Received: 7 March 2019 Revised: 21 May 2019
DOI: 10.1111/jep.13209
ORIGINAL PAPER
Cost‐benefit analysis of clinical pharmacist intervention in
preventing adverse drug events in the general chronic diseases
outpatients
Rajaa A. Al‐Qudah MSc1
Shoroq M. Altawalbeh PhD3
1
Department of Clinical Pharmacy and
Therapeutics, Faculty of Pharmacy, Applied
Science Private University, Amman, Jordan
2
College of Pharmacy, QU Health Cluster,
Qatar University, Doha, Qatar
3
Department of Clinical Pharmacy, Faculty of
Pharmacy, Jordan University of Science and
Technology, Irbid, Jordan
Correspondence
Iman A. Basheti, Faculty of Pharmacy, Applied
Science Private University, Amman, Jordan.
Email: dr_iman@asu.edu.jo
J Eval Clin Pract. 2019;1–10.
Accepted: 22 May 2019
| Daoud Al‐Badriyeh PhD2 | Farah M. Al‐Ali BSc1 |
| Iman A. Basheti PhD1
Abstract
Rationale, aims, and objectives: Clinical pharmacy services are vital in the preven-
tion of adverse drug events (ADEs) in clinical practice, extending beyond the hospital
to chronic disease management in outpatient settings. This study sought to evaluate
the cost benefit of a clinical pharmacy intervention in resolving treatment‐related
problems (TRPs) among hospital outpatients with chronic diseases.
Methods: From the hospital system perspective, the cost‐benefit analysis was
based on a randomized clinical trial in the general outpatients of the major hospital
in Jordan. Eligible patients were randomly assigned to either an intervention or a con-
trol group. TRPs were identified in both study groups, but interventions were deliv-
ered only to the intervention group via a home medication management review
(HMMR) by a clinical pharmacist. A follow‐up in both groups took place 3 months
after recruitment. The total economic benefit was the sum of (a) cost savings due
to intervention and (b) cost avoidance associated with preventable ADEs. The primary
outcome measures were the net benefit and benefit‐to‐cost ratio with the clinical
pharmacist‐based HMMR.
Results: In both groups, 158 TRPs were identified, and 79 interventions were pro-
vided in the study group. The monthly cost of intervention was JD764 (US $1078),
and the total monthly benefit was JD4570 (US $6444), leading to a benefit‐to‐cost
ratio of 5.98 and an annual net benefit of JD45 669 (US $64 393). Sensitivity analy-
ses confirmed the robustness of results.
Conclusion: The RCT‐based cost‐benefit evaluation provided evidence‐based
insight into the economic benefit of a clinical pharmacist‐provided HMMR for
preventing ADEs in the general chronic diseases outpatients. This intervention
method against the TRPs among outpatients is cost beneficial and offers substantial
cost savings to the health care hospital payer in Jordan.
K E Y W OR D S
clinical pharmacy, cost avoidance, cost saving, Jordan, outpatient, treatment‐related problems
wileyonlinelibrary.com/journal/jep © 2019 John Wiley & Sons, Ltd. 1
2 AL‐QUDAH
1 | I N T RO D U CT I O N
Treatment‐related problems (TRPs) have a substantial effect on
1-3
human health and economic status. In the United States, for exam-
ple, the costs associated with adverse drug events (ADEs) doubled
between 1995 and 2000, from US $76.6 billion to more than US
4,5
$177.4 billion. The early identification of TRPs and preventable
ADEs is a current area of focus for many health care systems that
are in the pursuit of improving patient safety and reducing health care
6
expenditures.
It is well documented that clinical pharmacists across the globe
are key members of the health care provider team and play an
important role in improving safety while minimizing economic
7-10
burdens in inpatient settings. While, through the medication
management review (MMR) and the home medication management
review (HMMR), countries such as Australia have realized that 81%
of identified TRPs are resolved, well managed, or regressed in outpa-
tients' settings,11,12 with other countries such as the United States
and United Kingdom also applying the programmes,13 the studies
reporting the economic impact of clinical pharmacists in the general
outpatient clinics are lacking in literature. Research studies have
proposed that MMR and HMMR services can also be effective in
3,14
Jordan. To ensure sustainability, however, it is necessary for
health care systems to demonstrate the cost‐effectiveness of their
services.14,15
The aim of this study is to evaluate the economical benefit of a
clinical pharmacist intervention as part of an HMMR service for
resolving TRPs in the general chronic diseases outpatients of the hos-
pital. The scope of this is limited to cost consequences of TRPs and
interventions addressing them and does not include humanistic and
clinical outcomes of interventions.
2 | METHODS
Methods are consistent with the international guidelines for preparing
economic evaluations16 and with similar cost‐benefit studies in the
literature.8,10,17,18 A cost‐benefit analysis from the perspective of
the hospital was conducted, based on a prospective single‐blind ran-
domized control trial (RCT) for evaluating the economic impact of a
clinical pharmacist's identifying and managing of TRPs as part of an
HMMR (ClinicalTrials.gov Identifier: NCT03803033). Chronic diseases
patients were initially assigned either to 3 months of routine care ser-
vice (control group) or to an experimental clinical pharmacy‐based
HMMR service (intervention group) in the outpatient clinic setting of
the Jordan University Hospital in Amman, Jordan, the main health care
provider in Jordan, with 600 beds and serving over 500 000 outpa-
tients annually.19 To emphasize, the HMMR service in this study is
experimental. There are currently no established or accredited HMMR
services in Jordan. The follow‐up study duration was based on being
consistent with the follow‐up time used by the physicians in the hos-
pital to re‐see their patients (ie, 3 mo).
ET AL.
2.1 | Ethical approval
All procedures involving human participants were in accordance with
the ethical standards of the Deanship of Academic Research at the
University of Jordan and from the Institutional Review Board at
Jordan University Hospital (approval number IRB/2014/50).
2.2 | Patients
Consecutive patients visiting the outpatient clinic at Jordan University
Hospital were eligible for study inclusion based on the following
criteria:
• 18 years old or older;
• with at least one chronic disease, defined as a condition requiring
prolonged management for a minimum of 3 months;
• living in Jordan for the past year;
• intention to remain in Jordan for the 3‐month study duration;
• met at least one of the following criteria:
‐. Taking five or more medications, taking 12 or more doses a
day, discharged from the hospital within the past 4 weeks,
exposed to significant changes in medication regimens within
the past 3 months, demonstrating symptoms of potential
adverse drug reactions, or demonstrating a poor therapeutic
response to medication therapy. A significant change to med-
ication regimen was defined as discontinuing a medication,
starting new medications, or stepping up because of actual
or potential therapy failure or guideline recommendations. A
poor therapeutic response was defined as persistence of
symptoms despite treatment.
Medications used by the patients in the trial were generics given
that patients receive their medications from the hospital pharmacy.
Adherence to medications was assessed using the patient interview
method via a questionnaire, which was developed and validated by
AbuRuz et al.2 The questionnaire is composed of five items including
questions of “how often during the last month patients forgot to take
their medication,” “skipped their medication,” “stopped their medica-
tion when they felt better,” “stopped their medication when they felt
worse,” or “stopped their medication when they experienced a side
effect.” Informed consent was obtained from all individual participants
included in the study.
2.3 | Study protocol
A baseline interview was conducted with patients at their homes to
assess their use of treatment and to collect all relevant information
needed to identify TRPs: patient's demographic data, current diseases,
current drugs, history of previous diseases and drugs, side effects,
allergy, lifestyle, and self‐care adherence.
AL‐QUDAH ET AL.
• If patients rejected the home visit, assessments were completed at
the clinic.
• Home visits did not exceed 1 hour, which is the usual duration in
similar studies.3,20,21
• Medical files and laboratory data were checked through the outpa-
tient clinic to collect any relevant information regarding patients'
health status.
• A clinical pharmacist aimed to provide patient care through the
management of TRPs in an intervention group but not in the con-
trol group, vide infra. Patients did not know which study group they
were assigned to.
• In both study groups, the clinical pharmacist performed a follow‐up
interview with patients 3 months after the initial interview, during a
regular follow‐up visit to their physician at the hospital. Assess-
ments in the follow‐up interview, regardless of the study group,
involved changes in treatment and number of TRPs.
TRPs that actually or potentially affected clinical outcomes for each
patient were identified and classified via the use of the validated clas-
sification system of AbuRuz et al, including in outpatient settings in
Jordan,2,3,22 as a standardized pharmacotherapy recommendation
form in the study.
As an integral part of the controlled study, patients were informed
that they can only receive counselling or health care services from
the study hospital. External non‐hospital or community resources of
services were not allowed in the study and resulted in patient
exclusion.
2.3.1 | Intervention group
Upon TRP identification at baseline, the clinical pharmacist generated
a written report of findings and recommendations, which was deliv-
ered directly to the patient's physician in a sealed envelope. Examples
of recommendations included patient education when a potential
drug‐drug interaction between ferrous gluconate and levothyroxine
(category D) was found, and dosage adjustment in a type 2 diabetes
mellitus patient discharged on Glimepiride 2 mg two tablets twice
daily; this drug should have been administered once (8 mg once daily).
• Physicians were directly identified based on recruited patients'
reported information in records or personally selected by the
patient if patient had more than one physician.
• All interventional recommendations to physicians were referenced
by relevant, up‐to‐date guidelines. The recommendations had to
be accepted by the physician before they were returned to the
pharmacist, allowing the pharmacist to convey the approved
changes to patients. If recommendations were not approved by
the physician, they were not implemented. Patients were asked
to refer back to their physicians if they required confirmation of
any changes in treatment. Physicians maintained the blinding of
patients with regard to whether changes were based on recom-
mendations by the pharmacist.
3
• Also, patient education on the importance of adherence to their
medication regime was delivered to patients. The delivered infor-
mation did not contradict what the physicians had said or instruc-
tions given to patients. For each patient, all of the provided
counselling was documented. Education was provided as per the
theory explained in the HMMR service delivered in Australia11
(the HMMR service still does not formally exist in Jordan).
All patients knew that they would be visited by a clinical pharmacist
and that they might be exposed to changes in treatment in either
study group. However, they did not know whether medication
changes were based on recommendations by the pharmacist or were
part of usual care. They also did not know about the education com-
ponent of the intervention.
2.3.2 | Control group
The objective of the control group was to identify changes in treat-
ment and associated costs that take place in patients as part of the
usual practice, regardless of the clinical pharmacist intervention.
• As with the intervention group, patients in the control group were
interviewed at baseline in their homes to assess their use of medi-
cations and identify TRPs.
• However, no intervention based on communicating findings and
recommendations to patients' physicians or patient education was
performed.
• As per protocol, a follow‐up visit took place with control group
patients 3 months after the initial visit. Any changes in treatment
and the number of TRPs identified at follow‐up were due to usual
practice and not recommendations by the pharmacist.
• Patients in the control group with life‐threatening TRPs (extremely
detrimental on health status if no action is taken) were excluded
from the study due to ethical considerations, and patients' physi-
cians were contacted immediately.
2.4 | Data analysis
Data were tabulated and analysed using the Statistical Package for
Social Sciences (SPSS) software program (v.20). Categorical data were
expressed as proportions (%) and the continuous data as mean ± SD.
Chi‐squared tests and independent sample t tests were used to assess
the differences between the two groups at baseline.
2.5 | Sample size and randomization
No prior relevant studies exist that clearly report a change in ADE with
MMR services. The sample size calculation was based on the relative
improvement of the TRP with the MMR service. Based on previously
published work,23 a study population of 131 patients was identified
as necessary to detect a significant change in TRP of 1‐point
4 AL‐QUDAH ET AL.

difference, with a significance level of 5%, and power of 80%, and with TABLE 1 Definitions of reduced therapy costs in cost savings
a standard deviation of 2.92. Recruited patients were randomly calculations
assigned to study groups according to a predetermined randomization
Reduced cost of therapy The reduced cost of therapy with the
list developed via a computer‐based randomization generator program with the intervention intervention was the cost of before‐
(www.randomization.com). intervention patient therapy minus the
cost of after‐intervention patient
therapy. The cost of the before‐
2.6 | Economic evaluation intervention patient therapy was based
on the assumed duration of the full
The total economic benefit of the intervention was calculated as the course of the original therapy without
sum of the cost savings and the cost avoidance associated with the the intervention, while the cost of the
after‐intervention patient therapy was
intervention.
based on the actual original therapy
duration until intervention, added to the
2.6.1 | Cost savings cost of the alternative therapy (therapy
after the change) based on the duration
Cost savings based on the intervention were the reduced cost of ther- of its full course.
The cost of any drug therapy was
apy associated with treatment changes due to the intervention. Cost
calculated as the cost of drug therapy
savings were calculated as the reduced cost of therapy in the interven- per unit * frequency per day * duration
tion arm minus the reduced cost of therapy in the control arm. Detailed of therapy.
definitions of reduced therapy costs are summarized in Table 1. Reduced cost of therapy If changes in treatment took place in the
with the control arm control arm as a usual part of care, the
cost of the reduced therapy in the
2.6.2 | Cost avoidance control arm was the cost of drug
therapy at baseline in the control group
Cost avoidance was the cost avoided by eliminating the occurrence of minus the cost of patient therapy at
ADEs as a consequence of the pharmacist interventions.24-26 follow‐up. The cost of patient therapy at
baseline in the control arm was based on
the assumed duration of the full course
• Based on the method of Nesbit et al,24 utilizing an expert panel of of the original therapy without the
four specialist clinical pharmacists, the likelihood of an ADE in the intervention, while the cost of the
absence of the intervention was set as illustrated in Table 2. The therapy at follow‐up was based on the
actual original therapy duration until
specialist pharmacists were specialized in respiratory, cardiology,
changed, added to the cost of the
endocrinology, and nephrology medicine, with a minimum of alternative therapy (therapy after
3 years of experience in the clinical field. change) based on the duration of its full
course.
• The cost of an ADE was calculated on the assumption that an ADE
The cost of any drug therapy was
in an outpatient will lead to a single admission to an internal med- calculated as the cost of drug therapy
icine ward via an emergency department visit. per unit * frequency per day * duration of
therapy.
• Only for the intervention with the potential to prevent an ADE,
cost avoidance was calculated by multiplying the probability of an
ADE in the absence of the intervention (calculated via the Nesbit
method) by the cost of an ADE. The overall cost avoidance was
the sum of avoided cost with all interventions. up to 2 to 3 hours are needed to identify TRPs, write the
physician letter, contact the physician, and implement the
recommendations.
2.6.3 | Cost‐benefit analysis
• The cost of the intervention was calculated as the salary of a regu-

As discussed above, the net benefit was calculated as cost sav- lar outpatient pharmacist plus any increased cost of therapy in the

ing plus cost avoidance. It was assumed that no intervention would intervention arm, measured as −ve cost saving. Here, the increased

increase the probability of a preventable ADE. cost of therapy with intervention is referred to as “−ve cost saving”
in contrast to +ve cost saving, which indicates the reduction in the

• Calculating monthly cost savings and avoidance was based on a cost of therapy because of treatment changes in the intervention

capacity on the part of the pharmacist to perform three HMMRs group, as discussed above.

in a day, for an underestimated average of 21 working days a • The benefit‐to‐cost ratio was the sum of cost savings and cost
month, summing to a total of 63 patients per month. The three avoidance divided by cost of the intervention. The net benefit of
HMMRs per day are based on the expectation that a single home the intervention was the sum of cost savings and cost avoidance
visit will last a maximum of 1 hour, as discussed earlier, and that minus cost of the intervention.
AL‐QUDAH ET AL.
TABLE 2 Nesbit method for calculating cost avoidance
Probability of
ADE Probability
Occurrence Score Example
Zero 0 Information requested
Very low .01 For problem orders such as clarifications,
missing information, or missing
strengths. For example, pharmacist
suggests changing patient medication
from esomeprazole to omeprazole
exclusively for economic reasons
Low .1 For preventing a potentially significant
reaction, eg, 2× to 4× normal dose,
ineffective dose to produce therapeutic
effect, or potential for therapeutic
failure/toxicity due to incorrect
schedule/route, duplicated therapy. For
example, patient takes metformin twice
daily, while the recommended dose
would be three times daily.
Medium .4 For preventing a potentially serious
reaction, eg, allergy to an ordered drug,
missing allergy information, 4× to 10×
normal dose, no adjustment for renal or
hepatic failure. For example, allopurinol
dose is not reduced despite patient
demonstrating renal impairment.
High .6 For preventing a potentially fatal or severe
reaction, eg, 10× normal dose, narrow
therapeutic index, life‐threatening
reaction. For example, patient prescribed
warfarin while currently taking green
vegetables in large amounts without
continuous warfarin dose and INR
monitoring.
Only direct medical costs were considered in calculations. Drug
costs were based on their generic prices. All costs were adjusted
based on the Jordanian consumer price index27 to the financial year
2018/2019.
2.6.4 | Sensitivity analysis
One‐way sensitivity analysis
The values of individual uncertain input variables were substituted
with new values of the input variables to analyse the effect on the
study conclusions. Targeted uncertain inputs included the clinical
pharmacist salary and the cost and probability of the internal medicine
admission consequent to an ADE.
Multivariate uncertainty analysis
Multivariate uncertainty analysis was performed by targeting several
underlying uncertain probabilistic inputs in the economic model before
rerunning the model several times. In this study, probabilistic inputs of
interest are the probabilities of ADEs that were set by the expert
5
panel. These values were each associated with a ±50% uncertainty
range.
Both one‐way and multivariate probabilistic analyses were con-
ducted via Monte Carlo simulation, using @Risk‐5.7 (Palisade Corpora-
tion, New York). In this method, the value of any targeted input in the
economic model is “randomly” sampled from the uncertainty range
assigned to the input. This random sampling of the input value occurs
in every simulation of the model, which can amount to thousands of
iterations. In the current study, a triangular‐type distribution of ran-
dom input selection from the uncertainty range was used, based on
1000 simulations.
Scenario analysis
The sensitivity analysis evaluated the outcome of the study with the
alternative scenario that the Nesbit method was also used to estimate
the probability and cost of preventable ADEs in the control arm due to
changes in therapy (ie, reduced TRPs, if any) based on usual care by
the follow‐up interviews. This reduced cost of ADEs in usual practice
was then used as the baseline against which cost avoidance in the
intervention group was calculated.
3 | RESULTS
Of 112 eligible patients initially recruited into the study, 97 patients
(48 in the intervention group and 49 in the control group) eventually
completed the study follow‐up period and were included into the anal-
ysis. No interventions were collected for the drop‐out patients, and
hence, these were not included in the analysis. In 25.8% of the popu-
lation, patients refused home visits and were assessed at the clinic.
There were no significant differences between the study groups
regarding demographic parameters, except for a higher age and prev-
alence of moderate caffeine intake in the intervention group (Table 3).
There were also not life‐threatening TRPs identified in any study
patient. TRPs relevant to chronic diseases are summarized in Table 4.
No patients reported the use of external non‐hospital counselling or
health care services in the study.
3.1 | Cost savings
After conducting the home visits, 79 proposed interventions were
provided for TRPs by the clinical pharmacist in the intervention group;
with 67 of these actually implemented by follow‐up. Of the latter, the
interventions associated with cost savings were for five and two
TRPs in the categories of “unnecessary drug therapy” and “efficacy,”
respectively. Interventions associated with increased cost of therapy
(−ve cost saving) were for three and two TRPs and one TRP in the cat-
egories of “untreated condition,” “efficacy,” and “safety,” respectively.
There were also 79 TRPs in the control group, with eight of
these resolving via usual practice upon follow‐up. Of these resolving
TRPs, only one was associated with a reduced cost under the category
of safety, and the remaining resolutions were categorized under
“inappropriate knowledge.” Table 5 summarizes the cost savings
6 AL‐QUDAH ET AL.

TABLE 3 Demographic characteristics of the study sample at baseline

Parameter Total Population Intervention Group Control Group P Value

Total no. of patients (%) 97 48 (49.5) 49 (50.5) ‐

Age (year); mean (SD*) 60.73 (10.90) 63.13 (7.99) 58.39 (12.8) .032a
Gender
Male N** (%) 29 (30) 17 (35.4) 12 (24.5) .240b
Female N (%) 68 (70) 31 (64.6) 37 (75.5)
Height (cm); mean (SD)* 165.23 (8.63) 166.23 (9.32) 63.94 (7.72) .191a
Weight (kg); mean (SD) 78.22 (17.47) 7 8.55 (19.93) 77.65 (15.06) .803a
Body mass category, N (%)
Under weight 0 (0) 0 (0) 0 (0) .582b
Normal 33 (34.0) 19 (39.6) 14 (28.6)
Overweight 31 (32.0) 16 (33.3) 15 (30.6)
Obese 19 (19.6) 5 (10.4) 14 (28.6)
Morbid obesity 14 (14.4) 8 (16.7) 6 (12.2)
Number of chronic medical condition per patient mean (SD) 3.97 (1.56) 4.23 (1.653) 3.71 (1.43) .104a
Number of medications per patient mean (SD) 8.46 (3.01) 8.90 (3.06) 8.04 (2.94) .164a
Most frequent medical conditions, N (%)
Hypertension 76 (78.4) 39 (81.3) 37 (75.5) .493b
Asthma 60 (60.8) 27 (56.3) 32 (65.3) .361b
Diabetes 51 (52.6) 28 (58.3) 23 (46.9) .264b
Hyperlipidaemia 25 (25.8) 13 (27.1) 12 (24.5) .770b
Most frequent drug classes, N (%)
Anti‐asthmatic 2.75 (0.96) 2.74 (0.94) 2.75 (0.98) .971a
Anti‐hypertensive 2.13 (0.84) 2.21 (0.86) 2.05 (0.82) .436a
Anti‐diabetic 1.43 (0.58) 1.41 (0.57) 1.45 (0.6) .780a
Anti‐hyperlipidaemic 1.2 (0.41) 1.15 (0.38) 1.25 (0.45) .567a
Marital status, N (%)
Married 87 (89.7) 44 (91.7) 43 (87.8) .515b
Single 7 (7.2) 2 (4.2) 5 (10.2)
Widow 1 (1.0) 1 (2.1) 0 (0.0)
Divorced 2 (2.1) 1 (2.1) 1 (2.0)
Insurance, N (%)
No 0 (0.0) 0 (0.0) 0 (0.0) ‐
Yes 97 (100.0) 48 (100.0) 49 (100.0)
Diet, N (%)
Regular 68 (70.1) 33 (68.8) 35 (71.4) .773b
Healthy 29 (29.9) 15 (31.2) 14 (28.6)
OTC and complementary medicines***
Yes 29 (29.9) 14 (29.2) 15 (30.1) .876b
No 68 (70.1) 34 (70.8) 34 (69.4)
Exercise, N (%)
No 65 (67.0) 34 (40.8) 31 (63.3) .428b
Regular 32 (33.0) 14 (29.2) 18 (36.7)
Smoking, N (%)
None 75 (77.3) 35 (72.9) 40 (81.6)
Former 12 (12.4) 8 (16.7) 4 (8.2) .545b
Heavy 7 (7.2) 3 (6.2) 4 (8.2)

*SD = Standard Deviation.

**N = Number.
***OTC = Over the counter.
a
By Independent‐sample t‐test.
b
By Chi‐square test.
AL‐QUDAH ET AL. 7

TABLE 4 Treatment‐related problems at baseline 3.3 | Cost‐benefit analysis

Number of TRPs Related to
Medical Conditions (%) Most Frequent TRPs, N (%), Within In Jordan, the minimum monthly salary of a pharmacist is JD300 (US
(Total TRPs = 158) Disease Category $423) and that of an outpatient clinical pharmacist is JD500 (US

Diabetes mellitus, 29 (18.4) Lack of knowledge about 9 (31.0)

Hyperlipidaemia, 29 (18.6)
Hypertension, 24 (15.2)
Asthma, 15 (9.5)
$705).29 In this study, however, the average monthly salary was
nonpharmacological overestimated at JD750 (US $1058). Taking into consideration this
treatment therapy or self‐ and the monthly −ve cost saving in the intervention group (Table 5),
care advice the total intervention cost is calculated as JD764.3 (US $1077.6) per
Lack of adherence to 7 (24.1)
month. The final cost‐benefit outcomes are reported in Table 6.
medication
A need for additional or more 4 (13.8)
frequent monitoring
3.4 | Sensitivity analyses
A need for additional or more 15 (51.7)
frequent monitoring
Input uncertainties and their sensitivity analysis distributions are
Lack of adherence to 4 (13.8)
medication shown in Table 7. The economic model was insensitive to uncertainty
Safety interaction issues 3 (10.3) in the pharmacist salary, varying the net benefit within the range of
Efficacy dosage regimen issues 3 (10.3) JD1850 to JD6606 (US $2609‐$9314), with an average of JD3984
Lack of knowledge about 11(45.8) (±SD 857) (US $5617 ± SD 1208) per month. The model was also
nonpharmacological insensitive to the rate and cost of admission due to ADEs. The study
treatment therapy or self‐
conclusion only changed when the average cost of admission fell
care advice
Lack of adherence to 4 (16.7) below JD9.7 (US $13.7), equivalent to less than 1.9% of those with
medication ADEs being admitted to the hospital, which is very unlikely. The inter-
More effective drug is 2 (8.3) vention's net benefit probability curve with the cost of admission is
available/recommended
shown in Figure 1.
Safety interaction issues 2 (8.3)
Based on the multivariate uncertainty analysis, a net benefit prob-
Lack of knowledge about 8 (53.3)
nonpharmacological
ability analysis demonstrated a 100% probability that the pharmacist
treatment therapy or self‐ intervention is associated with a +ve net benefit, in the range
care advice JD1913 to JD6116 (US $2697‐$8623), with an average of JD3988
Allergic reaction or 3 (20.0) (±SD 828) (US $5623 ± SD 1167) per month. Based on a tornado anal-
undesirable effects
ysis, the TRPs most affecting the study outcome were those with prob-
Lack of adherence to 3 (20.0)
medication ability scores for preventable ADEs of .1, followed by .4, and then .01.

Pre‐DM, 10 (6.3) Untreated condition 5 (50.0) Based on the scenario analysis that accounted for resolving TRPs under
the usual course of care in the control group, the probability scores for
preventable ADEs were estimated by the expert panel as .1 and .6,
associated with resolved TRPs in both study groups. Accounting for with six and two TRPs, respectively, in the “inappropriate knowledge”
the cost outcomes in the control group, the overall cost savings asso- and “safety” categories. The consequential total reduced cost of
ciated with the clinical pharmacist intervention were calculated to be preventable ADEs in the control group is JD1272.8 (US $1794.6) per
JD15.12 (US $21.3) per month. month. The adjusted final cost avoidance of the study intervention is,
therefore, JD3282.1 (US $4627.8) per month (ie, JD4554.9 minus
JD1272.8 per month), translating into a monthly net benefit of
JD2532.9 (US $3571.4) and a benefit‐to‐cost ratio of 4.31.
3.2 | Cost avoidance

The probability of preventable ADEs with interventions was .4 for two
interventions under the “unnecessary drug therapy” TPR category; .1
for 54 interventions under the categories of “unnecessary drug
therapy,” “untreated condition,” “efficacy,” “safety,” “inappropriate
knowledge,” “inappropriate adherence,” and “miscellaneous”; and .01
for 11 interventions under the “miscellaneous” category. Based on
a reported average internal medicine admission cost of JD522.5
(US $736.7) and a cost of JD 14.1 (US $19.9) per emergency visit
(a total of JD536.6 [US $756.6] per case of admission via emer-
28
gency), the overall cost avoidance in the intervention arm was calcu-
lated to be JD4554.9 (US $6422.4) per month.
4 | DISCUSSION
This is the first study to reveal the economic impact of managing TRPs
by a pharmacist intervention in Jordan. This is also the first interven-
tional cost‐benefit evaluation of clinical pharmacy services in the gen-
eral outpatient setting of a hospital. The control group prevents an
overestimation of impact because of counting prescription modifica-
tions by physician's judgement as pharmacist interventions.
The clinical pharmacist produced 79 interventions in 48 patients.
Extrapolating to a monthly capacity of 63 patients per pharmacist,
the interventions result in a monthly benefit of JD3806 (US $5366),
8 AL‐QUDAH ET AL.

TABLE 5 Cost savings and cost avoidance as per intervention category

“Cost Saving” in “Cost Saving” in “Cost Avoidance” in Intervention

Intervention Group, Control Group, Group, JD/month
Intervention Category JD/mo JD/mo

Unnecessary drug therapy 13.91 ‐c 794.04

Untreated condition −5.81 a
‐ 288.74
Efficacy 2.91 ‐ 866.23
−2.42a
Safety −6.05a 1.70 505.29
Inappropriate knowledge 0.00 0.00 866.23
Inappropriate adherence 0.00 ‐ 794.04
Miscellaneous 0.00 ‐ 440.34
Total 16.82b (US $23.72) 1.70 (US $2.40) 4554.90 (US $6422.41)
a
−ve cost saving; increased cost due interventions (total of JD14.29), which was added to the overall cost of calculated clinical pharmacist intervention.
b
Only the +ve cost saving with intervention.
c
No therapy change in control group.

TABLE 6 Cost‐benefit analysis

Outcome Value, JD (US$)

Cost saving per month 15.12 (21.32)

Cost avoidance per month 4,554.90 (6,422.41)
Cost of intervention per month 764.29 (1,077.65)
Benefit‐to‐cost ratio 5.98
Net benefit per month 3805.73 (5366.08)
Net benefit per year 45 668.75 (64 392.94)

TABLE 7 Input variables and uncertainty distributions used in

Monte Carlo simulation

Input Variables Uncertainty Distribution FIGURE 1 The intervention's net benefit probability curve with the
cost of admission
One‐way analyses
Salary of pharmacist Triangular distribution
(JD500, JD750, and JD1500)a Ideally, the exact economic benefit of resolving TRPs is based on
Cost of admission due to Triangular distribution the difference in real medical costs associated with the TRPs in both
adverse drug events (ADEs) (JD0, JD522.5, JD522.5)a study groups. This, however, is infeasible as targeting the economic
Multivariate analysis value of a TRP requires following up the problem through the end of
Very low likelihood for ADEs Triangular distribution all relevant consequences, and these (and their durations) are very dif-
(.005, .01, .015) ficult to uniformly identify; such method is further complicated by the
Low likelihood for ADEs Triangular distribution (.05, .1, .15) fact that different TRPs occur in the study groups to different extents
Medium likelihood for ADEs Triangular distribution and that the cost encountered will need to be compared for the same
(.2, .4, .6) TRPs in both arms. Furthermore, it is ethically challenging to prospec-
a
JD1 = US $1.41. tively ignore TRPs in the control group until final consequences. In
addition, a retrospective survey cannot be carried out because, as
discussed earlier, NMMR services do not yet exist in Jordan. The
with net annual economic benefit of JD45 669 (US $64 393). The Nesbit method arguably provides the best‐published estimate of the
benefit‐to‐cost ratio of the service is 6:1; that is, for every one JD cost of an ADE.8,10,17,18,24,30 Regardless of the TRPs and how they
(US $1.41) invested, a JD5.98 (US $8.43) of benefit is generated. vary in severity and duration, they are uniformly compared based on
In the current study, with further specialized training and utilizing a the value of the ADEs associated with them. The majority of estimated
clinical pharmacist who is part of the care team at the clinic (familiar probability scores were low, which is consistent with most relevant
with patients' history), an even higher economic benefit is anticipated. studies adopting the same methods.9,17,24,31,32
AL‐QUDAH ET AL.
The results of the current study are supported by the economic
benefits of community‐based pharmacy interventions demonstrated
in previous studies. In a US‐based retrospective study by Branham
33
et al, the cost avoidance generated from 634 interventions via
pharmacist‐provided medication therapy management of common dis-
ease states encountered in community pharmacy practice totalled US
$494 000 over the course of 4 months. In another example, from
Brazil, Borges et al reported a statistically significant reduction in the
antidiabetics prescription cost among patients with poorly controlled
diabetes (due to, among other reasons, poor drug regimen compliance)
based on a cost analysis of a prospective experimental pharmaceutical
care programme that was provided to outpatients regularly seen at the
34
endocrinology unit.
The entire salary of a clinical pharmacist was used rather than a
proportion of salary based on the duration spent performing interven-
tions, which underestimates the calculated benefit‐to‐cost ratio,17,24
and despite overestimating the monthly salary of the pharmacist, the
cost of intervention was outweighed by its benefits. The study results
were not sensitive to a threefold increase in the basic salary of the
pharmacist.
The study is not without limitations. Data on how much a prevent-
able ADE accurately costs in Jordan were not available. Also, some
intervention costs such as the cost of transportation and the time
spent by physicians on reviewing pharmacist‐suggested interventions
have not been considered. Besides, as already discussed, cost avoid-
ance calculations were based on estimated ADE probabilities and not
real observed economic data. Sensitivity analyses, however, demon-
strated study robustness against the ADE cost, intervention cost,
and potential uncertainty in probability scores. Other study limitations
include the short follow‐up duration and single pharmacist‐based
interventions. The targeted sample size was not achieved in this
RCT. Based on the size of the observed differences and the results
of the sensitivity analyses, however, there is no reason to assume that
the study conclusion would be any different if the sample size was
achieved. In any case, it is important to note that, unlike clinical
research, the current economic evaluation is not concerned in terms
of hypothesis testing but it is about making cost estimation. In this
case, even if an economic evaluation is underpowered, it still provides
important information that may guide decision making.35
5 | W H A T I S N E W A N D C O N C LU S I O N
The first‐time RCT‐based research provided a cost‐benefit evaluation
of a clinical pharmacist‐provided HMMR service for general chronic
diseases outpatients in Jordan. Taking into consideration the setting,
methods, and assumptions in the study, the intervention method
considerably reduced the TRPs costs among the outpatients, providing
relevant evidence‐based insight into the potential benefits of having
a clinical pharmacist‐based medication review programme for
preventing ADEs in the general outpatients of hospital clinics in Jor-
dan and in the Middle East.
9
The current RCT remains a proof‐of‐concept study, and accord-
ingly, the results of this should be validated in a larger trial, with longer
follow‐up periods and additional intervention pharmacists.
FUNDING
No funding was received in support of this study.
CONFLIC T OF INT E RE ST
All authors declare that they have no conflict of interest.
CONSE NT T O PAR TIC IP AT E
Informed consent was obtained from all individual participants
included in the study.
ORCID
Iman A. Basheti https://orcid.org/0000-0002-8460-1158
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How to cite this article: Al‐Qudah RA, Al‐Badriyeh D, Al‐Ali
FM, Altawalbeh SM, Basheti IA. Cost‐benefit analysis of clini-
cal pharmacist intervention in preventing adverse drug events
in the general chronic diseases outpatients. J Eval Clin Pract.
2019;1–10. https://doi.org/10.1111/jep.13209