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Myristoylation, the N-terminal addition of the fatty acid myristate to proteins, regulates membrane-bound signal transduction pathways important in cancer cell biology. This modification is catalyzed by two N-myristoyltransferases, NMT1 and NMT2. Zelenirstat is a first-in-class potent oral small molecule inhibitor of both NMT1 and NMT2 proteins. Patients with advanced solid tumors and relapsed/refractory (R/R) B-cell lymphomas were enrolled in an open label, phase I dose escalation trial of oral daily zelenirstat, administered in 28-day cycles until progression or unacceptable toxicity. The endpoints were to evaluate dose-limiting toxicities (DLT) to establish a maximum tolerated dose (MTD), pharmacokinetic parameters, and anticancer activity. Twenty-nine patients were enrolled (25 advanced solid tumor; 4 R/R B-cell lymphoma) and 24 were DLT-evaluable. Dosing ranged from 20 mg once daily (OD) to 210 mg OD without DLT, but gastrointestinal DLTS were seen in the 280 mg cohort. MTD and recommended phase 2 dose were 210 mg OD. Common adverse events were predominantly Gr ≤ 2 nausea, vomiting, diarrhea, and fatigue. Plasma concentrations peaked at 2 h with terminal half-lives averaging 10 h. Steady state was achieved by day 15, and higher doses achieved trough concentrations predicted to be therapeutic. Stable disease as best response was seen in eight (28%) patients. Progression-free survival and overall survival were significantly better in patients receiving 210 mg OD compared to those receiving lower doses. Zelenirstat is well-tolerated, achieves plasma exposures expected for efficacy, and shows early signs of anticancer activity. Further clinical development of zelenirstat is warranted. [ABSTRACT FROM AUTHOR]

Cannabis is well established to impact affective states, emotion and perceptual processing, primarily through its interactions with the endocannabinoid system. While cannabis use is quite prevalent in many individuals afflicted with psychiatric illnesses, there is considerable controversy as to whether cannabis may worsen these conditions or provide some form of therapeutic benefit. The development of pharmacological agents which interact with components of the endocannabinoid system in more localized and discrete ways then via phytocannabinoids found in cannabis, has allowed the investigation if direct targeting of the endocannabinoid system itself may represent a novel approach to treat psychiatric illness without the potential untoward side effects associated with cannabis. Herein we review the current body of literature regarding the various pharmacological tools that have been developed to target the endocannabinoid system, their impact in preclinical models of psychiatric illness and the recent data emerging of their utilization in clinical trials for psychiatric illnesses, with a specific focus on substance use disorders, trauma-related disorders, and autism. We highlight several candidate drugs which target endocannabinoid function, particularly inhibitors of endocannabinoid metabolism or modulators of cannabinoid receptor signaling, which have emerged as potential candidates for the treatment of psychiatric conditions, particularly substance use disorder, anxiety and trauma-related disorders and autism spectrum disorders. Although there needs to be ongoing clinical work to establish the potential utility of endocannabinoid-based drugs for the treatment of psychiatric illnesses, the current data available is quite promising and shows indications of several potential candidate diseases which may benefit from this approach. [ABSTRACT FROM AUTHOR]

Purpose Training represents a considerable portion of research activities and is vastly different for each clinical trial. This variation is partially explained by the lack of detailed regulations surrounding training procedures, which hinders the ability of investigational drug service (IDS) staff to plan their workload. The aim of this study was to quantify the workload associated with trial-specific training of IDS staff. The secondary aim was to identify the factors associated with training complexity. Methods A retrospective study was carried out in the IDS of a mother and child university hospital. Trial-specific documents on which the pharmacy staff was trained were analyzed. Workload was calculated by measuring reading time. The readability of each document was determined by the Flesch Reading Ease score. The complexity of the trials was established using the scoring method of Calvin-Lamas et al. The influence of the following factors on training was assessed by analysis of variance: sponsor type, research phase, and research focus by medical specialty. Results A total of 93 clinical trials and 433 documents were included. Investigator's brochures were the longest (a mean [SD] of 107 [46] pages; P < 0.0001) and most difficult documents to read (mean [SD] readability score, 25.5 [4.4]; P < 0.0001). Trials with industry sponsors required a significantly longer overall reading time (mean [SD], 12.26 [6.72] hours; P < 0.0001). On average, a mean (SD) of 9.42 (7.16) hours of reading were necessary to train one employee for a clinical trial. Conclusion This study is the first to document reading time necessary for training of IDS staff. The training workload varied by sponsor type, while the research phase and medical specialty had little impact. IDS units would benefit from a tool that could identify complex trials. [ABSTRACT FROM AUTHOR]

Introduction: The unique evidentiary, economic and ethical challenges associated with health technology assessment (HTA) of precision therapies limit access to novel drugs and therapeutics for children and youth, for whom such challenges are amplified. We elicited citizens' perspectives about values‐based criteria relevant to the assessment of paediatric precision therapies to inform the development of a child‐tailored HTA framework. Methods: We held four citizen panels virtually in May–June 2021, informed by a plain‐language citizen brief summarizing global and local evidence about the challenges, policy and programmatic options and implementation strategies related to enhancing access to precision therapies for Canadian children and youth. Panellists were recruited through a nationally representative database, medical/patient networks and social media. We inductively coded and thematically analysed panel transcripts to generate themes and identify priority values. Results: The perspectives of panellists (n = 45) coalesced into four overlapping themes, with attendant subthemes, relevant to a child‐tailored HTA framework: (1) Childhood Distinctions: vulnerability, 'fair innings', future potential, family impacts; (2) Voice: agency of children and youth; lived versus no lived experience; (3) One versus Many: disease severity, rarity, equity, unmet need and (4) Health System Governance: funding, implementation inequities, effectiveness and safety. Participants broadly agreed that childhood distinctions, particularly family impacts, justify child‐tailored HTA. Dissent arose over whose voice should inform HTA and how such perspectives are best incorporated. Conclusions: Citizens can offer unique insights into criteria relevant to the development or revision of HTA frameworks to capture holistic, societally responsive dimensions of value attached to unique contexts or populations, including children. Balancing the hopes and expectations of patients and caregivers for access to expensive but potential life‐altering therapies against the opportunity costs borne by encompassing health systems is a fundamental challenge that will require rigorous methods to elicit, weigh and reconcile varied views. Patient or Public Contribution: A patient advocate served on the steering committee of this study and co‐authored this article. Key informants for the Citizen Brief included patient advocates and caregivers; a separate patient advocate reviewed the Brief before dissemination. Qualitative and quantitative data were collected from the general public and caregivers of children, with written consent. [ABSTRACT FROM AUTHOR]

Objective. Examine the use of priority and provisional approval pathways by the Australian Therapeutic Goods Administration (TGA) for evaluating new medicines. Methods. This observational study assessed all new medicines approved by the TGA between 1 January 2018 and 18 October 2021. It examined how frequently priority and provisional approval pathways are being used, the conditions which the medicines are being approved to treat, how long medicines are spending in the approval pathways, the additional therapeutic value of the medicines being approved through these pathways and how the use of the pathways compares with similar regulatory pathways used by Health Canada. Results. The TGA approved 138 new medicines in the time period under study, of which 33 were approved through either the priority or provisional approval pathways. Sixteen were approved to treat cancer. It took the TGA a mean of 130 (95% CI 118, 143) and 144 (95% 101, 188) working days for priority and provisional pathways, respectively. Therapeutic evaluations were available for 16 of these medicines and 11 offered little to no therapeutic gain over existing medicines. There was moderate agreement between the TGA and Health Canada in their use of these pathways (Kappa = 0.5458, 95% CI 0.3900, 0.7016). Conclusions. The priority and provisional approval pathways are now being used by the TGA for about one-third of all new medicine approvals. Although the medicines approved in these ways are moving through the review process more quickly than those approved through the standard approval pathway, the majority of these medicines, for which an evaluation of therapeutic value is available, do not offer any substantial additional therapeutic value over existing medicines. [ABSTRACT FROM AUTHOR]

Background: Drug survival analysis of biologic agents in psoriasis is of extreme importance, as it allows not only the evaluation of objective clinical outcomes (such as effectiveness and safety) but also of factors that are associated with patients' adherence to treatment. The aim of this study was to evaluate and compare the drug survival of the most recent biologic agents approved for the treatment of moderate-to-severe psoriasis—ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, and risankizumab—and to identify clinical predictors that can influence the drug survival of these drugs. Methods: This retrospective multicentric cohort study from 16 dermatology centers in Portugal, Spain, Italy, Switzerland, Czech Republic, Canada, and the United States included patients that started IL-12/23, IL-17 (IL-17A and IL-17R) and IL-23 inhibitors for the treatment of psoriasis between January 1, 2012 and December 31, 2019. Survival analysis was performed using a Kaplan-Meier estimator, to obtain descriptive survival curves, and proportional hazard Cox regression models. Results: A total of 3312 treatment courses (total patients: 3145) were included in the study; 1118 (33.8%) with an IL-12/23 inhibitor (ustekinumab), 1678 (50.7%) with an IL-17 inhibitor [911 (27.5%) on secukinumab, 651 (19.7%) on ixekizumab, 116 (3.5%) on brodalumab], and 516 (15.5%) with an IL-23 inhibitor [398 (12.0%) on guselkumab, 118 (3.5%) on risankizumab]. At 18 months, the cumulative probability of survival was 96.4% for risankizumab, 91.1% for guselkumab, 86.3% for brodalumab, 86.1% for ustekinumab, 82.0% for ixekizumab, and 79.9% for secukinumab. Using ustekinumab as reference, drug survival of guselkumab was higher (HR 0.609; 95% CI 0.418–0.887) and that of secukinumab was lower (HR 1.490; 95% CI 1.257–1.766). In the final multivariable model, secukinumab, female sex, higher BMI, and prior exposure to biologic agents significantly increased the risk of drug discontinuation, whereas risankizumab was protective. Conclusion: In this multinational cohort with 8439 patient-years of follow-up, the cumulative probability of drug survival for all drugs was >79% at 18 months. Prescribed biologic, female sex, higher BMI, and previous exposure to biologic agents were predictors of drug discontinuation. Drug survival of guselkumab and risankizumab was higher than that of ustekinumab, and secukinumab was lower. [ABSTRACT FROM AUTHOR]

Although randomized controlled trials (RCTs) examine "objective" indicators of safety and efficacy of investigational drugs, participants may not perceive study medications as neutral entities. Some medications are imbued with social and cultural meaning, such as stigmatized medications for opioid use disorders. Such perceptions surrounding substance use treatments can extend to the research context and shape RCT participants' experiences with and adherence to study medications. Considering these complexities in substance use research, we conducted a nested qualitative study within a multi-site, pragmatic RCT in Canada testing two treatments (methadone versus buprenorphine/naloxone) for opioid use disorder. Between 2017 and 2020, we conducted 115 interviews with 75 RCT participants across five trial sites in British Columbia, Alberta, Ontario, and Quebec. Using an abductive coding approach, we characterized participants by their previous experience with medication for opioid use disorder and by their exposure to drug culture and drug scenes. Across these experience types, we identified systematic differences around participants' perceptions of the study medications, sources of information and expertise, and medication stigma. Our findings illustrate the critical importance of social context in shaping medication beliefs and study experiences among people who use drugs, with implications for the conduct of future RCTs in substance use. • Medications for opioid use disorder have social meaning that can influence research. • Participants' prior experiences shape medication beliefs and RCT participation. • Nested qualitative studies within RCTs provide robust data on research experiences. [ABSTRACT FROM AUTHOR]

Background: Authors from the Canadian Agency for Drugs and Technologies in Health (CADTH) presented an analysis of submissions to the Common Drug Review (CDR) between 2004 and February 3, 2016 for drugs for rare disorders (disorders with a prevalence of <50 per 100,000).Objective: The aim of this analysis was to examine the same CDR submissions to evaluate whether the negative reimbursement recommendation rate, clinical evidence of efficacy and statements concerning the drug's cost in the CDR reports varied with the prevalence of the disorder treated by the drug grouped into three decreasing categories: <50 to >10, ≤10 to >1, and ≤1 per 100,000.Results: As the prevalence of the treated disorder decreased, the median daily cost of the drug, the negative recommendation rate and the proportion of submissions with statements in the CDR reports highlighting the cost of the drug increased, while the proportion of submissions with acceptable evidence of clinical efficacy decreased. Moreover, although the CADTH authors reported that only two submissions received a negative recommendation due to a "lack of cost-effectiveness/high cost," high cost was mentioned in the CDR reports of 15 drugs with negative recommendations, all for disorders with a prevalence of ≤10 per 100,000.Conclusions: The aggregated analysis of CDR submissions for drugs for disorders with wide ranging prevalence rates concealed information of concern to patients. The negative reimbursement recommendation rate and the significance of cost in the CDR assessments increased as the prevalence of the treated disorder decreased. Since 2012, the manner in which high cost drugs for rare disorders have been dealt with by the CDR has changed. Cost has ceased to be a factor in negative recommendations but is included in criteria accompanying positive recommendations. This trend is associated with the integration of the CDR process with the system for price negotiation between public drug plans and pharmaceutical companies. [ABSTRACT FROM AUTHOR]

Background SB939 is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDACs). These three HDAC classes are highly expressed in castration resistant prostate cancer (CRPC) and associated with poor clinical outcomes. We designed a phase II study of SB939 in men with metastatic CRPC. Methods Patients received SB939 60 mg on alternate days three times per week for 3 weeks on a 4-week cycle. Primary endpoints were PSA response rate (RR) and progression-free survival (PFS). Secondary endpoints included objective response rate and duration; overall survival; circulating tumor cell (CTC) enumeration and safety. Exploratory correlative studies of the TMPRSS2-ERG fusion and PTEN biomarkers were also performed. Results Thirty-two patients were enrolled of whom 88 % had received no prior chemotherapy. The median number of SB939 cycles administered was three (range 1-8). Adverse events were generally grade 1-2, with five pts experiencing one or more grade three event. One patient died due to myocardial infarction. A confirmed PSA response was noted in two pts (6 %), lasting 3.0 and 21.6 months. In patients with measurable disease there were no objective responses. Six patients had stable disease lasting 1.7 to 8.0 months. CTC response (from ≥5 at baseline to <5 at 6 or 12 weeks) occurred in 9/14 evaluable patients (64 %). Conclusion Although SB939 was tolerable at the dose/schedule given, and showed declines in CTC in the majority of evaluable patients, it did not show sufficient activity based on PSA RR to warrant further study as a single agent in unselected patients with CRPC. [ABSTRACT FROM AUTHOR]

Background Activation of the vascular endothelial growth factor receptor (VEGFR) and the oncogenic Src pathway has been implicated in the development of castration-resistant prostate cancer (CRPC) in preclinical models. Cediranib and dasatinib are multi-kinase inhibitors targeting VEGFR and Src respectively. Phase II studies of cediranib and dasatinib in CRPC have shown single agent activity. Methods Docetaxel-pretreated CRPC patients were randomized to arm A: cediranib alone (20 mg/day) versus arm B: cediranib (20 mg/day) plus dasatinib (100 mg/day) given orally on 4-week cycles. Primary endpoint was 12-week progression-free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2). Patient reported outcomes were evaluated using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Present Pain Intensity (PPI) scales. Correlative studies of bone turnover markers (BTM), including bone alkaline phosphate (BAP) and serum beta-C telopeptide (B-CTx) were serially assayed. Results A total of 22 patients, 11 per arm, were enrolled. Baseline demographics were similar in both arms. Median number of cycles =4 in arm A (range 1-12) and 2 in arm B (range 1-9). Twelve-week PFS was 73 % in arm A versus 18 % in arm B ( p = 0.03). Median PFS in months (arm A versus B) was: 5.2 versus 2.6 (95 % CI: 1.9-6.5 versus 1.4-not reached). Most common grade 3 toxicities were hypertension, anemia and thrombocytopenia in arm A and hypertension, diarrhea and fatigue in arm B. One treatment-related death (retroperitoneal hemorrhage) was seen in arm A. FACT-P and PPI scores did not significantly change in either arm. No correlation between BTM and PFS was seen in either arm. Conclusions Although limited by small numbers, this randomized study showed that the combination of VEGFR and Src targeted therapy did not result in improved efficacy and may be associated with a worse outcome than VEGFR targeted therapy alone in patients with CRPC. ClinicalTrials.gov number: NCT01260688. [ABSTRACT FROM AUTHOR]

Summary: Background: Depletion of B lymphocytes is associated with suppression of inflammatory activity in multiple sclerosis. We aimed to assess the safety and efficacy of atacicept, a recombinant fusion protein that suppresses B-cell function and antibody production. Methods: In this placebo-controlled, double-blind, 36-week, phase 2 trial (ATAMS) in Australia, Canada, Europe, and the USA, patients aged 18–60 years with relapsing multiple sclerosis were randomly assigned via an interactive voice response system in a 1:1:1:1 ratio, stratified by geographical region, to receive weekly subcutaneous injections with atacicept (25, 75, or 150 mg) or placebo. Both patients and study personnel were masked to treatment assignment. The primary endpoint was the change in mean number of gadolinium-enhancing lesions on T1-weighted MRI per patient per scan between weeks 12 and 36. Efficacy endpoints were analysed in the intention-to-treat population. Patients who completed week 36 were eligible to participate in a long-term extension study (ATAMS EXT), consisting of a double-blind phase followed by an open-label phase, for a total study time of up to 5 years. The study was terminated early after the independent data and safety monitoring board noted an increased annualised relapse rate with atacicept. The protocol was subsequently amended to include a 60-week safety follow-up, to allow treatment with approved multiple sclerosis drugs, and to change the primary endpoint to gadolinium-enhancing T1 lesions per scan during the entire double-blind period of ATAMS. Both the trial and the extension are registered with ClinicalTrials.gov, numbers NCT00642902 (ATAMS) and NCT00853762 (ATAMS EXT). Findings: Between April 23, 2008, and early study termination on Sept 11, 2009, 255 patients were randomly assigned: 63 to placebo, 63 to atacicept 25 mg, 64 to 75 mg, and 65 to 150 mg. 90 (35%) patients completed the week 36 treatment visit, 26 (10%) discontinued before study termination (including one who dropped out before receiving study treatment), and 139 (55%) discontinued because of study termination. During the double-blind period of ATAMS, annualised relapse rates were higher in the atacicept groups than in the placebo group (atacicept 25 mg, 0·86, 95% CI 0·43–1·74; 75 mg, 0·79, 0·40–1·58; 150 mg, 0·98, 0·52–1·81; placebo, 0·38, 0·17–0·87). Mean numbers of gadolinium-enhancing T1 lesions per scan were similar in all groups (25 mg, 2·26, 0·97–5·27; 75 mg, 2·30, 1·08–4·92; 150 mg, 2·49, 1·18–5·27; placebo, 3·07, 1·40–6·77). Seven patients (one taking placebo and six atacicept) discontinued treatment because of adverse events. One death occurred in the placebo group. During the safety follow-up, immunoglobulin concentrations and B-cell counts returned towards predose values and annualised relapse rates in the atacicept groups decreased until they were similar to that of the placebo group Interpretation: Increased clinical disease activity associated with atacicept suggests that the role of B cells and humoral immunity in multiple sclerosis is complex. For studies that explore therapeutic immunomodulation in multiple sclerosis, rigorous monitoring for negative effects on clinical and MRI outcomes is warranted. Funding: Merck Serono (Merck KGaA) and EMD Serono (Merck KGaA). [Copyright &y& Elsevier]

Purpose AT9283 is a potent inhibitor of the mitotic regulators, Aurora-kinases A and B, and has shown anti-tumor activity in patients with solid and haematological malignancies. This phase I study assessed safety, tolerability, pharmacokinetic and pharmacodynamic properties of AT9283. Patients and methods Patients with advanced, incurable solid tumors or non-Hodgkin's lymphoma received AT9283 as a continuous 24-hour infusion on days 1, 8 of a 21-day cycle. A 3 + 3 dose escalation design was used with a starting dose of 1.5 mg/m/day. Pharmacokinetic samples were collected from all patients on cycle one, and pharmacodynamic samples were collected from 4 patients at the recommended phase II dose (RP2D). Results 35 patients were evaluable for toxicity and 32 were evaluable for response. AT9283 was well tolerated, with main toxicities being reversible dose-related fatigue, gastrointestinal disturbance, anemia, lymphocytopenia and neutropenia. The dose limiting toxicities were febrile neutropenia (two patients) and neutropenia with grade 3 infection (1 patient) at 47 mg/m/day (established as the maximum tolerated dose). The RP2D was 40 mg/m/day. Pharmacokinetic analyses showed AT9283 appeared to follow linear kinetics, with a mean elimination half-life of 8.2 h. Pharmacodynamic analyses showed no consistent or significant changes, but trends suggested evidence of AT9283 inhibition and anti-proliferative activity. One patient had partial response and four patients experienced RECIST stable disease (median 2.6 months). Conclusion In this study, AT9283 was well tolerated. The RP2D is 40 mg/m/day on days 1, 8 of a 21-day cycle. Ongoing AT9283 trials will assess efficacy and safety in solid and haematological cancers. [ABSTRACT FROM AUTHOR]

Background: Expanded access is the use of investigational drugs (IDs) outside of clinical trials. Generally it is performed in patients with serious and life-threatening diseases who cannot be treated satisfactorily with authorized drugs. Legal regulations of expanded access to IDs have been introduced among others in the USA, the European Union (EU), Canada and Australia. In addition, in the USA an alternative to expanded access is treatment under the Right-to-Try law. However, the treatment use of IDs is inherently associated with a number of ethically relevant problems.Main Text: The objective of this article is to present a coherent framework made up of eight requirements which have to be met for any treatment use of an ID to be ethical. These include a justified need for the use of an ID, no threat to clinical development of the ID, adequate scientific evidence to support the treatment, patient's benefit as the primary goal of the use of an ID, informed decision of a patient, fair access of patients to IDs, independent review, as well as the dissemination of treatment results.Conclusions: While this framework is essentially consistent with the legal regulations of expanded access of the USA, the EU, Canada and Australia, it is substantially wider in scope because it addresses some important issues that are not covered by the regulations. Overall, the framework that we developed minimizes the risks and threats, and maximizes potential benefits to each of the four key stakeholders involved in the treatment use of IDs including patients, doctors, drug manufacturers, and society at large. [ABSTRACT FROM AUTHOR]

2′3′-cyclic-GMP-AMP (cGAMP) is a second messenger that activates the antiviral stimulator of interferon genes (STING) pathway. We recently identified a novel role for cGAMP as a soluble, extracellular immunotransmitter that is produced and secreted by cancer cells. Secreted cGAMP is then sensed by host cells, eliciting an antitumoral immune response. Due to the antitumoral effects of cGAMP, other CDN-based STING agonists are currently under investigation in clinical trials for metastatic solid tumors. However, it is unknown how cGAMP and other CDNs cross the cell membrane to activate intracellular STING. Using a genome-wide CRISPR screen, we identified SLC19A1 as the first known importer of cGAMP and other CDNs, including the investigational new drug 2′3′-bisphosphosphothioate-cyclic-di-AMP (2′3′-CDAS). These discoveries will provide insight into cGAMP's role as an immunotransmitter and aid in the development of more targeted CDN-based cancer therapeutics. • A CRISPR screen identifies the reduced folate carrier SLC19A1 as a cGAMP importer • Other cyclic dinucleotides (CDNs) also utilize SLC19A1 with varying selectivity • Other CDN import mechanisms exist and vary by cell type 2′3′-cyclic-GMP-AMP (cGAMP) is an immunotransmitter produced and secreted by cancer cells that is uptaken by host cells to elicit an antitumoral immune response. Using a CRISPR screen, Ritchie et al. identify SLC19A1 as the first importer of cGAMP and other cyclic dinucleotides (CDNs). [ABSTRACT FROM AUTHOR]

Background/aims: In comparison with commercial drugs, there are few regulations concerning the labeling of investigational drugs. This leads to variability in their content and layout. This increases the risk of errors during storage, validation, compounding, dispensing and administration. The aim of this study was to evaluate the conformity and variability of investigational drug labels. Additional exploratory aims were to evaluate the use of an automated script to describe the labels and to identify the factors associated with the ease of finding a kit number., Methods: An 87-criterion list was developed to evaluate content, format and readability. It included eight criteria to evaluate the conformity to the Canadian Food and Drugs Regulation. A systematic cross-sectional evaluation of all investigational drug labels in our 500-bed mother-child center was performed. All active protocols during the period of 14-22 February 2018 were included. Labels from drugs that were sourced locally were excluded. Labels affixed to the outside (external) and inside (internal) containers, as well as labels from American and European sponsors, were compared with the chi-square and Student's t tests. A script was developed in Python to automatically determine key information (number of words, main colors and their proportion). A short survey was conducted with a convenience sample of pharmacists to rate the ease of finding the kit number on labels. Correlation was evaluated with different factors., Results: A total of 27 protocols were included (24 internal and 34 external labels). The majority (33/34) of external labels were compliant with the Regulation. Some internal labels did not state the expiry date (9/13), the sponsor address (2/13) or storing conditions (1/13). A total of 10 criteria were different between internal and external labels, for instance, the number of languages was higher on external labels (median 3 (2-14) vs 10 (2-50); p = 0.013). Five criteria were different depending on the sponsors' location, for instance, European sponsors were more prone to use bold characters (25% vs 61%, p = 0.034). There was a mean of 146 ± 111 words and 78.3% ± 7.3% empty space per label. These were positively correlated (p < 0.001). The proportion of free space on a label was also correlated with the ease of finding the kit number (p = 0.002)., Conclusion: We measured a high variability in the labeling of investigational drugs. Key information was missing from labels affixed to internal containers, despite the use of a high number of pages. The automation worked well and further work is needed to identify criteria that may improve readability and reduce error risk. Detailed and harmonized international guidelines are needed.