Summary

• Please refer to your local labeling for further information regarding STELARA and adverse reactions.
• To evaluate the occurrence of major adverse cardiovascular events (MACE) in the overall STELARA plaque psoriasis (PsO) clinical development program, safety data were pooled across 4 clinical studies (phase 2 and phase 3) and included results from adult patients with up to 5 years of treatment with STELARA (2011 Safety Analysis).¹
• Adjudication of serious cardiovascular (CV) events was performed in a retrospective, independent, and blinded fashion, to determine events that might represent either MACE (including CV death, myocardial infarction [MI], and stroke) or other ischemic CV events.²
• A pooled analysis from a phase 2 (n=146) and two phase 3 (PSUMMIT I [n=615], PSUMMIT II [n=312]) studies evaluated the occurrence of MACE in adult patients with active psoriatic arthritis (PsA) exposed to STELARA for up to 2 years.³
• The incidence of MACE for adult patients with PsO enrolled in PSOLAR (Psoriasis Longitudinal Assessment and Registry) was reported.^4,5 PSOLAR is an international, prospective, observational study evaluating the long-term safety and clinical outcomes for patients who are eligible to receive systemic therapies.^6-8
• In a phase 3 clinical study of STELARA in 110 adolescent patients (age 12 to 17 years) with moderate to severe plaque PsO and in a phase 3 clinical study of STELARA in 44 pediatric patients (age 6 to 11 years) with moderate to severe plaque PsO, there were no reports of MACE through week 60 and week 56, respectively.^9-11
• Analyses of MACE were performed for pooled data from phase 2 and 3 clinical trials through 4 years in ulcerative colitis (UC) and 5 years in Crohn’s disease (CD).^12,13
• An integrated safety analysis of data from phase 2/3 and phase 3b studies in CD and UC showed that through up to 1 year of treatment, the rate of MACE (events per 100 patient-years [PY]) was 0.00 in STELARA-treated bio-naïve patients and 0.89 in placebo-treated bio-naïve patients. Through up to 5 years of treatment, the rate of MACE (events per 100 PY) was 0.07 in STELARA-treated bio-naïve patients and 0.53 in placebo-treated bio-naïve patients.¹⁴ Through up to 5 years of treatment in patients with a history of prior biologic failure, the rate of MACE (events per 100 PY) was 0.25 in STELARA-treated patients and 0.21 in placebo-treated patients.¹⁵

CLINICAL DATA IN adult PLAQUE PSORIASIS

In a retrospective, independent, and blinded fashion, the Cleveland Clinic Coordinating Center for Clinical Research performed adjudication of serious CV events in adult patients that might represent either MACE or other ischemic CV events.²

Controlled Portions of Psoriasis Clinical Studies

• An analysis of the PsO phase 2 and phase 3 (PHOENIX 1 and PHOENIX 2) clinical studies showed the risk differences observed in MACE between placebo and STELARA-treated subjects for each individual study, and for data combined from these PsO studies. See Figure: Risk Difference in MACE During the Placebo-Controlled Period in PsO Studies.
• In the placebo-controlled portions of the phase 2 and phase 3 PsO studies, 5 MACE were reported in 1582 STELARA-treated patients (0.3%; 95% confidence interval [CI], 0.10.7) compared with no events in 732 placebo-treated patients (0.0%; 95% CI, 0.0-0.5).
• Within the 12- and 20-week controlled periods of the phase 2 and 3 studies, no clustering of MACE was observed, with the 5 MACE occurring at weeks 2, 6, 10, 14, and 17, and all MACE occurred in patients with at least 3 established CV risk factors.

Cumulative Safety Experience: Results from Psoriasis Clinical Studies

2011 Safety Analysis

Papp et al (2013)¹ evaluated the cumulative safety experience of STELARA in adult patients with up to 5 years of treatment across phase 2 (n=301/320) and phase 3 (PHOENIX 1 [n=753/766], PHOENIX 2 [n=1212/1230], and ACCEPT [n=851/903]) PsO clinical studies (referred to as the 2011 Safety Analysis).

Study Design/Methods

• Patients with moderate to severe PsO from 4 randomized, blinded, phase 2 and 3 STELARA studies were included. All studies were placebo-controlled, except for the ACCEPT study with etanercept as the active-comparator.
• The 2011 Safety Analysis included 3117 patients receiving at least 1 dose of STELARA with 8998 PY of follow-up, including 1855 exposed up to 1 year, 1653 exposed up to 2 years, 1569 exposed up to 3 years, 1482 exposed up to 4 years, 1435 exposed up to 4.5 years, and 838 exposed up to 5 years.

Results

• Through the 2011 Safety Analysis, the numbers of events of MACE per 100 PY with 95% CIs were 0.56 (0.35-0.85) for the 45 mg, 0.36 (0.22-0.57) for the 90 mg, and 0.44 (0.32-0.61) for the combined groups. The overall rate of MACE was comparable between the 45 mg and 90 mg groups. Individual event rates were 0.08 and 0.06 (CV death), 0.40 and 0.31 (MI), 0.08 and 0.00 (stroke) for the 45 mg and 90 mg groups, respectively.
• Forty MACE (45 mg [n=21] and 90 mg [n=19]) were reported in 37 STELARA-treated patients; most were MIs, accounting for 77.5% (31/40) of all MACE reported. There was year-to-year variability, but no trend toward increasing events over time was noted. The proportion of patients with CV risk factors was similar at year 5 compared with baseline. All patients with MACE in this analysis had at least 2 established CV risk factors.

The 2011 Safety Analysis is the final summary from the STELARA PsO clinical development program. The long-term safety profile of STELARA remained stable over time, and is consistent with the previous reports after 3 and 4 years of follow-up.^17,18,19

CLINICAL DATA IN PSORIATIC ARTHRITIS

McInnes et al (2013)^20,21 reported results from PSUMMIT I, a phase 3, multicenter, double-blind, placebo-controlled study to assess the efficacy and safety of STELARA in reducing signs and symptoms of active PsA in adult patients.

• No MACE occurred during the placebo-controlled study period through week 16.
• The average duration of follow-up through week 108 was 91.9 weeks for the combined STELARA treatment groups.
• Three MACE were reported after the placebo-controlled period in patients receiving STELARA 45 mg, including MI (1 case at 8 weeks after placebo-controlled period, 1 case at 22 weeks after placebo-controlled period), and 1 stroke at 29 weeks after placebocontrolled period.
• MACE occurred at a rate of 0.66 per 100 PY of follow-up through week 108.

Ritchlin et al (2014)²² evaluated the efficacy and safety of STELARA in PSUMMIT II, a phase 3, multicenter, double-blind, placebo-controlled study in adult patients with active PsA with and without previous anti-tumor necrosis factor (anti-TNF) agent experience.

• No MACE occurred during the placebo-controlled study period through week 16.
• Through week 60, 3 MACE were reported, 2 in patients in the STELARA 45 mg group and 1 in a patient in the STELARA 90 mg group. Two of these cases were adjudicated as MIs (rate = 0.74 per 100 PY). All 3 patients had a history of CV risk factors (history of stroke, hypertension, smoking, and/or symptoms of metabolic syndrome) and had been previously treated with an anti-TNF agent.

Kavanaugh et al (2014)³ reported the pooled safety of STELARA from the phase 2 and 3 studies in adult patients with active PsA exposed to STELARA for up to 2 years.

• For this analysis, safety data from a phase 2 study of STELARA in 146 patients with active PsA (36-week study with a 12-week placebo-controlled period) were included with PSUMMIT I and PSUMMIT II.
• The rates of MACE per 100 PY were 0.69 for placebo, 1.04 for STELARA 45 mg, 0.32 for STELARA 90 mg, and 0.71 for STELARA-combined groups through 2 years of follow-up.

PSOLAR REGISTRY

PSOLAR is a multicenter, longitudinal, 8+ year, observational study evaluating the longterm safety and clinical outcomes for adult patients receiving (or eligible to receive) treatment for plaque PsO with biologics and/or conventional systemic agents in academic and community practices throughout North America, as well as in Europe and South America. Treatment is prescribed by the physician according to clinical practice or standard of care for plaque PsO; there are no randomized assignments to treatment or restrictions on the use of concomitant medication. Information on safety, clinical outcomes, quality of life, comorbidities, pharmacoeconomics and treatment regimens are collected at enrollment, and approximately every 6 months thereafter.⁶ MACE within PSOLAR is defined as nonfatal cerebrovascular accidents (CVA), nonfatal MI, and CV death.^4,5

Papp et al (2015)⁷ reported the occurrence of MACE events in PSOLAR patients based on an ever-exposed analysis of data from June 20, 2007, through August 23, 2014. Patients in PSOLAR may receive biologic and nonbiologic PsO therapies other than STELARA and infliximab. Switching treatments over the course of the registry was allowed. Start and stop dates for biologics are recorded, while capture of duration of nonbiologic therapies is limited to query regarding usage in the preceding 6-month interval. Rates of MACE are assessed using definitions of exposure based on the timing of STELARA treatment relative to the timing of the reported adverse event. For patients exposed to >1 therapy preceding the MACE event, the attribution order is: STELARA, infliximab, nonsponsor biologics, then nonbiologic therapy (i.e., if a patient was exposed to STELARA and a TNF inhibitor regardless of the sequence or duration of therapies, the MACE was attributed to STELARA or if another sponsor biologic and nonsponsor biologic agent was used, the MACE was attributed to the other sponsor biologic). Conservative attribution rules were used for these analyses for purposes of potential safety signal detection for STELARA.⁷

As of August 23, 2014, 12,093 adult patients (40,388 PY) were enrolled in PSOLAR. Baseline characteristics included: mean age, 48.6 years; 54.9% male; 82.9% Caucasian; mean body mass index (BMI), 30.90; and, mean body surface area (BSA) score, 12.1. Medical history includes: 38.4% CV risk factors and diseases (29.9% hypertension, 18.9% hyperlipidemia, and 3.1% coronary artery disease), 35.7% PsA (14.2% confirmed by a joint specialist), 11.5% diabetes type II, 6.2% skin cancer (including melanoma, basal cell carcinoma, squamous cell carcinoma, and unknown skin cancers), and 3.8% other cancers. Obesity was significant in the study with 32.2% of enrolled patients being overweight (BMI, 25.0-29.9) and 48.2% being obese (BMI >30.0). At study entry, 74.7% of patients were previously exposed to biologics with 39.2% of patients received 1 biologic prior to study entry, 20.3% received 2 biologics prior to study entry, 9.2% and 3.0% received 3 or 4 biologics, respectively. Approximately 0.8% of patients received 5 or more biologics at study entry.⁷

Unadjusted rates of MACE per 100 PY for PSOLAR patients with any exposure to therapy were as follows: STELARA-exposed patients = 0.59 (74/12,472 PY); other sponsor biologics (infliximab) = 0.62 (32/5176 PY); nonsponsor biologics rates of MACE = 0.51 (82/15,991 PY); the rate of MACE in patients with no biologic exposure = 0.64 (43/6749 PY). The unadjusted rate of MACE in all patients was 0.57 (231/40,388 PY).⁴

Multivariate analysis showed that STELARA was not associated with an increased risk of MACE compared with nonbiologic therapy (hazard ratio [HR], 1.34 [95% CI, 0.89-2.02; P=0.160]). Statistically significant predictors of MACE risk are described in Table: Independent Predictors of Time to First Occurrence of MACE.⁴

Due to the observational nature of PSOLAR, inherent biases (e.g., participation, selection, and reporting/recall biases) may affect data interpretation, as may the bias resulting from the attribution rules applied to the unadjusted data presented here and described above. While multivariate models are free from attribution bias and adjust for confounding factors, some variables such as prescribing tendency and family history may not be addressed. Lastly, other than STELARA, individual biologic and immunomodulator therapies have not been evaluated independently, as stipulated in the prespecified analytic plan. Nevertheless, results from PSOLAR are derived from a broad group of patients receiving biologic agents and other systemic treatments for PsO in a real-world setting and provide valuable insights into the safety profiles of such treatments.⁷

Results of these analyses identified that treatment with biologics did not increase risk of MACE in patients with PsO enrolled in PSOLAR.⁴

Bissonnette et al (2017)⁸ evaluated the occurrence of MACE events utilizing a cohort analysis within PSOLAR with data as of August 23, 2015. Biologic cohorts, including TNF inhibitors and STELARA, combined and by class, were compared with a topical/phototherapy cohort. For the biologic cohorts, only the first cohort-defining biologic was considered; biologic usage after switching was excluded. Patients in all cohorts may have been exposed to previous topical/phototherapy, methotrexate, or other systemic nonbiologic therapies. No concomitant systemic PsO therapy was allowed for any cohort, whereas concomitant topical/phototherapy was allowed for biologic cohorts. The exposure period for new biologic users (incident user and bio-naïve subpopulations) started at the date of the first cohort-defining dose on registry and ended at the earlier of 90 days after the last cohort-defining biologic dose, the date of switching to a different biologic, discontinuation from the registry, registry data cut (August 23, 2015), or death. The exposure period for prevalent biologic users started at registry enrollment and ended similarly to new biologic users. The topical/phototherapy cohort was composed of both prevalent and incident users. The topical/phototherapy cohort exposure time was consistent for all 3 populations and ranged from first to last visit with usage of these treatments.

A total of 7550 patients from PSOLAR, followed for 4.2 years, were included in this analysis, reflecting 21,999 total PY of observation. Overall, 66.2% of patients receiving biologics (59.5% receiving TNF-a inhibitors, 75.7% receiving STELARA), and 55.3% receiving topical/phototherapy remained in PSOLAR through the analysis interval. Mean duration of exposure was 2.8 years for the combined biologics group and 4.1 years for the topical/phototherapy group. Mean patient age at enrollment was 48.1 years, 58.1% were men and most (83.8%) were white. Most patients were overweight/obese (mean BMI, 30.7 kg/m²). The mean duration of PsO was 18.4 years and mean BSA involvement was 11.3% at enrollment. CV risk factors were prevalent among PSOLAR patients at baseline: overall, 28.6% had hypertension, 18.4% had hyperlipidemia, 10.9% had type II diabetes mellitus, and 56.6% were current or former smokers.

In the overall population, the unadjusted incidence rates of MACE were 0.47/100 PY (95% CI, 0.38-0.88) for the combined biologics cohort (0.43/100 PY [95% CI, 0.31-0.57] and 0.52/100 PY [95% CI, 0.38-0.70] in the TNF-a inhibitor and STELARA cohorts, respectively).⁵ The unadjusted incidence rate of MACE was 0.46/100 PY (95% CI, 0.26-0.77) for the topical/phototherapy cohort. In the incident user subpopulation, the incidence rates of MACE were 0.58/100 PY (95% CI, 0.40-0.80) for the combined biologics cohort (TNF-a inhibitors 0.54/100 PY [95% CI, 0.30-0.89] and STELARA 0.61/100 PY [95% CI, 0.37-0.94]) The incident rate of MACE for the topical/phototherapy cohort was 0.46/100 PY (95% CI, 0.26-0.77).

Multivariate analysis of the overall population showed that exposure to biologic agents, including combined biologics HR 1.281 (95% CI, 0.690-2.381), TNF-α inhibitors HR 1.200 (95% CI, 0.628-2.296), and STELARA HR 1.401 (95% CI, 0.720-2.728), was not associated with increased risk of MACE compared with topical/phototherapy treatment.⁵ Among other covariates tested in the model, increasing age HR 1.829 (95% CI, 1.517-2.205), male gender HR 1.980 (95% CI, 1.247-3.144), history of coronary artery disease HR 1.911 (95% CI, 1.081-3.379), history of transient ischemic attack/CVA/stroke HR 2.407 (95% CI, 1.090-5.314), history of diabetes I/II HR 1.708 (95% CI, 1.090-2.676), and history of hypertension HR 1.661 (95% CI, 1.053-2.621) were associated with statistically significant increased risk of MACE.

Results of these analyses identified that treatment with biologics did not increase risk of MACE in patients with PsO enrolled in PSOLAR.⁵

Langley et al. (2021)²³ conducted a nested case-control analysis to assess the mortality risk associated with PsO treatment exposure in patients enrolled in the PSOLAR registry.

Study Design/Methods

• PSOLAR data was collected in 12,090 patients for approximately 11 years with a median follow-up of 6.76 years.
• CV deaths included deaths due to known or suspected CV or cerebrovascular causes, which included but were not limited to sudden cardiac death, heart failure, coronary artery disease, MI, and stroke.
• Treatment exposure was defined as receiving at least 1 dose of therapy including methotrexate, STELARA, and anti-TNF therapy during a 3-month period before the recorded date of death (index date).
• Exposure was further stratified by total duration: no exposure, 1 day to <1 year, or ≥1 year.
• The incidence of CV mortality was calculated per 100 PY.

Results

• The total amount of CV deaths among all treatment was 85/341 deaths and the incidence rate was 0.12 per 100 PY; 95% CI (0.10-0.15). For CV death and treatment exposures, see Table: Adjusted Odds Ratios for Cardiovascular Death.

Clinical data in pediatric (ages 6 to 17) plaque psoriasis

The safety of STELARA was assessed in 110 adolescent patients (age 12 to 17 years) with moderate to severe plaque PsO in a phase 3, randomized, double-blind, placebo-controlled, multicenter clinical study (CADMUS). Patients received treatment through week 40.⁹

• Through week 60 of the CADMUS study, there were no reports of MACE.¹⁰

The safety of STELARA was assessed in 44 pediatric patients (6 to 11 years of age) with moderate to severe plaque PsO in a phase 3, open-label, single-arm, multicenter study (CADMUS Jr). Patients received treatment through week 40.¹¹

• Through week 56 of the CADMUS Jr study, there were no reports of MACE defined as CV death, MI, or nonfatal stroke.

additional clinical data in Plaque Psoriasis

MACE reports in plaque PsO comparator studies are summarized in Table: MACE in Phase 3 Comparator Studies. Refer to individual publications for additional detail on how MACE is defined in each study.

Rungapiromnan et al (2020)³⁴ performed a prospective cohort study to determine the comparative risk of MACE in adults with chronic PsO receiving anti-TNF therapies (adalimumab, etanercept) and STELARA.

Study Design/Methods

• Patients with moderate to severe PsO and adult patients ≥18 years of age with chronic PsO who were biologic-naïve with no prior history of MACE enrolled in the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) were included in this 11-year analysis.
• MACE was defined as acute coronary syndrome, unstable angina, MI, and stroke.
• The risk of MACE was studied over 2 periods:
  • Drug exposure
  • Drug exposure and an extension period (90 days after the last dose)
• Number of events and incident rates per 1000 PY of follow-up were selected outcomes in this analysis.

Results

• A total of 5468 patients were included in the main analysis.
  • Among these patients, 4517 and 951 patients were taking anti-TNF and STELARA therapy, respectively.
• For incidence rates among patients receiving anti-TNF and STELARA therapy, see Tables: Incidence Rates Among STELARA and Anti-TNF Therapy: Outcomes During Drug Exposure and Incidence Rates Among STELARA and Anti-TNF Therapy: Outcomes During Drug Exposure and Extension.

• There was no statistically significant difference found in the risk of MACE in either treatment period assessed.

CLINICAL DATA IN CROHN’S DISEASE and Ulcerative colitis

Ghosh et al (2024)¹² reported long-term safety data (up to 5 years in CD and 4 years in UC) from the cumulative analysis of six phase 2/3 studies (5 CD studies and 1 UC study) in patients with CD and UC.

• Patients who received ≥1 dose of STELARA were included in the analysis. Concomitant immunomodulators and corticosteroids were permitted.
• The PY of follow-up on IBD for STELARA and placebo were 4826 and 943, respectively. A total of 2575 patients received STELARA and 1389 patients received placebo.
• The rate of MACE (per 100 PY) was 0.25 (95% CI, 0.13-0.43) in the STELARA group and 0.32 (95% CI, 0.07-0.93) in the placebo group.
• The rates of deep vein thrombosis and pulmonary embolism (DVT/PE) events per 100 PY were infrequently reported across IBD, and they are as follows (STELARA vs placebo, respectively):
  • DVT: 0.35 (95% CI, 0.21-0.56) vs 0.11 (95% CI, 0.00-0.59)
  • PE: 0.08 (95% CI, 0.02-0.21) vs 0.42 (95% CI, 0.12-1.09)
• The overall rates of DVT and PE for STELARA and placebo were 0.44 (95% CI, 0.27-0.67) and 0.53 (95% CI, 0.17-1.24), respectively.
• For data across the overall study population, see Table: MACE Across Overall Population.

Ghosh et al (2021)¹³ reported rates of MACE observed during the STELARA phase 2 and 3 clinical studies for CD and UC. The analysis included data through 5 years in CD and 2 years in UC.

Study Design/Methods

• Data from six phase 2 and 3 clinical studies were analyzed which included all patients who received at least 1 dose of STELARA.
• The populations included in this analysis were:
  • All patients randomized to induction (weeks 0-8; phase 3 only)
  • Randomized maintenance (weeks 0-44, phase 3 only; including placebo patients who were responders to STELARA intravenous [IV] induction dose)
  • Patients in phase 2/3 clinical trials treated through 1 year
  • Long-term pooled safety dataset through 2020 (5 years in CD and 2 years in UC)
• Number of events and events per 100 PY of follow-up were outcomes included in this analysis.

Results

• No MACE was identified in STELARA-treated patients in phase 3 CD/UC studies throughout induction and randomized maintenance. In UC, 1 MACE of nonfatal stroke during induction and 1 MACE of nonfatal MI during randomized maintenance were reported in placebo-treated patients.
• Throughout 1 year of treatment in phase 2/3 CD and UC studies, 2 events of MACE were reported in the STELARA and placebo groups constituting rates of 0.12 (95% CI, 0.01-0.42) and 0.34 (95% CI, 0.04-1.21), respectively.
• In the long-term pooled 2020 safety dataset, 2575 patients were treated with STELARA with 3960 PY of follow-up with 12 (0.30 events per 100 PY) events and 3 (0.33 events per 100 PY) events in the STELARA and placebo group, respectively.
• For MACE data through 1 year in CD and UC, see Tables: MACE in the Induction/Randomized Maintenance Population and All-Treated Patients through 1 Year for Crohn’s Disease and MACE in the Induction/Randomized Maintenance Population and All-Treated Patients through 1 Year for Ulcerative Colitis.

• For MACE data in the CD and UC long-term pooled safety dataset, see Tables: MACE in the Long-Term Pooled Safety Dataset for Crohn’s Disease and MACE in the Long-Term Pooled Safety Dataset for Ulcerative Colitis.

Danese et al (2022)¹⁴ conducted an integrated safety analysis incorporating data from phase 2/3 and phase 3b studies in CD and UC for bio-naïve patients (up to 5 years in CD and up to 2 years in UC).

• Bio-naïve was defined as patients who were never treated with biologics. Concomitant immunomodulators and corticosteroids were permitted.
• Through up to 1 year, the median duration of follow-up for placebo and STELARA was 27.61 and 39.26 weeks, respectively. The total PY of follow-up was 226 for placebo and 582 for STELARA.
• Through up to 5 years, the median duration of follow-up was 45.96 weeks for placebo and 101.90 weeks for STELARA. The total PY of follow-up for placebo and STELARA was 376 and 1511, respectively.
• MACE are presented as event rates per 100 PY of follow-up.
• Through up to 5 years, there were 425 bio-naïve patients who received placebo and 771 bio-naïve patients who received STELARA.
• Through up to 1 year of treatment, the rate of MACE (events per 100 PY) was 0.00 (95% CI, 0.00-0.51) in STELARA-treated bio-naïve patients (n=771) and 0.89 (95% CI, 0.11-3.20) in placebo-treated bio-naïve patients (n=425).
• Through up to 5 years of treatment, the rate of MACE (events per 100 PY) was 0.07 (95% CI, 0.00-0.37) in STELARA-treated bio-naïve patients (n=771) and 0.53 (95% CI, 0.06-1.92) in placebo-treated bio-naïve patients (n=425).

Loftus et al (2022)¹⁵ reported long-term safety data (up to 5 years in CD and up to 2 years in UC) from an integrated analysis of five phase 2/3 and phase 3 studies in CD and UC patients with a history of prior biologic failure.

• All patients who received ≥1 dose of STELARA and were identified to have a history of prior biologic failure were included in this analysis.
• Through up to 5 years, the average duration of follow-up for placebo and STELARA was 29.06 and 64.18 weeks, respectively. The total PY of follow-up was 473 for placebo and 1970 for STELARA.
• Through up to 5 years of treatment, the rate of MACE (events per 100 PY) in patients with a history of prior biologic failure are presented below:
  • Placebo-treated patients (n=847): 0.21 (95% CI, 0.01-1.18)
  • STELARA-treated patients (n=1596): 0.25 (95% CI, 0.08-0.59)

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 18 March 2024.