Blood Tests	100	90
Complete Blood Count	100	60
Serum Calcium	75	45
Colonoscopy	50	60
Anti-tissue Transglutaminase Antibody (tTG) test (celiac disease test)	25	10
Erythrocyte Sedimentation Rate	20	10
C-Reactive Protein	10	8
EGD/Flexible Sigmoidoscopy	5	8
Barium enema	5	1
Others (please specify)	0	0
Upper Gastrointestinal Series/Endoscopy	5	0
Sitz-Marker Test	–	8
Defecography	–	7
CAT scan	–	10
Ultrasound	–	0
Manometry	–	4
MRI scan	–	0
Physicians advising return within 3 months in case of non-response	100	100
Physicians referring to a gastroenterologist in case of non-response	80	–
Physicians advising return within 3 months in case of response	50	30
Physicians advising tests in case of response	0	0

Table A4. Costs of procedures and tests for irritable bowel syndrome with constipation.

Procedure/test	Cost of procedure/test ($)	CPT codes
Thyroid Function Blood Tests	42.89	84439, 84442, 84479*
Complete Blood Count	11.02	85025
Serum Calcium	7.30	82310
Colonoscopy	744.40	45380
Anti-tissue Transglutaminase Antibody (tTG) Test (celiac disease test)	16.34	83516
Erythrocyte Sedimentation Rate	5.02	85651
C-Reactive Protein	7.33	86140
EGD/Flexible Sigmoidoscopy	330.00	45330, 43235**
Barium enema	344.80	7427, 74280**
Upper GI Series/Endoscopy	351.61	74246, 43235**
Sitz-Marker Test	50.38	74000
Defecography	278.77	74270
CAT scan	920.38	74150, 72192*
Ultrasound	279.46	76700
Manometry	816.90	91120
MRI scan	838.68	74181
Cost of Moderate Office Visit	180.40	99214

Note: Costs were based on the 2012 Medicare Physician Payment Schedule. Costs for procedures were calculated by summing the national average payment for both facility and non-facility charges. Laboratory tests were based on the average payment corresponding with Medicare’s 60% National Limitation Amount.

*Sum of the cost for all CPT codes were used since this test will include all procedures.

**Average cost for the CPT codes were used.

Figure A1. Treatment failure calculation.

Center for Drug Evaluation and Research. Medical review: Lubiprostone for the treatment of irritable bowel syndrome with constipation (Application 21-908s005). United States Food and Drug Administration, 2008

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