Citation: Marquez-Megias, S.;
Nalda-Molina, R.; Sanz-Valero, J.;
Más-Serrano, P.; Diaz-Gonzalez, M.;
Candela-Boix, M.R.; Ramon-Lopez, A.
Cost-Effectiveness of Therapeutic
Drug Monitoring of Anti-TNF
Therapy in Inflammatory Bowel
Disease: A Systematic Review.
Pharmaceutics 2022, 14, 1009.
https://doi.org/10.3390/
pharmaceutics14051009
Academic Editor: Koyo Nishida
Received: 30 March 2022
Accepted: 30 April 2022
Published: 7 May 2022
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pharmaceutics
Systematic Review
Cost-Effectiveness of Therapeutic Drug Monitoring of
Anti-TNF Therapy in Inflammatory Bowel Disease: A
Systematic Review
Silvia Marquez-Megias 1,†, Ricardo Nalda-Molina 1,2,*,† , Javier Sanz-Valero 3,4 , Patricio Más-Serrano 1,2,5 ,
Marcos Diaz-Gonzalez 2, Maria Remedios Candela-Boix 6 and Amelia Ramon-Lopez 1,2
1 School of Pharmacy, Miguel Hernández University, 03550 San Juan de Alicante, Spain;
silvia.marquez@goumh.umh.es (S.M.-M.); mas_pat@gva.es (P.M.-S.); aramon@umh.es (A.R.-L.)
2 Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), 03010 Alicante, Spain;
diaz_marcosgon@gva.es
3 Department of Public Health and History of Science, School of Medicine, Miguel Hernandez University,
03550 Alicante, Spain; fj.sanz@isciii.es
4 Carlos III Health Institute, National School of Occupational Medicine, 28029 Madrid, Spain
5 Clinical Pharmacokinetics Unit, Pharmacy Department, Alicante University General Hospital,
03010 Alicante, Spain
6 Virgen de la Salud General Hospital of Elda, 03600 Elda, Spain; candela_marboi@gva.es
* Correspondence: jnalda@umh.es
† These authors contributed equally to this work.
Abstract: Infliximab and adalimumab are monoclonal antibodies against tumor necrosis factor (anti-
TNF) used to manage inflammatory bowel disease (IBD). Therapeutic Drug Monitoring (TDM) has
been proven to prevent immunogenicity, to achieve better long-term clinical results and to save costs
in IBD treatment. The aim of this study was to conduct a systematic review on cost-effectiveness
analyses of studies that apply TDM of anti-TNF in IBD and to provide a critical analysis of the best
scientific knowledge available in the literature. The quality of the included studies was assessed
using Consolidated Health Economic Evaluation Reporting Standards (CHEERS). Cost-effectiveness
of the TDM strategies was presented as total costs, cost savings, quality-adjusted life-years (QALY)
and incremental cost-effectiveness ratio (ICER). Thirteen studies that examined the health economics
of TDM of anti-TNF in IBD from 2013 to 2021 were included. Eight of them (61.5%) achieved a score
between 17 and 23 on the CHEERS checklist. The comparison between the TDM strategy and an
empirical strategy was cost saving. The ICER between reactive TDM and an empirical strategy was
dominated (favorable) by reactive TDM, whereas the ICER value for proactive TDM compared to an
empirical strategy ranged from EUR 56,845 to 3,901,554. This systematic review demonstrated that a
TDM strategy is cost-effective or cost-saving in IBD.
Keywords: inflammatory bowel diseases; drug monitoring; pharmacokinetics; tumor necrosis factor
inhibitors; adalimumab; infliximab; cost–benefit analysis; cost-effectiveness
1. Introduction
Crohn’s disease (CD) and ulcerative colitis (UC) are autoimmune inflammatory bowel
diseases (IBD) characterized by the chronic inflammation of the intestinal tract [1,2]. In
2017, there were 6.8 million cases of IBD globally [3–5]. According to several European
studies, the risk of colorectal cancer is two times higher in UC patients than in the general
population, whereas patients with CD have a higher risk of extraintestinal cancers and
increased mortality compared to the general population [6–10].
Infliximab and adalimumab are monoclonal antibodies against tumor necrosis factor
(anti-TNF), which are increasingly used to treat patients with moderate-to-severe IBD older
Pharmaceutics 2022, 14, 1009. https://doi.org/10.3390/pharmaceutics14051009 https://www.mdpi.com/journal/pharmaceutics
Pharmaceutics 2022, 14, 1009 2 of 18
than 6 years who had an inadequate response with corticosteroids or immunomodula-
tors [11,12]. However, nearly 40% of IBD patients experience a loss of response (LOR) to
anti-TNF treatment every year, requiring either dose intensification or switching to another
drug [13].
Numerous studies reveal that higher serum drug concentrations are associated with
better therapeutic outcomes, including mucosal healing [14–18]. Related to this, some
authors have shown that patients can experience LOR to anti-TNF due to developing
antibodies against anti-TNF (AAA) after long periods of subtherapeutic drug levels [19–22].
In this line, Therapeutic Drug Monitoring (TDM) of anti-TNF has been proven to prevent
immunogenicity and to achieve better long-term outcomes in terms of IBD-related surgery
or hospitalization [23–25]. Since the mean direct cost per patient-year is around EUR
3500 for CD patients and EUR 2000 for UC patients including diagnostic procedures,
hospitalizations and biological treatment in Europe [26], TDM could be a tool of special
relevance to optimize the treatment and save costs.
In the literature, other systematic reviews confirmed that TDM of anti-TNF is cost-
effective in rheumatoid arthritis [27,28]. Recently, another systematic review of the TDM of
immunomodulators and anti-TNF therapy in IBD proved to be cost-effective or cost-saving
compared with an empirical strategy without TDM. However, the main limitation of this
review is the inclusion of only model-based analyses with simulations of patients [29].
The aims of this systematic review are to evaluate studies concerning the cost-effectiveness
analysis of TDM of anti-TNF in IBD and to provide a critical analysis of the best scientific
knowledge available on the use of TDM.
2. Materials and Methods
2.1. Design
This systematic review consisted of a cross-sectional descriptive study and a criti-
cal analysis of studies found in the literature. The structure of this review followed the
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guide-
lines [30] (Supplementary Table S1), and the methodological framework proposed for
scoping studies [31,32].
2.2. Source of Data Collection
The data were obtained from direct consultation and access, via the Internet, to the
following bibliographic databases in the field of health sciences: MEDLINE (via PubMed),
Embase, Cochrane Library, PsycINFO, Scopus, Web of Science, and Latin American &
Caribbean Health Sciences Literature (LILACS) and Medicina en Español (MEDES). The
published articles were analyzed and retrieved from the indicated bibliographic databases.
2.3. Information Processing
Search terms were selected using the Thesaurus of Health Sciences Descriptors
(DeCS) developed by the Latin American and Caribbean Center on Health Sciences
Information (BIREME) and equivalent terms established by the US National Library
of Medicine, Medical Subject Headings (MeSH). The MeSH descriptors “Inflammatory
Bowel Diseases”, “Tumor Necrosis Factor Inhibitors”, “Infliximab”, “Adalimumab”,
“Cost-Benefit Analysis”, “Cost Savings” and “Drug Monitoring” were considered suitable.
Likewise, these terms were used to query the database using the title and abstract field
(Title/Abstract). It was not necessary to use filters (limits). The search equations are
available in Supplementary Table S2. This review was not registered; although, the protocol
was developed before the research began.
This strategy was subsequently adapted to the characteristics of each database con-
sulted, from the first available date in each of the selected databases until December 2021.
Additionally, a complimentary search strategy was performed to reduce the possibility of
publication bias by manually searching the reference lists of the articles that were selected
for the review. Likewise, experts in the subject under study were contacted to determine
Pharmaceutics 2022, 14, 1009 3 of 18
the possible existence of gray literature (materials and research produced by organizations
outside traditional commercial or academic publications that are disseminated through
other distribution channels).
2.4. Final Selection of Articles
For the review and critical analysis, articles that met the following criteria were chosen:
Inclusion: original articles published in peer-reviewed journals and articles that met
the objectives of the search.
Exclusion: full text could not be found; no relationship between the intervention and
the outcome under study (causality criterion); articles that included any diseases different
to IBD such as rheumatoid arthritis, psoriasis or ankylosing spondylitis; studies regarding
different drugs to anti-TNF antagonists such as Vedolizumab or Ustekinumab and studies
developed in animals.
There was no language, publication date or publication status restriction. The selection
of relevant articles was performed by two authors of the present review (S.M.-M. and
A.R.-L.). To validate the inclusion of the articles, the assessment of the agreement between
the authors using the kappa index, had to be greater than 0.60 [33]. In case of discrepancies,
a third reviewer (R.N.-M.) was responsible for reaching a resolution and subsequent
consensus amongst all the authors.
2.5. Quality Assessment, Level of Evidence and Grade of Recommendation
The quality of all identified studies was evaluated by the Consolidated Health Eco-
nomic Evaluation Reporting Standards (CHEERS) checklist [34], which consists of 24 items
to appraise the quality of the included studies. For each item, it was assigned one point
for each item present (if not applicable, it was not scored). The percentage of total scores
assigned to each study was used to evaluate the study quality. All studies were classified
into four categories: “excellent” (≥85%), “very good” (70–84%), “good” (55–69%), and
“insufficient” (<55%).
The quality assessment was conducted by two reviewers (S.M.-M. and A.R.-L.) inde-
pendently. It was established that the inter-rater agreement for the authors (using the kappa
index) should be higher than 60%. In case of discrepancies, a third reviewer (R.N.-M.) was
responsible for reaching a resolution and subsequent consensus amongst all the authors.
To assess the risk of bias due to missing results, the methods and the results sections
of the selected articles were compared. To determine the level of evidence and its degree of
recommendation, the recommendations of the Scottish Intercollegiate Guidelines Network
Grading Review Group (SIGN) [35] were used.
2.6. Data Extraction
Data from eligible articles were collected to systematize and facilitate the interpretation
of the results. Data were extracted by one reviewer and verified by a second reviewer.
The following items were extracted: general information of study (first author, country
of the study and year of publication); study design (population, intervention, type of
TDM approach used, time horizon and methods of measuring outcomes); and results
(primary outcomes). The primary outcomes collected were the cost-effectiveness of the
TDM strategies, presented as the total costs, cost savings, quality-adjusted life-years (QALY)
or incremental cost-effectiveness ratio (ICER). Costs were converted to the same currency
(euros) in the year of publication of each study to allow the comparison between the differ-
ent studies. Moreover, all the costs were normalized to a one-year period to homogenize
the results. If the information was available, average costs per patient per year were calcu-
lated according to the total costs and the number of patients in each group of treatment in
each study.
Pharmaceutics 2022, 14, 1009 4 of 18
3. Results
This systematic review identified a total of 102 publications: 33 were found in Medline
(via PubMed), 16 in Embase, 1 in Cochrane Library, 18 in Scopus and 34 in Web of Science.
No article was retrieved from PsycINFO, LILACS and MEDES. A total of 13 original articles
were included in this review [36–48] after removing duplicates, applying the inclusion
and exclusion criteria and consulting the bibliographic lists of the selected articles from
the search strategy. The list of excluded studies and the reasons for exclusion is available
in Supplementary Table S3. The inter-rater agreement for the selected studies was 0.815
(p < 0.001) according to the kappa index.
The process of study selection is presented in a flowchart in Figure 1.
Pharmaceutics 2022, 14, x  4 of 18 
 
 
according to the total costs and the number of patients in each group of treatment in each 
study. 
3. Results 
This systematic review identified a total of 102 publications: 33 were found in Med-
line (via PubMed), 16 in Embase, 1 in Cochrane Library, 18 in Scopus and 34 in Web of 
Science. No article was retrieved from PsycINFO, LILACS and MEDES. A total of 13 orig-
inal articles were included in this review [36–48] after removing duplicates, applying the 
inclusion and exclusion criteria and consulting the bibliographic lists of the selected arti-
cles from the search strategy. The list of excluded studies and the reasons for exclusion is 
available in Supplementary Table S3. The inter-rater agreement for the selected studies 
was 0.815 (p < 0.001) according to the kappa index. 
The process of study selection is presented in a flowchart in Figure 1. 
 
Figure 1. Selection procedure of the studies. 
All included studies examined the health economics of TDM in IBD patients treated 
with anti-TNF from 2013 to 2021. Moreover, 12 of them evaluated the TDM of infliximab 
and only one (ST1) evaluated the use of adalimumab. The summary of the characteristics 
of each study is listed in Table 1. 
 
 
Records identified through database 
search 
n = 102 
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ee
n
in
g
 
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cl
u
d
ed
 
S
el
ec
ti
o
n
 
Id
en
ti
fi
ca
ti
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Duplicate records 
(Retrieved from more than 1 database) 
n = 41 
Selected records 
n = 67 
Excluded records: n = 38 
- Not original article 
Studies with complete text 
available evaluated for 
selection  
n = 29 
Excluded studies: n = 16 
- Causality criterion 
 
Included studies  
n = 13 
Additional studies identified from other 
sources (manual search and contribution by 
experts)  
n = 6 
Figure 1. Selection procedure of the studies.
All included studies examined the health economics of TD in IBD patients treated
with anti-TNF from 2013 to 2021. oreover, 12 of them evaluated the TDM of infliximab
and only one (ST1) evaluated the use of adalimumab. The summary of the characteristics
of each study is listed in Table 1.
Pharmaceutics 2022, 14, 1009 5 of 18
Table 1. Summary of the characteristics of the included studies.
Study Authors, Year Country Study Design Drug Studied Study Population(n, m/f, Age)) Study Duration
Measure of
Outcomes Intervention CHEERS (n, %)
ST1 Yao et al.,2021 [36] US
Modeling
approach Adalimumab
20,000 simulated CD pediatric
biologic-naïve patients
3 years and
4 weeks
Costs
Cost savings
QALY
ICER
Proactive TDM (n = 10,000) vs.
Reactive TDM (n = 10,000)
21 (87.5%)
Excellent
ST2 Negoescu et al.,2020 [37] US
Modeling
approach Infliximab 100,000 CD simulated patients 5 years
Costs
Cost savings
QALY
ICER
Proactive TDM (n = NA) vs.
Reactive TDM (n = NA) vs.
Empirical strategy (n = NA)
19 (79.2%)
Very good
ST3 Attar et al.,2019 [38] France
Modeling
approach Infliximab
40,000 CD simulated
adult patients 2 years
Costs
Cost savings
Proactive TDM (n = 20,000) vs.
Empirical strategy (n = 20,000)
7 (29.2%)
Insufficient
ST4 Freeman et al.,2016 [39] UK
Modeling
approach Infliximab
Simulations of CD patients in
maintenance treatment of
infliximab
10 years
Costs
Cost savings
QALY
ICER
Proactive TDM (n = NA) vs.
Empirical strategy (n = NA)
23 (95.8%)
Excellent
ST5 Roblin et al.,2015 [40] France
Modeling
approach Infliximab
10,000 Simulations of CD
patients with LOR to
infliximab
1, 3 and 5 years Cost savings Reactive TDM (n = NA) vs.Empirical strategy (n = NA)
10 (41.7%)
Insufficient
ST6 Velayos et al.,2013 [41] US
Modeling
approach Infliximab
10,000 simulations of CD
patients with LOR
to infliximab
1 year
Costs
Cost savings
QALY
ICER
Reactive TDM (n = NA) vs.
Empirical strategy (n = NA)
17 (70.8%)
Very good
ST7 Wu et al.,2021 [42] Australia
Prospective
observational
study
Infliximab 428 IBD patients (322/296,36 ± 18.7 yo) 56 weeks Cost savings
Proactive TDM (n = 181) vs.
Reactive TDM (n = 247)
12 (50.0%)
Insufficient
ST8 Ganesnanthanet al., 2020 [43] UK
Retrospective
observational
study
Infliximab 85 IBD patients (54/31,39.13 ± 14.25 yo) NA Cost savings
Proactive TDM (n = NA) vs.
Reactive TDM (n = NA) vs.
Proactive TDM post-induction
(n = NA)
7 (29.2%)
Insufficient
ST9 Guidi et al.,2018 [44] Italy
Prospective
observational
study
Infliximab
148 IBD patients in treatment
for at least 4 months with LOR
to infliximab (75/73,
40.8 (37.05–42.5) yo)
12 weeks CostsCost savings
Reactive TDM (n = 96) vs.
Empirical strategy (n = 52)
17 (70.8%)
Very good
ST10 Taks et al.,2017 [45]
The
Netherlands
Non-
randomized
clinical trial
Infliximab 33 IBD adult patients (20/13,43 (32–59) yo) 1 year Cost savings
Proactive TDM (n = 28) vs.
Reactive TDM (n = 33)
4 (16.7%)
Insufficient
Pharmaceutics 2022, 14, 1009 6 of 18
Table 1. Cont.
Study Authors, Year Country Study Design Drug Studied Study Population(n, m/f, Age) Study Duration
Measure of
Outcomes Intervention CHEERS (n, %)
ST11 Vande Castelee et al.,
2015 [46]
Belgium
Randomized
controlled
clinical trial
Infliximab
251 IBD adult patients with a
stable clinical response for at
least 14 weeks (138/113,
41 (34.5–49.0) yo)
2 years and 16
weeks
Costs
Cost savings
QALY
ICER
Proactive TDM (n = 128) vs.
Empirical strategy (123)
18 (75.0%)
Very good
ST12 Steenholdt et al.,2015 [47]
Denmark
Randomized
controlled
clinical trial
Infliximab
69 CD adult patients with LOR
to infliximab (27/69,
37 (19–81) yo)
20 and 52 weeks
Costs
Cost savings
Reactive TDM (n = 33) vs.
Empirical strategy (n = 36)
17 (70.8%)
Very good
ST13 Steenholdt et al.,2014 [48] 12 weeks
17 (70.8%)
Very good
M: male; f: female; CHEERS: Consolidated Health Economic Evaluation Reporting Standards; CD: Crohn’s disease; QALY: quality-adjusted life-years; ICER: incremental cost-effectiveness
ratio; IBD: inflammatory bowel disease; yo: years old; NA: not available; LOR: loss of response.
Pharmaceutics 2022, 14, 1009 7 of 18
3.1. Study Design
Regarding the study design, three were randomized controlled clinical trials (ST11–13),
one was a non-randomized clinical trial (ST10), two were prospective observational studies
(ST7, 9) and one was a retrospective observational study (ST8).
Alternatively, six studies considered simulated patients using a modeling approach,
based on a Markov model (ST1, 4, 6), a stochastic simulation model (ST2) and a discrete
event model (ST3, 5).
3.2. Population
Twelve studies were carried out on adult patients (ST3, 10, 4–6, 11–13) while only one
studied the pediatric population (ST1). Eight studies considered only CD patients (ST1–4, 6,
11–13), whereas five included IBD patients (CD and UC) (ST7–11). Eight studies included
patients only in a maintenance phase of treatment (ST3, 4, 6, 7, 9, 10, 12, 13), and in the
others, patients were in both induction and maintenance stages.
3.3. Interventions
The included studies show three types of intervention: proactive TDM, reactive TDM
and an empirical strategy. Proactive TDM can be defined as the measurement of concen-
trations and AAA levels in all patients, at specific time points, to optimize drug dosage
and to achieve a threshold drug concentration that can improve response rates and prevent
secondary LOR and the development of AAA [49]. Reactive TDM is the measurement
of drug concentration and antibody levels only when patients had experienced primary
or secondary LOR to a biological treatment to inform about reasons for the lack of re-
sponse and to facilitate the next therapeutic decisions such as increasing drug, adding
immunomodulators or switching to another drug either in or out of class [49]. Another
approach is an empirical strategy that bases its dosage changes on clinical symptoms.
Four compared a proactive TDM versus a reactive TDM (ST1, 7, 8, 10), three compared a
proactive TDM versus an empirical strategy (ST3, 4, 11), five compared a reactive TDM
versus an empirical strategy (ST5, 6, 9, 11–13) and one study included the three strategies
as part of its intervention (ST2).
3.4. TDM
All studies, either proactive or reactive TDM, applied an algorithm to decide the next
decision in the treatment based on drug concentrations. Three studies developed and used
their own algorithm (ST2, 3, 12) while the rest adapted or used others found in the literature.
Five of the algorithms included an optimal drug concentration interval (ST1, 4, 7, 10, 11),
five considered a threshold (ST3, 5, 9, 12, 13), whereas three did not mention the interval or
threshold used to change the dosage or to switch drug (ST2, 6, 8). Seven algorithms took
into account the use of immunomodulators (ST1, 2, 4, 5, 9, 12, 13); although, four of them
did not include their cost in the analysis (ST5, 9, 12, 13).
Six studies defined the clinical or biochemical criteria to establish response (ST6, 9–13)
while four described the criteria to determine LOR (ST1, 9, 12, 13). Even though they
were distinct from each other, all of them included the Crohn’s Disease Activity Index to
determine either response or LOR. In relation to LOR, four out of five studies that included
induction patients considered the primary LOR and the discontinuation of the drug due to
adverse events (ST1, 2, 5, 11). Regarding secondary LOR, three studies (ST1, 5, 6) included
the cost of the treatment with another drug after switching from the main drug, whereas
one study (ST8) did not include this cost in the final result.
The analytical assay to measure AAA and trough concentrations differed in each
study: five (ST3–5, 7, 9) used LISA TRACKER duo (Theradiag, Marne la Vallée, France);
one (ST8) IDK monitor ELISA kit; one (ST10) homemade ELISA (Sanquin, Amsterdam, The
Netherlands); two (ST12, 13) radioimmunoassay (Biomonitor A/S, Copenhagen, Denmark);
and the rest did not specify it. In addition to this, three studies only measured AAA if
Pharmaceutics 2022, 14, 1009 8 of 18
trough concentrations were below an established threshold (ST7, 10, 11), one study only
measured trough concentrations in absence of AAA (ST6), whereas the others tested the
levels of both AAA and trough concentrations simultaneously at every measurement,
which considerably affected the cost.
3.5. Costs
The costs analyzed varied from each study. The outcomes were measured as costs
in nine studies (ST1–4, 6, 9, 11–13), as cost savings in all included studies, as QALY and
as ICER in five studies (ST1, 2, 4, 6, 11). Eight studies (ST1–4, 6, 9, 12, 13) included
an extensive detailed amount of costs such as clinic visits, hospitalization, surgery and
diagnosed tests, among others. The cost of the anti-TNF treatment was evaluated in all of
the included studies; although, in some studies patients were treated with biosimilars such
as Inflectra (ST8), CT-P13 (ST3, 9) and another study (ST7) did not specify it. Attar et al.
(ST3) defined two scenarios to calculate the cost of the treatment with all patients treated
with the originator (Remicade) and with the biosimilar CT-P13, whereas Guidi et al. (ST9)
added a third scenario to calculate half patients treated with each one. The summary of the
costs of each study is listed in Table 2.
Total costs ranged from EUR 14,927 to 186,635,650 per year for a proactive TDM
strategy; from EUR 14,263 to 3,230,810 per year for a reactive TDM strategy; and from
EUR 14,268 to 201,879,000 per year for an empirical strategy. In this line, cost savings of
proactive TDM compared to reactive TDM ranged from EUR 558 to 196,394 per year; cost
savings of proactive TDM compared to an empirical strategy ranged from EUR 1391 to
15,243,350 per year; and cost savings of reactive TDM compared to an empirical strategy
ranged from EUR 5.39 to 26,260,059 per year (Table 2).
On the other hand, QALY ranged from 0.63 to 0.82 for a proactive TDM strategy; from
0.73 to 0.80 for a reactive TDM strategy; and from 0.65 to 0.84 for an empirical strategy.
The ICER between reactive TDM and an empirical strategy was dominated (favorable) by
reactive TDM in two studies (ST2, 6). When it comes to ICER between proactive TDM and
reactive TDM, the proactive TDM dominated in one study (ST1) while in another study
(ST2) its value was EUR 131,858 (below the cost-effective thresholds in the United States).
The ICER between proactive TDM compared to an empirical strategy ranged from EUR
56,845 to 3,901,554.
Pharmaceutics 2022, 14, 1009 9 of 18
Table 2. Summary of the economic outcomes of each study per year.
Study Authors, Year Total Cost Cost Savings Average CostSavings per Patient QALY ICER
ST1 Yao et al., 2021 [36] PA: USD 110,851.18 (EUR 94,223.50)RA: USD 111,508.01 (EUR 94,781.81)
PA: USD 656.83 (EUR 558.31)
compared to RA
PA: EUR 0.06
compared to RA
PA: 0.81
RA: 0.74 RA-PA: Dominated by PA
ST2 Negoescu et al., 2020[37]
PA: USD 16,585.42 (EUR 14,926.88)
RA: USD 15,847.69 (EUR 14,262.92)
ES: USD 15,853.68 (EUR 14,268.31)
RA: USD 737.73 (EUR 663.96)
compared to PA and USD 5.99
(EUR 5.39) compared to ES
NA
PA: 0.74
RA: 0.73
ES: 0.73
RA-PA: USD 146,509.12
(EUR 131,858.21)
ES-RA: Dominated by RA
ST3 Attar et al., 2019 [38] PA: EUR 186,635,650ES: EUR 201,879,000
PA: EUR 15,243,350 compared
to ES
PA: EUR 0.76
compared to ES NA NA
ST4 Freeman et al., 2016[39]
PA: GBP 13,980 (EUR 18,174)
ES: GBP 15,050 (EUR 19,565)
PA: GBP 1070 (EUR 1391)
compared to ES NA
PA: 0.63
ES: 0.65
ES-PA: GBP 43,727.01 (EUR
56,845.12)
ST5 Roblin et al., 2015 [40] NA RA: EUR 26,260,058.60compared to ES NA NA NA
ST6 Velayos et al., 2013 [41] RA: USD 31,870 (EUR 23,902.5)ES: USD 37,266 (EUR 27,949.5)
RA: USD 5396 (EUR 4047)
compared to ES NA
RA: 0.80
ES: 0.80 ES-RA: Dominated by RA
ST7 Wu et al., 2021 [42] NA PA: AUD 304,916.95 (EUR196,394.48) compared to RA NA NA NA
ST8 Ganesnanthan et al.,2020 [43] NA
PA: GBP 56,865 (EUR 62,551)
compared to ES
PA post-induction: GBP 51,595
(EUR 56,754.50)
compared to ES
RA: GBP 27,081.85 (EUR
29,790.04) compared to ES
NA NA NA
ST9 Guidi et al., 2018 [44] RA: EUR 3,230,810.44ES: EUR 3,788,285.67
RA: EUR 557,475.23
compared to ES
RA: EUR 39,197.38
compared to ES NA NA
ST10 Taks et al., 2017 [45] NA PA: EUR 47,026compared to RA NA NA NA
ST11 Vande Castelee et al.,2015 [46]
PA: EUR 5,201,473
ES: EUR 5,276,773
PA: EUR 75,300
compared to ES
PA: EUR 300
compared to ES
PA: 0.82
ES: 0.84 ES-PA: EUR 3,901,554.40
Pharmaceutics 2022, 14, 1009 10 of 18
Table 2. Cont.
Study Authors, Year Total Cost Cost Savings Average CostSavings per Patient QALY ICER
ST12 Steenholdt et al.,2015 [47]
RA: USD 22,066 (EUR 17,652.80)
ES: USD 29,072 (EUR 23,257.60)
RA: USD 7006 (EUR 5604.8)
compared to ES
RA: EUR 111.11
compared to ES NA NA
ST13 Steenholdt et al.,2014 [48]
RA: USD 26,164.67 (EUR 19,623.5)
ES: USD 39,771.33 (EUR 29,828.5)
RA: USD 13,606.67 (EUR
10,205) compared to ES
RA: EUR 233.92
compared to ES NA NA
QALY: quality-adjusted life-years; ICER: incremental cost-effectiveness ratio; PA: proactive TDM; RA: reactive TDM; ES: empirical strategy; NA: not available; USD: United States
Dollars; AUD: Australian dollars.
Pharmaceutics 2022, 14, 1009 11 of 18
3.6. Quality Assessment
The total score of the CHEERS checklist of each study is included in Table 1 and more
details are available in Supplementary Table S4. The scores ranged from 4 to 23. The
number of studies categorized as “excellent”, very good” and “insufficient” was 2 (15.4%),
6 (46.2%) and 5 (38.4%), respectively.
The inter-rater agreement for the determination of each score was 0.806 (p < 0.001)
according to the kappa index. No risk of bias was observed in the published papers.
Furthermore, following the recommendations of the Scottish Intercollegiate Guidelines
Network Grading Review Group (SIGN) [35], the level of evidence was 2++ (high-quality
case-control or cohort studies with a very low risk of confounding, bias or chance and a
high probability that the relationship is causal) and its degree of recommendation was B
(studies rated 2++ directly applicable to the target population).
4. Discussion
The objective of this systematic review was to identify and synthesize the scientific
evidence published around the cost-effectiveness analyses of the use of TDM of anti-TNF
in IBD. This review includes both model-based and trial-based studies. With the object of
minimizing publication bias, the database searches were exhaustive, with neither language
nor date restrictions. Moreover, the PRISMA guideline was followed to minimize bias and
the quality of identified studies was evaluated with the CHEERS checklist. The results of
the CHEERS checklist show that eight of thirteen (61.5%) included studies achieved very
good to excellent rankings.
After performing an exhaustive search in numerous databases, thirteen studies were
found in the literature. Six of them (ST1–6) used a modeling approach based on the
calculation of probabilities of having a flare or being included in a TDM strategy, obtained
from the literature. A modeling approach allows for the evaluation of large cohorts of
patients, which would be very difficult to acquire in real life. However, the main weaknesses
of these studies are the simplification of the events related to disease progression, the
reliability of the external clinical results used for the modeling and the difficulties in
predicting or reflecting a clinical setting.
With regard to the drug studied, 12 studies were focused on infliximab. Therefore,
there is a lack of evidence on the cost-effectiveness of using TDM of adalimumab since
only one study (ST1) found in the search evaluated the costs with a modeling approach.
Due to the limitations of the modeling approach, further studies, either clinical trials or
observational studies, are needed to provide a wider outlook.
Five studies (ST6, 9, 10, 12, 13) reported data with a follow-up lower than or equal to
1 year but, as IBD is a chronic disease, a higher follow-up is required to understand the
long-term impact on the costs of a TDM strategy [44,50].
Regarding the population, there is only one published study (ST1) based on a pediatric
population. Moreover, this study approximated the utility values of health states from stud-
ies on adult patients. For that reason, future cost–benefit analyses in pediatric populations
are needed to confirm the results of this study.
None of the selected studies recruited UC patients separately from CD and, conse-
quently, the cost-effectiveness evaluation of TDM in UC is lacking. In fact, there may be
differences in the response to infliximab between CD and UC patients since infliximab
could be more immunogenic and reach lower trough concentrations in UC patients than in
CD patients, affecting considerably the cost-effectiveness of TDM of anti-TNF in this group
of patients [43].
It has been shown that AAA are clinically relevant for disease progression or applying
TDM [19–22]; however, one study (ST3) did not include the presence of AAA to infliximab
because of the complexity generated in its model. Moreover, AAA to infliximab frequently
appear in the first year [39]; although, most studies included patients just in a maintenance
phase of treatment. Therefore, TDM including the induction of the treatment could lead
Pharmaceutics 2022, 14, 1009 12 of 18
to more benefits and be more cost-effective since it would prevent flares and decrease
hospitalizations and surgery rates [45,51–53].
Concerning the intervention, a proactive TDM strategy was included as one of the
interventions in eight studies (ST1–4, 7, 8, 10, 11). However, some of them (ST3, 7, 10)
applied this concept differently and interpreted it as a strategy for patients that had disease
remission and only measured drug trough concentrations and/or AAA levels once. Other
authors (ST1, 2, 4, 8, 11) repeatedly measured these levels to avoid LOR and to restrain
the disease and its clinical symptoms. In fact, an adequate sample schedule has not been
established so far. Consequently, every one of these studies differed in that schedule and
used either 8 weeks (ST1), 6 months (ST2) or 1 year (ST4). Therefore, the comparison of
the results is difficult due to the lack of generalizability and the fact that a high frequency
of TDM could increase the total cost of a proactive TDM strategy as was observed by
Yao et al. [36].
The progression of IBD is difficult to predict using a standardized algorithm because
different and random events may occur along a patient’s disease course and differ from one
patient to another. Conversely, each study applied a different algorithm to achieve a dosage
optimization with variations in the interval or threshold used. In this context, patients can
be switched to different groups of treatment when applying different algorithms and this
could considerably limit the generalizability and bias the overall costs. Moreover, there
is no homogeneity in the decisions taken by every algorithm since five studies (ST2, 6, 9,
12, 13) did not consider supratherapeutic drug concentration and, therefore, increasing the
dosage was the only possible decision in their algorithm. On the contrary, other studies
(ST3, 7) took into account only high drug trough concentrations and, therefore, increasing
the dosage was not an option. So far, the exposure target for anti-TNF is highly dependent
on the therapeutic objective (clinical, endoscopic, biochemical or histologic remission) and
whether patients are diagnosed with CD or UC [17]. Based on the currently available
evidence, an interval of 6–10 mg/L of infliximab trough concentrations is recommended
to achieve clinical response [25,54,55]. Regarding adalimumab, a target of 8–12 mg/L
adalimumab trough concentrations is required to achieve mucosal healing in 80–90% of
IBD patients [25,54,55]. In fact, a recent study showed that patients with adalimumab trough
concentrations lower than 8.3 mg/L had more risk to develop AAA and to experience LOR
by week 12 [56]. The generalization of the clinical use of these intervals would allow the
therapeutic decisions and to compare costs to be standardized.
Related to the dosages, 12 studies (ST1, 3–13) administered doses of 5 mg/kg and
10 mg/kg. Nevertheless, Negoescu et al. (ST2) included a medium dose of 7.5 mg/kg
of infliximab as an option, and observed that smaller dose increases would decrease the
overall cost of the drug and still achieve therapeutic trough concentrations [39].
Recently, adding immunomodulators to the anti-TNF therapy has shown clinical
relevance in the decrease or disappearance of AAA [39,57]. However, not all studies
included this option in their algorithm (ST3, 6–8, 10, 11) and some of those that included
the algorithm did not consider its costs (ST5, 9, 12, 13), which could considerably affect the
cost-effectiveness analysis.
The analytical assay varied from each study and, consequently, the limit to consider
undetectable AAA and trough concentrations and its cost differed largely from each other.
The selected intervals or thresholds are directly dependent on assay type and whether or
not AAA are measured. However, none of the assays can be classified as a gold standard.
Moreover, four studies (ST1, 2, 6, 11) did not mention which analytical assay was applied,
which is essential due to its direct impact on the cost-effectiveness of any TDM strategy.
The definitions of clinical response and LOR are essential to classify patients into
different groups and to decide their future treatment. However, seven studies (ST1–5, 7,
8) did not define the criteria to determine a clinical response to the drug and nine studies
(ST2–8, 10, 11) did not define the criteria to establish LOR. In those that included a definition
for either clinical response and LOR, there are significant variations between them across the
studies that have large implications for the generalizability of study outcomes. Moreover,
Pharmaceutics 2022, 14, 1009 13 of 18
some studies (ST1, 2, 4, 6) carried out procedures such as endoscopies or colonoscopies that
significantly increased the overall costs.
Regarding the economic outcomes, it is difficult to compare the results given the
different number of patients, the number of drug or AAA samples per patient and the
different items included in the calculation of the final costs of each study. The overall costs
are closely related to the drug cost, but it is not homogeneous and varied between countries
and health systems. Furthermore, all selected studies only included direct medical costs
of health care such as drug cost, drug or AAA testing, surgery and hospitalization. As
none of them considered the indirect costs associated with flaring (e.g., time missed from
work) and the likelihood of experiencing an adverse event, the economic implications of
TDM might be underestimated. Moreover, biosimilars would enhance a more cost-effective
strategy due to their lower price [58,59]; although, all the selected studies concluded that
the TDM strategy is cost-effective compared to an empirical strategy.
All included studies used TDM to optimize the treatment of anti-TNF in IBD patients
through an algorithm. According to Papamichael et al., TDM was defined as the evaluation
of drug concentration and anti-drug antibodies [60]. However, Model-Informed Precision
Dosing (MIPD) is a more precise alternative, based on the use of population pharmacoki-
netics (PopPK) models and a prospective Bayesian approach to increase the homogeneity in
the drug exposure in patients and, therefore, to improve outcomes of treatments [61]. Some
authors have carried out MIPD of adalimumab and infliximab in IBD patients, applying
PopPk models found in the literature [62,63]. However, further investigations in this line
are required to estimate its cost and compare it with the ones obtained from a TDM strategy.
One limitation of this systematic review could be the high rate of non-relevant articles
(108) in relation to the final selection made (13). Scopus and Web of Science databases
initially retrieved many works that were finally irrelevant, which could be due to the
lack of indexing (the search was performed in text format querying the title, abstract and
keywords). Despite performing a comprehensive search, it cannot be ruled out that some
studies were not identified by the bibliographic databases searched or the manual search.
Another limitation of the present review relies on the fact that a meta-analysis was not
performed owing to clinical and methodological heterogeneity such as different study
designs, significant differences in the algorithms applied and follow-up periods, variability
in definitions of clinical criteria and different TDM approaches applied.
5. Conclusions
In conclusion, this systematic review identified 13 health economic studies, eight of
which were very good to excellent quality work per the CHEERS checklist.
The comparison between the TDM strategy and an empirical strategy was cost saving.
The ICER between reactive TDM and an empirical strategy was dominated (favorable)
by reactive TDM, whereas the ICER value for proactive TDM compared to an empirical
strategy ranged from EUR 56,845 to 3,901,554. This systematic review demonstrated that
TDM of anti-TNF drugs is a cost-effective or cost-saving tool in the management of IBD.
Supplementary Materials: The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/pharmaceutics14051009/s1, Table S1. PRISMA 2020 Checklist;
Table S2. Search strategies; Table S3. List of excluded studies and reasons *[64–110]*; Table S4.
CHEERS checklist assessment. References [64–110] are cited in the Supplementary Materials.
Author Contributions: Conceptualization, R.N.-M. and A.R.-L.; methodology, J.S.-V., S.M.-M.,
R.N.-M. and A.R.-L.; formal analysis, S.M.-M. and A.R.-L.; investigation, S.M.-M. and A.R.-L.; super-
vision, R.N.-M.; writing—original draft, S.M.-M., J.S.-V. and A.R.-L.; writing—review and editing,
R.N.-M., P.M.-S., M.D.-G. and M.R.C.-B. All authors have read and agreed to the published version of
the manuscript.
Funding: S.M.-M. received a predoctoral fellowship from Miguel Hernandez University (“Ayudas a
la contratación de personal investigador en formación 2021”).
Institutional Review Board Statement: Not applicable.
Pharmaceutics 2022, 14, 1009 14 of 18
Informed Consent Statement: Not applicable.
Data Availability Statement: Data are available from the corresponding author on reasonable request.
Conflicts of Interest: The authors declare no conflict of interest.
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