Adherence to risk minimization measures for alemtuzumab use in multiple sclerosis: a drug utilization study in four European countries

Abstract

Background:

The European Union Summary of Product Characteristics (EU SmPC) for alemtuzumab in multiple sclerosis (MS) was revised in January 2020 under an Article 20 EU-pharmacovigilance procedure to include a revised indication, additional contraindications, and new monitoring requirements.

Objectives:

To evaluate adherence to the revised SmPC for alemtuzumab across four European countries.

Design:

Descriptive cohort study using secondary healthcare data recorded between January 2020 (date of alemtuzumab EU SmPC revision) and the latest database update in each data source (ranging from March 2022 to January 2024).

Methods:

Data are used from: the Czech Republic MS registry (ReMuS), a cohort study of patients treated with alemtuzumab in Germany (long-Term study foR obsErvAtion of Treatment with alemtuzumab in active relapsing-remitting MS (TREAT-MS)), chart review data from three United Kingdom (UK) centers, and administrative healthcare data from the Belgian Social Security database (L’Agence InterMutualiste—Het InterMutualistisch Agentschap (AIM-IMA)). Adherence to revised indications, contraindications, and safety monitoring was summarized descriptively.

Results:

Data from 2046 people with MS treated with at least one course of alemtuzumab were assessed. Of 155 patients evaluable for adherence to the indication, 66.7% met the revised indication in ReMuS (n = 54/81; increasing to 75.3% after manual checks), 87.5% in TREAT-MS (n = 7/8), 66.7% in UK centers (n = 26/39; increasing to 79.5% in sensitivity analyses), and 100.0% in AIM-IMA (n = 22). Of 549 courses evaluated, 77.5%–97.8% were not contraindicated. While adherence to safety monitoring tests varied, heart rate and blood pressure were recorded for ⩾77.5% of courses before treatment and ⩾83.1% of courses during treatment. Platelet testing was conducted for 29.1%–51.4% of courses during treatment. Adherence to long-term (up to month 48) post-infusion monitoring was approximately 50%.

Conclusion:

Alemtuzumab was prescribed in accordance with the indication in 67%–88% of patients included in this study. It was prescribed in accordance with the listed contraindications in 78%–98% of courses included in the study. Adherence to the monitoring schedule is adequate to maintain the benefit–risk profile of alemtuzumab.

Trial registration:

This study was registered in the Heads of Medicines Agency European Medicines Agency (EMA) catalog (EUPAS42540). Results are available on the EMA website: https://catalogues.ema.europa.eu/node/3602/resources.

Keywords

alemtuzumab disease-modifying treatment drug utilization relapsing-remitting multiple sclerosis risk minimization measures

Introduction

Alemtuzumab (LEMTRADA^®) is a highly efficacious disease-modifying treatment (DMT) for active relapsing-remitting multiple sclerosis (RRMS). Treatment with two intravenous infusion courses of alemtuzumab (course 1: 12 mg per day for 5 days; course 2 (12 months post course 1): 12 mg per day for 3 days) significantly reduces relapse rates and accumulated disability for those with active RRMS.^1–5

Following the emergence of newly identified safety signals, including infusion-associated cardiovascular events and autoimmune conditions, the European Medicines Agency (EMA) initiated an Article 20 pharmacovigilance procedure for alemtuzumab in 2019.⁶ This resulted in revisions to the indications, contraindications, and safety monitoring recommendations included in the alemtuzumab European Union Summary of Product Characteristics (EU SmPC; revised January 16, 2020). The newly revised monitoring recommendations included cardiac function before and during infusion, serum transaminase measurements before infusion and then monthly for at least 48 months post treatment, and blood platelet count immediately after infusion on Days 3 and 5 for the first course and on Day 3 for any subsequent course. This was in addition to the existing monitoring requirements: full blood count (FBC), serum creatinine, urinalysis, and thyroid function before infusion, and then monthly (or every 3 months for thyroid function) for 48 months post-treatment.⁷

Given that alemtuzumab is associated with serious adverse events, effective risk minimization measures (RMMs) are essential to maintain a positive benefit–risk balance. A drug utilization study (DUS) was therefore conducted to assess the implementation of RMMs (i.e., revised indications, contraindications, and monitoring requirements) in routine clinical practice. This DUS used secondary healthcare data from the Czech Republic, Germany, the United Kingdom (UK), and Belgium.

Methods

Study design

This was a descriptive cohort study of people with MS (pwMS) who received alemtuzumab after February 16, 2016. The results are based on secondary use of healthcare data from four different European countries that were recorded between January 16, 2020 (date of alemtuzumab EU SmPC revision) and the latest database update in each data source (latest January 2024).

Study objectives

The primary objectives of this study were to assess: (1a) Adherence to the revised indication among pwMS who had their first alemtuzumab course after implementation of the revised EU SmPC (January 16, 2020); (1b) Adherence to the revised contraindications among first or continuing use alemtuzumab courses after the implementation of the revised EU SmPC. The secondary objectives of the study were to measure: (2a) Adherence to the newly required cardiac monitoring and blood tests before and during treatment at the treatment course-level; (2b) Adherence to long-term monitoring tests post alemtuzumab treatment at the patient level.

Patient population

The eligibility criteria were selected to include pwMS who had received at least one infusion of alemtuzumab, either as a new or continuing treatment course on or after January 16, 2020. For long-term monitoring (objective 2b), the population additionally included those who had received a course on or after February 16, 2016, and had completed at least part of the 48-month-long follow-up after January 16, 2020. As shown in Figure 1, three cohorts were created from this population. Cohort 1 was used to assess indication (objective 1a); Cohort 2 was used to evaluate contraindications and monitoring before and during treatment (objectives 1b and 2a); Cohort 3 was used to assess long-term monitoring post treatment (objective 2b; Supplemental Figure 1). There were no exclusion criteria.

Figure 1.

Generation of patient cohorts for assessment of study objectives. Cohort 1 comprised pwMS who were new users and received a new treatment course of alemtuzumab (i.e., the first ever use of alemtuzumab based on the patient’s complete MS treatment history) on or after the date of the EU SmPC change (January 16, 2020). Cohort 2 comprised pwMS who received a new or continuing treatment course of alemtuzumab on or after the EU SmPC change. Cohort 3 comprised pwMS who received a new or continuing treatment course of alemtuzumab on or after January 16, 2020 or pwMS who received a treatment course on or after February 16, 2016, and had part of the 48-month-long follow-up take place after January 16, 2020.

Data sources

Data were extracted from existing databases or collected from medical charts. The data extraction method varied between each data source, as outlined in Supplemental Table 1. Data sources included: MS registry data from the national Czech MS registry (ReMuS); a German ongoing prospective cohort study of alemtuzumab patients (Long-Term study foR obsErvAtion of Treatment with alemtuzumab in active relapsing-remitting MS (TREAT-MS))^8,9; chart review data from three UK MS centers (Cardiff, Cambridge, and Plymouth), and administrative healthcare data/insurance claims from L’Agence InterMutualiste—Het InterMutualistisch Agentschap (AIM-IMA, the Belgian Social Security database). Data from ReMuS were supplemented with chart review data to capture medical events unrelated to MS (e.g., contraindications to alemtuzumab). Data to address the four study objectives were assessed from January 16, 2020 until the latest database update in each data source: ReMuS and the UK centers, December 31, 2023; TREAT-MS, January 17, 2024; and AIM-IMA, March 2022. AIM-IMA stopped participation in the study in January 2023, resulting in a shorter study period relative to the other data sources. The time periods included the coronavirus 2019 (COVID-19) global pandemic.

Assessment of adherence to the revised alemtuzumab EU SmPC

Indication

The original approved indication for alemtuzumab in the EU was for the treatment of adult patients with RRMS with active disease, defined by clinical or imaging features.¹⁰ The revised EU SmPC states that alemtuzumab treatment is indicated for adults with: (1) highly active MS despite a full and adequate course of treatment with at least one DMT; or (2) rapidly evolving severe RRMS defined by two or more disabling relapses in 1 year, and with one or more gadolinium-enhancing lesions on brain magnetic resonance imaging (MRI) or a significant increase in T2 lesion load as compared with a previous recent MRI.⁷

In general, the basis for operational definitions in this study was the EU SmPC. However, the lack of international consensus on how to define highly active disease¹¹ meant that the operational definitions for the indication differed among countries, reflecting local reimbursement guidelines and the availability of data on different components of the indication in each database (Supplemental Table 2). For the operational definition, highly active disease was defined for all four countries based on relapses, as well as MRI activity in the Czech Republic and the UK, and an additional variable that identified active RRMS in Germany (available in the TREAT-MS cohort electronic case report form (eCRF)).

The operational definition of indication part 2 for the Czech Republic and the UK was any “significant” increase in T2 lesions on MRI over a 1-year period prior to alemtuzumab treatment (Supplemental Table 2); indication part 2 was not assessable in Belgium and Germany due to a lack of MRI data. Data from the 12-month period prior to index date were used.

Contraindications

The revised alemtuzumab EU SmPC includes the following contraindications: hypersensitivity to alemtuzumab or any of its excipients, human immunodeficiency virus infection, severe active infection until complete resolution, uncontrolled hypertension, history of arterial dissection of the cervicocephalic arteries, history of stroke, history of angina pectoris or myocardial infarction, known coagulopathy or on antiplatelet or anticoagulant therapy, and other concomitant autoimmune diseases besides MS. The time frames for measuring the history of contraindications varied according to the contraindication and were based on clinical input from the principal investigators of the study (Supplemental Table 3).

The operational definitions for contraindications differed by country and data source (Supplemental Table 4). Notably, for the Belgian data source, there were no data on diagnoses available. Instead, proxies based on medication usage measured using Anatomical Therapeutic Chemical Classification System codes and procedural codes were used.

Safety monitoring

Per the revised alemtuzumab EU SmPC, the monitoring tests required before treatment are electrocardiogram (ECG) and assessment of vital signs (heart rate (HR) and blood pressure (BP)), FBC with serum transaminase, serum creatinine, thyroid function test, and urinalysis with microscopy. Monitoring requirements during treatment are continuous/frequent (at least every hour) monitoring of HR and BP, with platelet count on Days 3 and 5 (first treatment course) and Day 3 (subsequent treatment courses). After treatment, long-term monitoring tests required are monthly FBC with serum transaminases, serum creatinine, urinalysis with microscopy, and 3-monthly thyroid function testing, for at least 48 months after the last infusion (Supplemental Figure 1).

The availability of data on monitoring tests differed by country and data source (Supplemental Table 5). Data on ECG and platelets were not available in TREAT-MS. For Belgium, monitoring tests and their dates were identified in AIM-IMA directly through codes for medical procedures, but there were no data available for ECG, HR, BP, and urinalysis (Supplemental Table 6).

Study size

As this was a descriptive, non-comparative study, formal sample size calculations were not required. All eligible pwMS from each contributing database were included.

Statistical analyses

Summary statistics

The data from each country were analyzed separately because of heterogeneity in data collection and availability.

Main analyses

For adherence to indication (objective 1a), analyses were conducted at the patient level. PwMS who were newly prescribed alemtuzumab were counted only once. For adherence to contraindications and monitoring before and during treatment (objectives 1b and 2a), analyses were conducted at the treatment course level, with a secondary analysis at the patient level. For the purposes of this study, an interval of 30 days prior to infusion was considered for tests required in advance of infusion. For long-term monitoring (objective 2b), analyses were conducted at the patient level (Table 1). To calculate long-term adherence at the patient level, designated testing periods were created for every patient, anchored to the start date of the alemtuzumab course at intervals of 30 days (with a tolerance window of ±15 days) for monthly tests and 90 days (with a tolerance window of ±30 days) for 3-monthly tests. If a monitoring test was present in a designated testing period, the patient was considered adherent for that period (Supplemental Figure 1). Only the time period after implementation of the revised EU SmPC was assessed.

Table 1.

Output variables for each study objective.

Analysis	Time period	Calculation
Objective 1a: Indication—stratified by age group, sex, and year of cohort entry date
The proportion and its 95% CI of pwMS who had a new-use course of alemtuzumab on or after January 16, 2020, and whose alemtuzumab treatment was in accordance with the newly revised indication	Based on a 12-month look-back period (preceding the index date)	Proportion of patients with correct indication $= \frac{total number of patients with correct indication in cohort 1 a}{total number of patients in cohort 1}$
Objective 1b: Contraindication—stratified by age group, sex, year of alemtuzumab course, course rank,^a and individual contraindications
The proportions (with 95% CI) of courses during the study period that were in adherence to the revised contraindications were calculated. Analyses were performed both for all courses without any contraindication and for each separate contraindication	Prior to course start date. Refer to Supplemental Table 3 for time periods.	Proportion of courses without contraindication $= \frac{total number of courses without contraindication}{total number of courses in cohort 2}$
Objective 2a: Safety monitoring before and during treatment—stratified by age group, sex, course rank,^a and year of alemtuzumab course
Monitoring prior to alemtuzumab course
Proportions (with 95% CI) of alemtuzumab courses that complied with the recommended monitoring prior to course initiation were calculated separately for each recommended monitoring test (ECG, BP, HR, FBC, transaminases, creatinine, thyroid, urinalysis)	30 days prior to alemtuzumab courses^b	$Proportion of courses adhering to test prior to course$ $= \frac{total number of courses with evidence of test prior to course start}{total number of courses in the study period (cohort 2)}$
Proportions (with 95% CI) of alemtuzumab courses during the study period that were in compliance with the recommended monitoring during the treatment course (BP Day 1, HR Day 1, BP Day 2, HR Day 2, BP Day 3, HR Day 3, platelets Day 3, BP Day 4, HR Day 4, BP Day 5, HR Day 5, platelets Day 5) were calculated for each recommended monitoring test. Monitoring at Days 4 and 5 of the treatment course were only assessed among new-use courses	During the alemtuzumab course	$Proportion of courses with test on Day x$ $= \frac{total number of courses with evidence of test on Day x of the course}{\begin{matrix} total number of courses in the study period for which \\ there is sufficient follow up to ascertain Day x monitoring \end{matrix}}$
The number of pwMS with 100% adherence for each monitoring test during the alemtuzumab course was reported. Proportions (with 95% CI) of pwMS who had monitoring tests during their alemtuzumab courses during the study period were calculated	During the alemtuzumab course	$Proportion of patients with monitoring tests during each course$ $= \frac{patients with evidence of tests during each course}{total number of patients in the study period (cohort 2)}$
Objective 2b: Long-term safety monitoring – stratified by age, sex, year of cohort entry date, and course rank^a (i.e., only considering the designated periods for one of the courses)
Percentage adherence (overall and by age category, sex, year of cohort entry, and course rank) was computed for each patient and each test (FBC, creatinine, transaminases, urinalysis, thyroid) within designated testing periods over 48 months from last alemtuzumab course initiation. Only designated testing periods after January 16, 2020 are included in the analysis (Supplemental Figure 1)	Within designated testing periods, anchored on the initial infusion date at 30 day (±15 days), or 90 day (±30 days) intervals^c	$Adherence to long term monitoring for test$ $= \frac{\sum_{i = 1}^{i = n} \begin{matrix} number of tests for course within the designated \\ subset of patients or courses \end{matrix}}{\sum_{i = 1}^{i = n} number of designated testing periods for course i} \times 100$

Course rank was defined as the number of alemtuzumab courses that the patient was administered. The course rank was equal to 1 only for a new-use course of alemtuzumab. The course rank was split into three categories: 1, 2, and ⩾3.

The 30-day period was selected for the purposes of this study as a reasonable timeframe to conduct testing prior to infusion. It is not specified per SmPC.

From the first course until the earliest of: the next course, the end of follow-up (or last visit date in TREAT-MS, Germany), or 48 months later.

BP, blood pressure; CI, confidence interval; ECG, echocardiogram; FBC, full blood count; HR, heart rate; MS, multiple sclerosis; pwMS, people with MS; SmPC, Summary of Product Characteristics; TREAT-MS, Long-Term study foR obsErvAtion of Treatment with alemtuzumab in active relapsing-remitting MS.

Sensitivity analyses

For adherence to indication (objective 1a), a sensitivity analysis was conducted using a 24-month period prior to infusion to capture data relating to indication (rather than 12 months in the main analysis). The rationale was to account for potential disruptions in patient care caused by the COVID-19 pandemic. For long-term monitoring (objective 2b), sensitivity analyses were performed to assess adherence to long-term monitoring tests by time since treatment and calendar year of intended monitoring, to explore if adherence was stable over time and evaluate whether there were time-related factors influencing adherence (e.g., the COVID-19 pandemic). In addition, long-term adherence was assessed by dividing the number of monitoring tests, regardless of the timing of those tests, by the total number of designated testing periods in the complete observation period. The rationale of this sensitivity analysis was to acknowledge that not all pwMS would follow the testing schedule within the designated testing period (i.e., anchored on the infusion date at 30-day intervals with a tolerance window of ±15 days). In routine care, monitoring tests may be rescheduled to best suit the personal schedules of pwMS to accommodate life events and personal circumstances. Subsequent tests would then be anchored on the last test received, not the original infusion.

Missing values

There were no missing data on age and sex in any of the data sources. If there were incomplete dates for diagnosis of contraindications, the 15th of the month and July 1st were used, when only month or year were available, respectively. For incomplete dates of monitoring tests, the 15th of the month was used if month and year were available, but dates were not imputed if only the year was available. No imputation was performed for other variables.

Study approval

The study protocol was approved by the EMA Pharmacovigilance Risk Assessment Committee in July 2021. The study was registered in the Heads of Medicines Agency EMA catalogue (EUPAS42540). Data are reported according to the REporting of studies Conducted using Observational Routinely-collected Data Pharmacoepidemiology (RECORD-PE) guidelines.¹²

Results

Study population

Data from 2046 pwMS treated with at least one course of alemtuzumab were analyzed. Of them, 155, 406, and 2046 pwMS were evaluated for indication (objective 1a), contraindication and monitoring before/during treatment (objectives 1b and 2a), and long-term monitoring (objective 2b), respectively (Table 2). Patient demographics and clinical characteristics are provided in Table 3 and show that most pwMS across the included cohorts were female and aged ⩽40 years at study entry.

Table 2.

Number of patients and alemtuzumab courses in each cohort and database.

Cohort	ReMuS		TREAT-MS		UK centers		AIM-IMA
Cohort	Courses	Patients	Courses	Patients	Courses	Patients	Courses	Patients
Cohort 1 for indication (objective 1a)	81	81	8	8	39	39	27	27^a
Cohort 2 for contraindications and monitoring before/during treatment (objectives 1b and 2a)	204	129	89	72	154	118	102	87
Cohort 3 for long-term monitoring (objective 2b)	350	228	870	791	603	498	604	529

An alemtuzumab course was defined as an intravenous infusion of 12 mg per day for 5 or 3 days, depending on whether a first course or a subsequent course.

AIM-IMA cohort for objective 1a included ⩽5 patients with insufficient history in the database to ascertain the new-use status of their alemtuzumab course.

AIM-IMA, L’Agence InterMutualiste—Het InterMutualistisch Agentschap (Belgian Social Security database); ReMuS, Czech multiple sclerosis registry; TREAT-MS, Long-Term study foR obsErvAtion of Treatment with alemtuzumab in active relapsing-remitting multiple sclerosis; UK, United Kingdom.

Table 3.

Patient demographics and clinical characteristics.

Variable	Cohort 1 for indication (objective 1a)				Cohort 2 for contraindications and monitoring before/during treatment (objectives 1b/2a)				Cohort 3 for long-term monitoring (objective 2b)
Variable	ReMuS, N = 81	TREAT-MS, N = 8	UK centers, N = 39	AIM-IMA,^a N = 27	ReMuS, N = 129	TREAT-MS, N = 72	UK centers, N = 118	AIM-IMA, N = 87	ReMuS,^b N = 228	TREAT-MS,^c N = 791	UK centers,^d N = 498	AIM-IMA, N = 529
Sex, n (%)
Male	23 (28.4)	3 (37.5)	13 (33.3)	8 (29.6)	35 (27.1)	13 (18.1)	28 (23.7)	31 (35.6)	65 (28.5)	224 (28.3)	123 (24.7)	164 (31.0)
Female	58 (71.6)	5 (62.5)	26 (66.7)	19 (70.4)	94 (72.9)	59 (81.9)	90 (76.3)	56 (64.4)	163 (71.5)	567 (71.7)	375 (75.3)	365 (69.0)
Year of cohort entry, n (%)
2020	21 (25.9)	8 (100.0)	5 (12.8)	>5	49 (38.0)	55 (76.4)	25 (21.2)	56 (64.4)	167 (73.2)	791 (100.0)	455 (91.4)	518 (97.9)
2021	29 (35.8)	0	7 (17.9)	11 (40.7)	37 (28.7)	13 (18.1)	36 (30.5)	>5	29 (12.7)	0	8 (1.6)	NA
2022^e	18 (22.2)	0	20 (51.3)	⩽5	29 (22.5)	4 (5.6)	45 (38.1)	⩽5	19 (8.3)	0	28 (5.6)	⩽5
2023^e	13 (16.0)	0	7 (17.9)	NA	14 (10.9)	0	12 (10.2)	NA	13 (5.7)	0	7 (1.4)	NA
2024^e	0	0	0	NA	0	0	0	NA	0	0	0	NA
Age at cohort entry, n (%)
<30	28 (34.6)	5 (62.5)	20 (51.3)	14 (51.9)	35 (27.1)	18 (25.0)	31 (26.3)	27 (31.0)	50 (21.9)	111 (14.0)	93 (18.7)	91 (17.2)
30–39	27 (33.3)	<3 (<37.5)	13 (33.3)	Not available	45 (34.9)	32 (44.4)	56 (47.5)	27 (31.0)	87 (38.2)	321 (40.6)	202 (40.6)	146 (27.6)
40–49	22 (27.2)	<3 (<37.5)	3 (7.7)	Not available	39 (30.2)	14 (19.4)	19 (16.1)	25 (28.7)	68 (29.8)	235 (29.7)	132 (26.5)	158 (29.9)
50–59	4 (4.9)	0	3 (7.7)	Not available	10 (7.8)	8 (11.1)	⩾3 (⩾2.5)	>5	⩾3 (⩾1.3)	105 (13.3)	63 (12.7)	101 (19.1)
60+	0	0	0	Not available	0	0	<3 (<2.5)	⩽5	<3 (<1.3)	19 (2.4)	8 (1.6)	33 (6.2)
Number of pwMS that have 1, 2, or more alemtuzumab courses during follow-up
1 course	NA	NA	NA	NA	61 (47.3)	57 (79.2)	84 (71.2)	73 (83.9)	121 (53.0)	721 (91.2)	397 (80.0)	458 (86.6)
2+ courses^f	NA	NA	NA	NA	68 (52.7)	15 (20.8)	34 (28.8)	14 (16.1)	107 (47.0)	70 (8.8)	101 (20.0)	71 (13.4)

The inclusion criteria for objectives 1b and 2a were the same; therefore, the same patient cohort was used. An alemtuzumab course was defined as intravenous infusion of 12 mg per day for 5 or 3 days, depending on whether a first course or a subsequent course.

AIM-IMA cohort 1 included ⩽5 pwMS with insufficient history in the database to ascertain the new-use status of their alemtuzumab course.

There were 228 pwMS included in the cohort 3 in ReMuS, however, only 223 pwMS had at least one complete designated testing period.

There were 791 pwMS included in the cohort 3 in TREAT-MS, however, only 571 pwMS had at least one complete designated testing period.

There were 498 pwMS included in the cohort 3 in the UK centers, however, only 494 pwMS had at least one complete designated testing period.

Data available until December 2023 in ReMuS and UK centers, January 2024 in TREAT-MS, and March 2022 in AIM-IMA.

Stratification for two and three or more courses not shown because of small cell masking for three and more courses.

AIM-IMA, L’Agence InterMutualiste—Het InterMutualistisch Agentschap (Belgian Social Security database); NA, not applicable; pwMS, people with multiple sclerosis; ReMuS, Czech multiple sclerosis registry; TREAT-MS, Long-Term study foR obsErvAtion of Treatment with alemtuzumab in active relapsing-remitting MS; UK, United Kingdom.

Indication

Across the four included countries, data were available for a total of 150 pwMS who were new users and received a new treatment course of alemtuzumab on or after the date of the EU SmPC change (January 16, 2020).

The percentage of pwMS meeting the revised alemtuzumab indication, based on 12 months of data prior to infusion, ranged from 66.7% in ReMuS and the UK centers, to 100.0% in AIM-IMA (Table 4). No patterns of note were observed when the results were stratified by age, sex, or year of cohort entry date (results not shown).

Table 4.

Proportions of pwMS with revised indication for alemtuzumab and proportion of courses with no contraindication.^a

Output variable	ReMuS	TREAT-MS	UK centers	AIM-IMA
Indication
Cohort 1: Number of new alemtuzumab users, n	N = 81	N = 8	N = 39	N = 22–27^b
Proportion of pwMS meeting revised indication for alemtuzumab, % (95% CI)^c	66.7^d (55.2, 76.5)^e	87.5 (46.7, 99.3)	66.7 (49.7, 80.4)	100.0 (84.0, 100.0)
Proportion of pwMS meeting indication part 1, % (95% CI)^c	53.1 (41.7, 64.1)^e	87.5 (46.7, 99.3)	7.7 (2.0, 22.0)	Not available
Proportion of pwMS meeting indication part 2, % (95% CI)^c	25.9 (17.1, 37.1)^e	0 (0, 60.4)^f	59.0 (42.2, 74.0)	Not available
Proportions of pwMS meeting revised indication for alemtuzumab using a 24-month assessment period
Proportion of pwMS meeting revised indication, % (95% CI)^c	Not available	87.5 (46.7, 99.3)	79.5 (63.1, 90.1)	100.0 (84.0, 100.0)
Proportion of pwMS meeting indication part 1, % (95% CI)^c	Not available	87.5 (46.7, 99.3)	20.5 (9.9, 36.9)	Not available
Proportion of pwMS meeting indication part 2, % (95% CI)^c	Not available	0 (0, 60.4)	66.7 (49.7, 80.4)	Not available
Contraindication
Cohort 2: Number of pwMS	129	72	118	87
Total number of courses, n	204	89	154	102
Courses with no contraindication, % (95% CI)^c	90.2 (85.1, 93.8)	97.8 (91.4, 99.6)	88.3 (81.9, 92.7)	77.5 (67.9, 84.9)
Stratified by new and continuing courses, % (95% CI)^c
First course (new use)	90.1 (81.0, 95.3)	100.0 (59.8, 100.0)	94.9 (81.4, 99.1)	84.6 (64.3, 95.0)
Second course (continuing use)	91.5 (82.7, 96.2)	97.4 (84.6, 99.9)	96.2 (85.7, 99.3)	77.1 (59.4, 89.0)
Third or more course (continuing use)	87.8 (73.0, 95.4)	97.7 (86.2, 99.9)	77.8 (65.2, 86.9)	72.5 (55.9, 84.9)
Stratified by contraindication, % (95% CI)^c
Courses with no hypersensitivity to alemtuzumab	100.0 (97.0,100.0)	97.8 (91.4, 99.6)	100.0 (97.7, 100.0)	Not assessable
Courses with no HIV	100.0 (97.7, 100.0)	100.0 (94.8, 100.0)	99.4 (95.9,100.0)	100.0 (95.5, 100.0)
Courses with no severe active infection	100.0 (97.0, 100.0)	100.0 (94.8, 100.0)	100.0 (97.0, 100.0)	96.1 (89.7, 98.7)
Courses with no uncontrolled hypertension	100.0 (97.0, 100.0)	100.0 (94.8, 100.0)	100.0 (97.7, 100.0)	Not assessable
Courses with no history of arterial dissection of the cervicocephalic arteries	99.5 (96.9, 100.0)	100.0 (94.8, 100.0)	100.0 (97.0, 100.0)	Not assessable
Courses with no history of stroke	100.0 (97.0, 100.0)	100.0 (94.8, 100.0)	100.0 (97.7, 100.0)	98.0 (92.4, 99.7)
Courses with no history of angina pectoris or myocardial infarction	100.0 (97.0, 100.0)	100.0 (94.8, 100.0)	100.0 (97.7, 100.0)	100.0 (95.5, 100.0)
Courses with no known coagulopathy or on antiplatelet/anticoagulant therapy	95.6 (91.5, 97.8)	100.0 (94.8, 100.0)	96.8 (92.2, 98.8)	88.2 (80.0, 93.5)
Courses with no other autoimmune disease	95.1 (90.9, 97.5)	100.0 (94.8, 100.0)	92.2 (86.5, 95.7)	91.2 (83.5, 95.6)

An alemtuzumab course was defined as intravenous infusion of 12 mg per day for 5 or 3 days, depending on whether a first course or a subsequent course.

Using a 12-month look-back period.

A range is provided because ⩽5 pwMS had insufficient history in the database to ascertain the new-use status of their alemtuzumab course.

The 95% CIs were two-sided and were calculated using Wilson score method with Yate’s continuity correction.

Increased to 75.3% after manual checking of pwMS meeting indication that were not included in programmed definitions.

For ReMuS, the indication categories were not mutually exclusive. Therefore, some pwMS met both part 1 and part 2 criteria.

For TREAT-MS indication part 2, n = 4.

AIM-IMA, L’Agence InterMutualiste—Het InterMutualistisch Agentschap (Belgian Social Security database); CI, confidence interval; HIV, human immunodeficiency virus; pwMS, people with multiple sclerosis; ReMuS, Czech multiple sclerosis registry; TREAT-MS, Long-Term study foR obsErvAtion of Treatment with alemtuzumab in active relapsing-remitting MS; UK, United Kingdom.

For ReMuS, following manual checking of pwMS meeting the indication that were not included in programmed definitions, the percentage of pwMS meeting the revised indication increased to 75.3%. In a sensitivity analysis that used a 24-month data period prior to infusion to assess the indication, the percentage of pwMS meeting the revised indication criteria increased from 66.7% to 79.5% in the UK centers. Similar results to the 12-month assessment period were observed for AIM-IMA and TREAT-MS. Data for the 24-month period were not available from ReMuS (Table 4).

Contraindications

There were 406 pwMS, across the four included countries, who received a new or continuing treatment course of alemtuzumab on or after the EU SmPC change. These pwMS had 549 alemtuzumab courses in total. Most alemtuzumab courses (ranging from 77.5% for AIM-IMA to 97.8% for TREAT-MS) were not contraindicated (Table 4). Across all data sources, a higher percentage of new-use courses were not contraindicated (84.6% for AIM-IMA and 100.0% for TREAT-MS) compared with third courses (72.5% for AIM-IMA and 97.7% for TREAT-MS; Table 4).

Stratification by type of contraindication showed that there were no alemtuzumab courses with contraindications of angina pectoris or myocardial infarction in any of the data sources, and no cases of uncontrolled hypertension (although this contraindication was not assessable in AIM-IMA). Where contraindications were present, they were typically single events observed in just one data source (Table 4). Exceptions were known coagulopathy or antiplatelet/anticoagulant therapy, detected in 11.8% of the 102 AIM-IMA courses, and other autoimmune disease, detected in 8.8% of the 102 AIM-IMA courses and 7.8% of the 154 UK center courses, respectively. The observed contraindications were similar between AIM-IMA, ReMuS, and the UK centers. In TREAT-MS, the only observed contraindication was hypersensitivity; however, this adverse reaction was likely minor rather than a true or serious hypersensitivity event, because a physician recorded the hypersensitivity prior to initiation of the alemtuzumab course, and after the recorded hypersensitivity the patient continued treatment with alemtuzumab for two more courses.

There were no notable patterns observed when contraindication results were stratified by age, sex, or year of alemtuzumab course (results not shown).

Safety monitoring

Data on monitoring before and during alemtuzumab infusion were available for 406 pwMS (549 courses; Table 5), while long-term monitoring data were available for 2046 pwMS (Table 6).

Table 5.

Proportion of courses with monitoring tests conducted before and during administration of the alemtuzumab infusion.

Output variable	ReMuS	TREAT-MS^a	UK centers	AIM-IMA^b
Total number of courses, n	204	89	154	102
Proportion of courses with monitoring tests done 30 days prior^c to alemtuzumab course, % (95% CI)^d
ECG	47.1 (40.1, 54.1)	Not assessable	59.7 (51.5, 67.5)	Not assessable
HR	77.9 (71.5, 83.3)	95.5 (88.3, 98.6)	100.0 (97.0, 100.0)	Not assessable
BP	77.5 (71.0, 82.9)	95.5 (88.3, 98.6)	100.0 (97.0, 100.0)	Not assessable
FBC	96.1 (92.1, 98.2)	88.8 (79.9, 94.2)	72.1 (64.2, 78.9)	97.1 (91.0, 99.2)
Creatinine	95.6 (91.5, 97.8)	85.4 (76.0, 91.7)	70.8 (62.8, 77.7)	97.1 (91.0, 99.2)
Transaminases	95.6 (91.5, 97.8)	56.2 (45.3, 66.5)	69.5 (61.5, 76.5)	89.2 (81.1, 94.2)
Thyroid function test	85.3 (79.5, 89.7)	83.1 (73.4, 90.0)	35.1 (27.7, 43.2)	89.2 (81.1, 94.2)
Urinalysis	95.6 (91.5, 97.8)	67.4 (56.6, 76.8)	26.6 (20.0, 34.5)	Not assessable
Proportion of monitoring tests performed during alemtuzumab treatment, % (95% CI)^d
BP Day 1	100.0 (97.7, 100.0)	95.5 (88.3, 98.6)	100.0 (97.0, 100.0)	Not assessable
BP Day 2	100.0 (97.7, 100.0)	92.0 (83.6, 96.4)	100.0 (96.9, 100.0)	Not assessable
BP Day 3	100.0 (97.7, 100.0)	83.1 (73.0, 90.1)	100.0 (96.9, 100.0)	Not assessable
BP Day 4	100.0 (94.3, 100.0)	100.0 (59.8, 100.0)	100.0 (88.3, 100.0)	Not assessable
BP Day 5	100.0 (94.2, 100.0)	100.0 (59.8, 100.0)	100.0 (88.3, 100.0)	Not assessable
HR Day 1	100.0 (97.7, 100.0)	95.5 (88.3, 98.6)	100.0 (97.0, 100.0)	Not assessable
HR Day 2	100.0 (97.7, 100.0)	92.0 (83.6, 96.4)	100.0 (96.9, 100.0)	Not assessable
HR Day 3	100.0 (97.7, 100.0)	83.1 (73.0, 90.1)	100.0 (96.9, 100.0)	Not assessable
HR Day 4	100.0 (94.3, 100.0)	100.0 (59.8, 100.0)	100.0 (88.3, 100.0)	Not assessable
HR Day 5	100.0 (94.2, 100.0)	100.0 (59.8, 100.0)	100.0 (88.3, 100.0)	Not assessable
Platelets Day 3	32.7 (26.4, 39.7)	Not assessable	42.7 (34.7, 51.0)	47.1 (37.2, 57.2)
Platelets Day 5	29.1 (19.7, 40.6)	Not assessable	51.4 (34.7, 67.8)	50.0 (32.1, 67.9)

An alemtuzumab course is defined as intravenous infusion of 12 mg per day for 5 or 3 days, depending on whether a first course or a subsequent course.

In TREAT-MS, ECG data were not collected or recorded as having been performed. Adherence with ECG monitoring was therefore not assessed.

In the AIM-IMA database, HR, BP, ECG, and urinalysis tests were not identifiable.

Prior means the time period from 30 days before index date until index date itself, included. In TREAT-MS, for the new courses, blood and urinalysis monitoring prior to infusion was collected at screening and/or at first infusion; the screening visit occurs at least 6 weeks prior to the first infusion. For continuing courses, this was collected throughout the follow-up and thus the 30-day period was applied.

The 95% CIs were two-sided and are calculated using the Wilson score method with Yate’s continuity correction.

AIM-IMA, L’Agence InterMutualiste—Het InterMutualistisch Agentschap (Belgian Social Security database); BP, blood pressure; CI, confidence interval; ECG, electrocardiogram; FBC, full blood count; HR, heart rate; ReMuS, Czech multiple sclerosis registry; TREAT-MS, Long-Term study foR obsErvAtion of Treatment with alemtuzumab in active relapsing-remitting multiple sclerosis; UK, United Kingdom.

Table 6.

Adherence to long-term monitoring at the patient level.^a

Output variable	ReMuS	TREAT-MS	UK centers	AIM-IMA
Total number of pwMS in cohort for objective 2b, N	228	791	498	529
Adherence to monthly tests, mean % (SD)
Number of pwMS in analysis,^b n	223	571^c	494	529
FBC	70.7 (23.6)	64.1 (31.4)	47.0 (31.4)	78.6 (23.8)
Creatinine	70.1 (24.2)	63.0 (31.6)	46.0 (31.1)	78.3 (23.6)
Transaminase	63.4 (28.2)	36.3 (34.7)	39.9 (29.2)	58.0 (27.7)
Urinalysis	68.8 (24.7)	65.7 (35.5)	7.5 (20.8)	Not assessable
Adherence to tests performed every 3 months, mean % (SD)
Number of pwMS in analysis,^d n	221	553	481	Not available
Thyroid function	55.8 (30.3)	53.9 (34.1)	37.0 (29.3)	71.9 (29.0)

Only pwMS with at least one complete designated testing period were included here.

PwMS with less than 1 month of available monitoring after the implementation of the revised EU SmPC were excluded from the analysis.

For TREAT-MS, there were 791 patients included in Cohort 3 but only 571 patients had at least one complete designated testing period for whom adherence could be calculated. Note that long-term monitoring was assessed until the last available visit date recorded in the TREAT-MS study, so patients were excluded if they had discontinued their participation in the TREAT-MS study prior to Jan 16, 2020.

PwMS with less than 3 months of available monitoring were excluded (⩽5 pwMS in each data source).

AIM-IMA, L’Agence InterMutualiste—Het InterMutualistisch Agentschap (Belgian Social Security database); EU SmPC, European Union Summary of Product Characteristics; FBC, full blood count; pwMS, people with multiple sclerosis; ReMuS, Czech multiple sclerosis registry; SD, standard deviation; TREAT-MS, Long-Term study foR obsErvAtion of Treatment with alemtuzumab in active relapsing-remitting multiple sclerosis; UK, United Kingdom.

Before alemtuzumab treatment

Adherence to testing in the 30-day period prior to alemtuzumab infusion varied between databases (Table 5). HR and BP testing were conducted for >77.0% of courses (range: 77.5% in ReMuS to 100.0% in UK centers). Generally, adherence to testing prior to alemtuzumab infusion was reasonable (test performed prior to >65.0% of courses, with the exception of ECG tests in ReMuS; ECG, thyroid function, and urinalysis tests in UK centers; and transaminases tests in TREAT-MS).

Adherence to tests conducted prior to infusion was similar in the patient-level compared to the course-level data (Supplemental Table 7). No patterns of note were observed when results were stratified by age, sex, or year of alemtuzumab course (results not shown).

During alemtuzumab infusion

During the alemtuzumab infusion, HR and BP were monitored for all courses (100.0%) in ReMuS and the UK centers (Day 1–Day 5), and for 83.1% (Day 3) to 100.0% (Day 5) of courses in TREAT-MS. However, platelet counts were less frequently measured, ranging from 29.1% of courses in ReMuS to 51.4% of courses in UK centers (based on Day 5 measurements; Table 5). No patterns of note were observed when results were stratified by age, sex, course rank, or year of alemtuzumab course (results not shown).

Long-term monitoring

While adherence to long-term monitoring across the 48-month post-treatment period varied among the data sources, the mean adherence to most of the required tests was over 50%, even in the 3rd and 4th year post-treatment (Table 6 and Supplemental Table 8). Mean adherence was lowest in the UK centers, ranging from 7.5% for urinalysis to 47.0% for FBC, and highest for the AIM-IMA, ranging from 58.0% for transaminases to 79.6% for FBC.

A sensitivity analysis that evaluated the total number of tests over the duration of the study period, without the restriction of anchoring 30-day (±15 days) testing intervals on the infusion date (i.e., the designated testing periods), showed approximately 5%–9% higher mean adherence to monitoring for both ReMuS and the UK centers (Supplemental Table 9). Long-term adherence to 3-monthly thyroid function testing increased by 31.8% for ReMuS and 22.5% for UK centers. There were minor differences in long-term adherence for TREAT-MS in the sensitivity analysis versus the main analysis. This sensitivity analysis could not be conducted for AIM-IMA.

When stratified by time period (Year 1 (1–12 months) to Year 4 (37–48 months) post treatment), adherence to long-term monitoring decreased from Year 1 to Year 4 for ReMuS, and increased for TREAT-MS (with the exception of transaminases and thyroid testing; Supplemental Table 8). No trends in adherence were discerned across the time periods for the UK centers.

An additional sensitivity analysis stratified by the year of intended monitoring showed higher adherence to most monitoring tests in 2023 compared with 2020, 2021, and 2022 in TREAT-MS and the UK centers (with the exception of thyroid and urinalysis in the UK and transaminases in TREAT-MS). No clear trends were observed for ReMuS (Supplemental Table 8).

No trends of note were observed when long-term monitoring results were stratified by age, sex, year of cohort entry date, or course rank (results not shown).

Discussion

Following the European Commission Article 20 pharmacovigilance procedure for alemtuzumab in 2019, this study evaluated adherence with the revised 2020 alemtuzumab EU SmPC. Using MS disease registry data, chart review data, and administrative data from four European countries, adequate adherence with the revised indications, contraindications, and safety monitoring recommendations for alemtuzumab was observed.

Indication

In this study, which assessed patient data between 2020 and 2024, most (>66.7%–88%) pwMS met the revised indication, suggesting that alemtuzumab is prescribed per the revised EU SmPC.

The operational definitions for the indication accommodated available data from each country, as well as local reimbursement guidelines. However, the operational definitions for the indication did not capture all established prognostic factors for disease severity, in part because there is no clinical consensus on the definition of “highly active” MS.¹¹ Some pwMS in the Czech Republic and the UK may have met clinical criteria for high disease activity according to a neurologist’s judgment, but may not have had those data recorded, or those data may not have met the operational definitions used here. For example, not all of the reimbursement criteria from the Czech Republic could be included in the programmable definition of indication due to the complexity of the criteria (refer to Supplemental Table 2).¹³ This likely restricted the number of pwMS fulfilling the indication definition. Indeed, a manual inspection of the medical charts in the Czech Republic led to 8% more pwMS meeting the indication (75.3% in total) based on additional reimbursement criteria not included in the programmable definition of the indication.

Another limitation is that the use of chart data from ReMuS and the UK centers may limit the ability to adequately capture DMT use in the 12 months before alemtuzumab administration because chart data are considered less complete than administrative claims data.¹⁴ Additionally, the use of a 12-month assessment period prior to infusion may not reflect the complexities of routine clinical practice, where treatment decisions often consider longer-term medical history, resulting in fewer pwMS meeting the indication in the current study. This is supported by the sensitivity analysis that used data for operational definitions over a 24-month assessment period, which showed an increased proportion of pwMS meeting the revised indication.

There was some variation in the proportion of pwMS who met part 1 versus part 2 of the indication across countries. For example, in the UK, fewer pwMS met part 1 indication (disease activity despite prior DMT) than in the other data sources. This was consistent with clinical practice at the three UK centers in this study, where alemtuzumab is commonly used as a first-line treatment for pwMS with rapidly evolving disease or with poor prognostic factors.¹⁵ Therefore, pwMS in the UK cohort were more likely to fulfill criteria for part 2 indication instead.

Contraindications

For most courses (ranging from 77.5% for AIM-IMA to 97.8% for TREAT-MS) of alemtuzumab, no contraindications were documented. When contraindications were present, they were mainly related to history of coagulopathy or other autoimmune disease (<12% of courses). The contraindications were more frequently observed in the third course compared with the first course of alemtuzumab. This trend likely occurred because many pwMS included in this analysis had their first treatment course prior to the revision of the EU SmPC (approximately 37% in ReMuS, 89% in TREAT-MS, 67% in the UK centers, and 69% in AIM-IMA). If a patient became newly contraindicated after the SmPC change but had previously been successfully treated in the presence of that contraindication, they may have continued with treatment regardless of the revised contraindication. The proportion of courses with contraindications in the Belgian data (22.5%) may have been overestimated due to the use of proxy variables to capture specific contraindications in the administrative claims database (refer to Supplemental Table 4). While the use of proxies was deemed appropriate for the study,^16–18 an overly sensitive proxy may have falsely indicated the presence of a contraindication where none existed. Notably, antiplatelet and anticoagulant therapies were used as proxies for treated coagulopathies; however, these medications may be used for other indications for example prophylactically during pregnancy for preventing pre-eclampsia.¹⁹ Therefore, they are not necessarily always indicative of coagulopathy. This may have led to false positives and underestimated adherence to the revised contraindications in Belgium.

Monitoring before and during treatment

Overall, monitoring tests in the 30-day period before alemtuzumab courses were well adhered to, but there was variability across tests and countries. Of note, the 30-day testing window was used for the purposes of operationalizing this study, it is not a timeframe that is required per SmPC. Thus, it may have underestimated the monitoring that occurs in real-world clinical practice before treatment, because tests performed outside of this window were excluded. In instances where adherence to monitoring before treatment was low, local clinical practice or data limitations explained the result. For example, in Germany, data on transaminase monitoring were collected through an optional field in the structured eCRF because the CRF was designed before the SmPC change. Therefore, there may have been transaminase tests that were conducted but simply not recorded due to the structure of the eCRF. In the UK, local practices vary: intervals of 3–4 months may be enforced and tests are not repeated if a recent result is available (especially if a test has been done within a month and there is no cause for repetition). Therefore, a test that occurred more than 30 days prior to the alemtuzumab course initiation may have been used to allow treatment initiation. This means that in some cases it is not possible to strictly adhere to the monitoring interval specified in the SmPC. For urinalysis, this is considered of limited clinical value in the UK, where a mixture of serology, patient education, and vigilance is preferred for identification of relevant side effects.

During the alemtuzumab infusion, HR and BP were consistently monitored in all countries where data were available (observed for ⩾83.1% and up to 100.0% of courses for all treatment days), suggesting appropriate adherence to the revised alemtuzumab EU SmPC to minimize cardiovascular and cerebrovascular safety events. Adherence to platelet monitoring on Days 3 and 5 of the initial infusion appeared lower than other tests (29.1%–51.4% of courses), but these observed results may not be wholly representative of all the platelet tests performed. For example, if platelet monitoring occurred on other days during the course, it would not be captured in this result.

Long-term monitoring

Adherence to long-term monitoring was approximately ⩾50% for most tests, even in the 3rd and 4th years since the last infusion. While results were heterogeneous among tests and countries, as previously noted, this may reflect differences in standard clinical practice and reporting for the UK and TREAT-MS cohorts, respectively. The results are broadly in line with studies that have examined adherence to post-treatment monitoring for oral and infused MS therapies. For example, a Canadian study using administrative and linked laboratory data (2011–2015) found that liver function tests were carried out for only 25% of teriflunomide patients 6 months post-treatment start.²⁰ The same study found that liver function monitoring was carried out for 55% of patients treated with fingolimod and 89% of patients treated with dimethyl fumarate 12 months post-treatment start.²⁰ Similar to the Canadian study, a retrospective study of 140 patients treated with fingolimod in a tertiary clinic in Saudi Arabia found that 55% of patients received the required pre and post-treatment monitoring for liver function.²¹ In a chart review of 343 patients attending a Johns Hopkins MS center of excellence MS clinic between November 2020 and December 2022, only 36% of patients treated with natalizumab, ocrelizumab, or rituximab had complete laboratory monitoring.²² In this context, the observed adherence to long-term safety monitoring in the present study (up to 78.6% over a 4-year period) is encouraging.

The results for long-term monitoring are likely underestimated because the strict operational definitions used 15-day tolerance windows around the intended testing date, which was anchored on the infusion date. Therefore, no flexibility in testing dates was allowed, even for real-world life events such as vacations, marriages, births, and deaths. Additionally, the relevance of the actual test date likely decreases as time since infusion increases. The inflexibility of the analysis was highlighted by a sensitivity analysis that removed anchoring on the index date. In this sensitivity analysis, adherence to long-term monitoring increased by 8.9%–9.4% in ReMuS and 5.5%–7.2%in the UK centers.

Importantly, the study period overlapped with the COVID-19 pandemic, which had a substantial impact on the delivery of routine care for pwMS.^23–26 This disruption included postponing or suspending regular laboratory monitoring. As the pandemic continued, formal guidance was issued on how to best proceed with laboratory monitoring in the context of this global emergency.^27,28 The guidance recommended that, ideally, EU SmPC-stipulated monitoring should be followed, but advised that where this was not possible, postponement of regular blood tests could occur within reasonable standards for safety monitoring. For example, in the UK, monthly monitoring could be postponed to 3-monthly instead. This recommendation facilitates better understanding and context for the results observed in this study.^27,28 Therefore, these data may not necessarily reflect true routine care due to the influence of the pandemic. This is further supported by analyses stratified on year of intended monitoring, which demonstrated an increase in adherence to monthly monitoring as more time passed since 2020 for the UK and Germany. In the Czech Republic, monthly tests were not postponed (information from local PI).

Study strengths and limitations

This study has several key strengths. The interpretation of these heterogeneous data at the country level offers an understanding of the nuances in alemtuzumab treatment and provides representative insights into how pwMS are monitored in routine clinical practice across European countries.^29,30 Additionally, even in the presence of heterogeneity, there was relative consistency between countries, increasing confidence in the interpretation of the results. The data sources also had several strengths with regards to data collection. In AIM-IMA, the data completeness was high, as the database included reimbursement claims for all medical procedures. In ReMuS, registry data were complemented by medical chart data, extracted specifically for this study. In the UK centers, apart from data collected from medical charts at the MS centers, data were also systematically obtained from primary care. In TREAT-MS, data collection was structured using the established Multiple Sclerosis Documentation System alemtuzumab TREAT-MS module, which ensured high data quality, completeness, anonymity, and data protection.³¹

This study also has limitations. As previously mentioned, there is no consensus on the definition for highly active disease, leading to variation in operational definitions for the indication.¹¹ No time window restriction has been specified for prior use of DMT as per SmPC, thus a 12-month period was used in this study for pragmatism.⁷ Sensitivity analyses assessed the impact of a 24-month period. Part 2 of the indication could not be wholly assessed in AIM-IMA or TREAT-MS due to limited data availability. In ReMuS and the UK centers, there was no information on potential missing data; therefore, if no relapses were recorded, it was assumed that no relapses had occurred. The proportion of pwMS meeting the indication may therefore have been underestimated due to the absence of data on relapses.

Many contraindications could not be assessed in AIM-IMA because there are no diagnosis codes in this database. Data on prior medications for conditions other than MS were not collected in TREAT-MS, limiting their use as proxies for the contraindication.

The availability of data on monitoring tests varied. In AIM-IMA, HR, BP, ECG, and urinalysis were not assessable. In TREAT-MS, ECG monitoring before treatment and platelet count at Days 3 and 5 of the first course were not assessable. Despite this, using data from different countries gave a holistic picture on the overall testing schedule.

In ReMuS, pwMS may have their long-term monitoring tests done in primary care, but data on these tests were not accessible for this study. The extent of missing data cannot be quantified. Despite this, under strict testing parameters, long-term monitoring was deemed acceptable in the Czech Republic.

Finally, this study examined adherence during a period of time that encompassed the COVID-19 pandemic. However, despite recommendations that pwMS could postpone monthly testing to 3-monthly testing, reasonable adherence to monitoring was still achieved.^27,28 In the UK centers and TREAT-MS, there was an indication of lower adherence to monitoring in 2020 compared with later years, reflective of monitoring practices recovering post-pandemic.

Conclusion

This study has demonstrated that alemtuzumab was prescribed in accordance with the indication in 67%–88% of patients included in this study. It was prescribed in accordance with the listed contraindications in 78%–98% of courses included in the study. While variation was observed for adherence to the intended monitoring tests, overall adherence to the full schedule of testing was deemed satisfactory, especially considering that the study was conducted during the COVID-19 pandemic and the associated reductions in access to healthcare at that time. In instances where adherence was low, there were qualitative reasons to explain why this was the case. Overall, adherence to the EU SmPC is adequate to maintain the benefit–risk profile of alemtuzumab and to facilitate detection of adverse events via routine monitoring.

Supplemental Material

sj-docx-1-tan-10.1177_17562864261444676 – Supplemental material for Adherence to risk minimization measures for alemtuzumab use in multiple sclerosis: a drug utilization study in four European countries

Supplemental material, sj-docx-1-tan-10.1177_17562864261444676 for Adherence to risk minimization measures for alemtuzumab use in multiple sclerosis: a drug utilization study in four European countries by Carmen de Keijzer, Jian-Yu E, Qian Yang, Robert Gitonga, David Hiller, Stephanie Jurgensen, Naji Salloum, Janete Cunha-Santos, Emmanuelle Hoogewys-Cynober, Laetitia Vinet, Magdalena Chirieac, Hadj Benzerdjeb, Daniela Thoene, Tjalf Ziemssen, Jiří Drahota, Dana Horáková, William Brown, Jeremy Hobart, Neil P. Robertson, Katja M. Hakkarainen and Sarah-Jo Sinnott in Therapeutic Advances in Neurological Disorders

Footnotes

Acknowledgements

The authors thank Elisabeth Grünewald of Winicker Norimed GmbH for analytical contributions. Medical writing support was provided by Laura Graham, PhD, and Catherine Bowe, PhD, of Parexel in accordance with Good Publication Practice (GPP) guidelines and funded by Sanofi.

Author’s note

Stephanie Jurgensen: Affiliation at time of study.

Declarations

ORCID iDs

Carmen de Keijzer

Jian-Yu E

Tjalf Ziemssen

Jiří Drahota

Dana Horáková

William Brown

Jeremy Hobart

Sarah-Jo Sinnott

Supplemental material

Supplemental material for this article is available online.

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