Access to biologicals in Crohn’s disease in ten European countries

Table 1 Clinical and reimbursement guidelines

Country	Guideline	Source, organization, last update, web-link
The Czech Republic	Clinical	Bortlík et al[25] 2016 by IBD Working Group of the Czech Society of Gastroenterology
	Reimbursement	Reimbursement criteria of the SUKL1; Edited by: SUKL, http://www.sukl.cz
France	Clinical	ECCO guidelines, Crohn's Disease Guidelines (2010), Check list ANTI TNF, Check list VEDOLIZUMAB by GETAID2https://www.getaid.org/recommandations.html
	Reimbursement	No
Germany	Clinical	German Guidelines on Crohn’s disease; DGVS German Society of Gastroenterology (2014)
	Reimbursement	No
Hungary	Clinical	Miheller et al[26] 2009
	Reimbursement	The diagnostic and treatment of Crohn’s disease] by NHIFA3 (2013) http://www.oep.hu/data/cms989735/0626_a_felnottkori_crohn_betegseg_diagnosztikajanak_es_kezelesenek_finanszirozasi_protokollja.pdf
Latvia	Clinical	No national guideline, but following the ECCO guideline
	Reimbursement	National Health Service of Latvia. No specific document, but part of the general regulations on medication reimbursement.(2016)
Poland	Clinical	[The treatment of Crohn’s Disease (ICD-10 K 50)], National Health Fund, (2014) http://onkologia-online.pl/upload/obwieszczenie/2015.10.28/b/b.32.pdf
	Reimbursement	No
Romania	Clinical	National Insurance Fund Protocol (2013) http://www.cnas.ro/default/index/index/lang/EN
	Reimbursement	National Insurance Fund protocol (2013) http://www.cnas.ro/default/index/index/lang/EN
Slovakia	Clinical	No national guideline, but following the ECCO guideline
	Reimbursement	Protocol for starting and continuing the biological treatment. Date first approvals: infliximab 2005, adalimumab 2008, vedolizumab 2016; The Slovakian Gastroenterology Association and The Union of Health Insurance Companies.
Spain	Clinical	Guidelines for biologics by GETECCU4 (2013) http://geteccu.org/formacion/guias-y-documentos-de-consenso; Cabriada et al[27] 2013
	Reimbursement	No
Sweden	Clinical	(1) National Guidelines for the treatment of Crohn’s disease; The Swedish Society of Gastroenterology (2017) http://www.svenskgastroenterologi.se/sites/default/files/pagefiles/Riktlinjer_Lakemedelsbehandling_vid_Crohns_2012.pdf
		(2) The use of IFX biosimilar in patients with IBD; Swedish Society of Gastroenterology (2017) http://www.svenskgastroenterologi.se/sites/default/files/pagefiles/SGF_riktlinjer_Biosimilarer_150903.pdf
		(3) The Medical Product Agency: Drug treatment of IBD, novel recommendations by the Medical Product Agency, Sweden (2012) https://lakemedelsverket.se/upload/halso-och-sjukvard/behandlingsrekommendationer/L%C3%A4kemedelsbehandling%20vid%20inflammatorisk%20tarmsjukdom%20-%20ny%20rekommendation_bokm%C3%A4rken.pdf
	Reimbursement	No

¹State Institute for Drug Control;

²Groupe d'Étude Thérapeutique des Affections Inflammatoires du Tube Digestif;

³National Health Insurance Fund Administration;

⁴Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa.

Table 2 Clinical and administrative requirements of biological treatment (2016)

	Cz	Fr	D	Hu	Lv	Pl	Ro	Sk	Es	Se
Required level of disease activity (such as CDAI) or disease severity required for initiation of biological treatment
Not specified (0 point)	x		x		x				x	x
CDAI > 220 (1 point)							x	x
CDAI > 300 (2 points)		x		x		x
Required failure of /intolerance to non-biological treatment before a patient is eligible for a biological
Steroids (1 point)			x
Immunosuppressive (1 point)							x
Steroids OR immunosuppressive (1 point)	x	x							x	x
Steroids AND Immunosuppressive (2 points)				x	x	x		x
Other procedures required after the indication of a biological treatment
No other procedures (0 point)	x	x	x	x	x	x			x	x
Other requirements (e.g., approval or authorization by the health insurance fund) (1 point)							x	x
Approved centers necessary for a biological treatment
No restriction to approved centers (0 point)		x	x							x
Restriction to approved centers (1 point)	x			x	x	x	x	x	x
Specialists who may indicate and prescribe biologicals for the treatment of CD in adults
Gastroenterologist, immunologist and GP/other (0 point)			x							x
Gastroenterologist and immunologist (1 point)		x
Only gastroenterologist (2 points)	x			x	x	x	x	x	x
Total availability score (min 0 to max 8)	4	4	1	7	5	7	6	7	4	1

Cz: The Czech Republic; Fr: France; D: Germany; Hu: Hungary; Lv: Latvia; Pl: Poland; Ro: Romania; Sk: Slovakia; Es: Spain; Se: Sweden.

Table 3 Affordability of biologicals - annual costs and annual costs (2016) as a percentage of gross domestic product per capita (2014)

	Cz	Fr	D	Hu	Lv	Pl	Ro	Sk	Es	Se
Annual total drug cost per patient (€)
Remicade	11925	13439	29081	15204	11202	10638	15469	12020	16591	16169
Remsima	11925	13439	23915	13694	11202	10638	12375	12020	12443	9157
Inflectra	11925	13439	22213	10674	11201	10638	12375	12020	12443	6841
Humira	11131	10625	24402	12326	14050	14800	24360	13697	12209	15286
Entyvio	-	-	24651	-	-	-	22275	20207	30218	19243
Annual cost, % of GDP (Affordability ratio)
Remicade	69%	36%	69%	124%	80%	84%	176%	74%	73%	31%
Remsima	69%	36%	57%	111%	80%	84%	141%	74%	55%	18%
Inflectra	69%	36%	53%	87%	80%	84%	141%	74%	55%	13%
Humira	65%	28%	58%	100%	101%	117%	277%	84%	54%	30%
Entyvio	-	-	59%	-	-	-	253%	124%	133%	37%
Average, without Entyvio	68%	34%	59%	106%	85%	92%	184%	77%	59%	23%
Average, all drugs	68%	34%	59%	106%	85%	92%	198%	86%	74%	26%

Annual total drug cost was calculated based on available list prices, and the EMA product information on the recommended drug dose and frequency. For infliximab we calculated with an average body weight of 75 kg. All costs were converted to Euros using the official exchange rate as of May 2016: 1 EUR= 27.025 CZK = 312.44 HUF = 4.3861 PLN = 9.2605 SEK. Cz: The Czech Republic; Fr: France; D: Germany; Hu: Hungary; Lv: Latvia; Pl: Poland; Ro: Romania; Sk: Slovakia; Es: Spain; Se: Sweden; GDP: Gross domestic product.

Table 4 Number of Crohn’s disease patients and the use of biologicals

Country	Estimated number of CD patients/source		Number of patients on biologicals1/source		Patients on biologicals per 100000 population (calculated)	Patients on biologicals per 1000 patients (calculated)
Cz	8768	Rencz et al[3], 2015 (based on estimation)	990	Rencz et al[3], 2015	9.4	112.9
Fr	72522	Kirchgesner et al[28], 2017 (administrative database)	22671	Estimation based on Kirchgesner et al[28], 2017	34.0	312.6
D	180000	Estimate by the collaborating expert based on CD incidence and prevalence in two regional cohort studies from the 90ties.	27000	Estimation (based on the estimated % of patients on biologicals and the total number of CD patients)	32.9	150.0
Hu	9775	Rencz et al[3], 2015 (based on epidemiology study)	1870	Rencz et al[3], 2015	19.0	191.3
Lv	1695	Rencz et al[3], 2015 (based on estimation)	3	Rencz et al[3], 2015	0.2	1.8
Pl	32049	Rencz et al[3], 2015 (based on estimation)	888	Rencz et al[3], 2015	2.3	27.7
Ro	11000	Estimate for 2016 by the collaborating expert based on National database including 13 IBD centers	253	Rencz et al[3], 2015	1.3	23.0
Sk	3687	Rencz et al[3], 2015 (epidemiology study)	690	Rencz et al[3], 2015	12.7	187.1
Es	60000	Arin Letamendia et al[29], 2008 (prospective, population-based study)	15000	Estimation (based on the estimated % of patients on biologicals from the ENEIDA database2 and the total number of CD patients)	32.3	250.0
Se	34318	SWIBREG3 combined with the Swedish National Patient Register	5270	SWIBREG3 combined with The Prescribed Drug Register	53.5	153.6

¹The sources of the number of patients on biologicals in Rencz et al[3], 2015 are National gastroenterology societies, ministries of health, IMS data, personal communication;

²ENEIDA is a large Spanish database (ENEIDA), promoted by the Spanish Working Group in Crohn’s and Colitis (GETECCU) (partial, not population based study);

³Swedish national quality registry for IBD. Cz: The Czech Republic; Fr: France; D: Germany; Hu: Hungary; Lv: Latvia; Pl: Poland; Ro: Romania; Sk: Slovakia; Es: Spain; Se: Sweden; GDP: Gross domestic product; CD: Crohn’s disease.

Table 5 Correlation matrix

	No. of patients on biologicals per 100000 population	Availability score	Affordability ratio	GDP per capita	% of public health expenditure in the total health expenditure	% of general government expenditure in public health expenditure
No. of patients on biologicals per 100000 population	1.0000	-	-	-	-	-
	-0.7497	1.0000	-	-	-	-
Availability score	(P = 0.0125)	-	-	-	-	-
Affordability ratio	-0.6920	0.5989	1.0000	-	-	-
	(P = 0.0266)	(P = 0.0673)	-			-
GDP per capita	0.9077	-0.8810	-0.7464	1.0000	-	-
	(P = 0.0003)	(P = 0.0008)	(P = 0.0132)	-	-	-
% of public health expenditure in the total health expenditure	0.3879	-0.5338	-0.1553	0.4907	1.0000	-
	(P = 0.2680)	(P = 0.1120)	(P = 0.6683)	(P = 0.149)	-	-
% of general government expenditure in public health expenditure	0.6661	-0.4384	-0.3741	0.4233	0.1547	1.0000
	(P = 0.0713)	(P = 0.2772)	(P = 0.3612)	(P = 0.296)	(P = 0.7146)	-

Sources: Population, GDP per capita (2014): The World Bank, % of public health expenditure in the total health expenditure (2015): The World Bank, European health for all database; % of general government expenditure in the total public health expenditure (2013) OECD. GDP: Gross domestic product.