Inflammatory Bowel Disease Trials Research Articles

Outcomes of patients with prior biologic intolerance are better than those with biologic failure in clinical trials of inflammatory bowel disease

Abstract Background and Aims Inflammatory bowel disease (IBD) trials often stratify patients by prior biologic exposure, including prior biologic failure or intolerance. This study aimed to assess clinical outcomes in IBD patients with prior biologic failure versus intolerance treated with ustekinumab or vedolizumab. Methods A post-hoc analysis of ulcerative colitis (UC) and Crohn’s disease (CD) clinical trials for ustekinumab (UNITI, UNIFI) and vedolizumab (GEMINI-1, GEMINI-2) was performed. Clinical response, clinical remission, and endoscopic improvement (for UC) were compared among biologic naïve, biologic-failure, and biologic intolerant patients. Statistical analyses, including chi-square tests and logistic regression, were performed. Results 1178 UC and 1439 CD patients received either ustekinumab or vedolizumab. In UC, biologic intolerant patients exhibited higher clinical response (54.7% vs. 38.8%, aOR 1.87 [95% CI 0.93-3.73]), clinical remission (25.0% vs. 11.0%, aOR 2.84 [95% CI 1.47-5.49]), and endoscopic improvement (40.6% vs. 24.8%, aOR 2.76 [95% CI 1.28-5.94]) compared to biologic failure, with outcomes similar to biologic naïve patients. In biologic-intolerant CD patients, clinical response was similar between prior biologic failure and intolerance (34.2% vs 32.8%), but after adjustment for potential confounders, biologic intolerance was associated with higher odds of clinical response (aOR: 1.67, 95% CI 1.09-2.55), with no significant difference observed for clinical remission (aOR: 1.48, 95% CI 0.88-2.49). Conclusion Improved treatment outcomes were generally observed in patients with biologic intolerance compared to failure, especially in UC, where outcomes were similar to biologic naïve patients. Future clinical trials should meticulously differentiate prior biologic failure versus intolerance to mitigate potential bias.

Navigating the complexities of drug development for inflammatory bowel disease.

Inflammatory bowel disease (IBD) - consisting of ulcerative colitis and Crohn's disease - is a complex, heterogeneous, immune-mediated inflammatory condition with a multifactorial aetiopathogenesis. Despite therapeutic advances in this arena, a ceiling effect has been reached with both single-agent monoclonal antibodies and advanced small molecules. Therefore, there is a need to identify novel targets, and the development of companion biomarkers to select responders is vital. In this Perspective, we examine how advances in machine learning and tissue engineering could be used at the preclinical stage where attrition rates are high. For novel agents reaching clinical trials, we explore factors decelerating progression, particularly the decline in IBD trial recruitment, and assess how innovative approaches such as reconfiguring trial designs, harmonizing end points and incorporating digital technologies into clinical trials can address this. Harnessing opportunities at each stage of the drug development process may allow for incremental gains towards more effective therapies.

Basket, Umbrella, and Platform Trials: The Potential for Master Protocol–Based Trials in Inflammatory Bowel Disease

Basket, Umbrella, and Platform Trials: The Potential for Master Protocol–Based Trials in Inflammatory Bowel Disease

Prepublication abstract-only reports compared with full-text manuscripts for randomised controlled trials in inflammatory bowel disease: a systematic review

IntroductionRandomised controlled trials (RCTs) of key therapies in inflammatory bowel disease (IBD) are often presented and available as abstracts for significant periods of time prior to full publication, often being...

Adverse events of biologic or small molecule therapies in clinical trials for inflammatory bowel disease: A systematic review and meta-analysis

BackgroundBiologic or small-molecule therapies are highly effective for the treatment of inflammatory bowel disease (IBD), and approval by the FDA has significantly increased both their clinical use and the development of novel regimens. However, the identification and management of their associated toxicities poses challenges for clinicians and researchers. MethodsA systematic review and meta-analysis of randomized controlled trials (RCTs) published from January 1, 2000, to October 15, 2022, and in the databases. A random-effects model with logit transformation was applied to the analysis heterogeneity between studies was evaluated using the I2 statistic with incidence and 95 % confidence interval (CI) for any adverse events (AEs), and serious AEs (SAEs). ResultsIn Crohn's disease (CD), the total AE incidence was 67.0 % (95 % CI, 66.2%–67.8 %; I2 = 97.2 %) for any AEs and 7.3 % (6.9–7.7; 97.2) for serious AEs. In ulcerative colitis (UC), the overall incidence of any and serious AEs was 63.6 % (63.0–64.3; 98.1) and 5.7 % (5.4–6.0; 88.9), respectively. The most common AEs were infections (21.5 [20.3–22.8], 32.6 [31.0–34.2], 25.9 [24.5–27.2], and 13.7 [10.7–16.7]) in CD patients that were treated with TNF antagonists, anti-integrins, anti-IL agents, and JAK inhibitors, respectively, and in UC patients also were infections (22.8 [21.7–24.0], 27.4 [25.9–28.9], and 18.4 [16.7–20.2]), respectively, as well as increases in lactic dehydrogenase levels (23.1 [20.8–25.4]) with JAK inhibitors. ConclusionThis study offers a comprehensive summary of toxic side effects of IBD treatments and a useful reference for both patients and clinicians.

P952 Why do patients with Inflammatory Bowel Disease Take Part in Pharmaceutical Clinical Trials? A qualitative study of Clinical Trial Participants

Abstract Background Recruitment rates to clinical trials in inflammatory bowel disease (IBD) continue to decline. A better understanding of motivations to participate as well as recommendations to reduce barriers to enrolment from a patient perspective may assist in design of future clinical trials. Methods We developed a 32-item electronic questionnaire to explore motivations, experiences and recommendations of patients with IBD, who have participated in pharmaceutical clinical trials in a tertiary centre in Canada. Results We distributed a total of 82 emails with surveys based on the patient details available to the study team. Using the DillMan Total Design Survey method, participants were followed up one week after the initial email with a reminder phone-call and we received 46 responses (56.1% response rate). Participants were mostly, male (58.7%), non-Hispanic white (93.5%), with a mean age of 45.5 years (SD 10.9). Most participants decided to participate in a clinical trial to benefit future patients with IBD (63.0%). Self-reported knowledge of the possibility of being assigned to placebo on a scale from 0 (no knowledge) to 100 (extremely knowledgeable) was a median of 100 (IQR 100-100) (Table 1). Half of participants (50.0%) reported they were worried about the possibility of receiving placebo, although the majority (63.0%) understood they could improve on placebo. The most challenging aspect reported was the number and length of questionnaires (32.6%), as well of the number of colonoscopies (30.4%). Strategies to increase enrolment recommended by participants were reduction in the chance of receiving placebo (43.5%), facilitating inclusion of patients who have failed multiple therapies (43.5%), allowing virtual visits (39.1%), including subtypes of disease that have traditionally been excluded in clinical trials (e.g., ostomies, fistula) (34.8%), and improving outreach to underrepresented populations (28.3%) (Figure 1). The vast majority (80.4%) reported their experience of participation to be better than expected and would recommend taking part in a clinical trial to other patients with IBD (97.8%). Conclusion Patients with IBD who took part in pharmaceutical trials reported a high level of satisfaction overall. The top three recommendations from patients to improve clinical trial design were reducing the chance of receiving placebo, allowing inclusion of patients who have failed multiple therapies and allowing for virtual visits to reduce travel burden to the clinical trial site. These results should help inform the design of patient centric clinical trials in IBD.

P835 Acceptability, feasibility, and adherence of an emulsifier-free diet in healthy volunteers

Abstract Background Emulsifiers are associated with intestinal inflammation and therefore excluded in new dietary strategies in inflammatory bowel diseases (IBD). We aimed to investigate the feasibility, acceptability, and adherence of an emulsifier-free diet (EFD) in healthy volunteers as part of the FOod Additives on the Mucosal barrier (FOAM) study. Methods We recruited 60 healthy volunteers to a 7-week interventional trial. After 1 baseline week of their habitual diet, participants followed an EFD for 6 weeks. Participants were instructed on how to follow an EFD yet were not advised on ultra-processed food (UPF) reduction. Every 2 weeks after starting the EFD (week 2, 4, and 6), subjects were asked about their experience on a 12-item questionnaire, including 5-point Likert scales, open-ended and multiple answer-type questions. Food logs were kept in the smartphone application 'Fatsecret', including photographs to capture brand names. Manual calculation of all days with plausible energy intakes (800-4200 kcals per day for men and 600-3500 kcals for women) for at least 79.5% of the time was performed to exclude incomplete reporting. Emulsifier intake was measured as number of servings of emulsifier-containing foods. Adherence rate was calculated as a percentage of mistake-free days. Results Of the 60 healthy volunteers, 2 were excluded due to NSAID use. Median (IQR) age was 25.5 years (23.0-33.0), median BMI was 22.7 kg/m2 (21.2-25.6) and 19.0% were male. Median percentage of plausible food logs was 100% (98.0-100%), and 1 subject was excluded due to inadequate dietary reporting. During the EFD, emulsifier intake significantly decreased (baseline vs week 1; p=2.3x10-9, vs week 6; p=5.3x10-9, Figure 1A), as well as UPF consumption according to the NOVA classification (baseline vs week 1; p=5.6x10-7, vs week 6; p=1.6x10-7, Friedman test with post-hoc paired Wilcoxon, Figure 1B). The adherence rate to the EFD was very high (median 88.1%, IQR 76.2-95.2%). Median number of mistakes during the EFD was 6 (2-14), for a median number of 3 selected food items (1-5). Most mistakes were made in the categories of dairy-like products, meat products, and bakery goods. The top 3 reported challenges included restricted food choices, checking food labels, and longer shopping times (Table 1). At week 6, For 70.7% the EFD was tasty to very tasty and for 72.4% it was acceptable to very acceptable. Hot meals and snacks were the most challenging meal types. Conclusion In this 7-week interventional trial in 60 healthy volunteers, adhering to an EFD was feasible and acceptable. While following the EFD, an inadvertent and stable decrease in UPF intake was noted. These finding represent important considerations when designing future dietary trials in IBD.

P791 Trends in gender representation in inflammatory bowel disease randomized trials from 1955-2023

Abstract Background Historically women have been underrepresented in the field of gastroenterology and continue to be under-represented in academic scholarship and leadership despite the rising number of female medical graduates in recent years.This study aims to characterize the representation of women in authorship of published clinical trials in inflammatory bowel diseases (IBD) and the trend in gender representation since 1955. Methods IBD randomized trials published between 1955 to 2023 were included. Author gender, trial specifics (phase, intervention, population) source of funding were examined. Results We included 241 trials with a total of 3,264 authors: 2,418 were men (74.1%), 834 women (25.6%) and 12 (0.4%) had unknown gender. Women authorship representation increased from 0% in 1971 up to 30% in 2023 (0.41% annual increase) Figure 1A. Women were first, second, corresponding and last authors in 36/241 (14.2%), 41/241 (15.3%), 27/241 (10.5%) and 30/241 (11.7%) of published trials, respectively, Figure 1. Statistical differences in authorship by gender were found in all study categories, with women being less represented than men in unicenter vs multicenter trials, adult vs pediatric population trials, different trial phases, type of intervention [standard, advance or other] and source of funding (p<0.0001 for all comparisons) Table 1. From 2000 to 2023, industry-sponsored studies (n=119) included 1,680 authors, with 1,295 (77.1%) men and 379 (22.9%) women. Among these authors, 576 had industry affiliation, and 318 (55.2%) were men and 258 (44.8%) women. Women were first, second, corresponding and last authors in 15/119 (12.6%), 12/119 (10.1%), 11/119 (11.2), 10/119 (8.4%) of these studies. Linear regression analysis revealed an upward trend since 1995 in the total number of authors listed per published trial, but with men consistently outnumbering women authors, the ratio of women to men authors per publication remains low over the years (p<0.0001) Figure 1B. Conclusion Our findings underscore persistent gender disparities in published IBD trials authorship. Despite an increase in representation over time, women still make up less than 35% of authors and less than 15% of lead authors with little if any improvement over recent years (Figure 1C, 1D). Recognizing that lead authorship in trials has an impact on research funding and academic promotion, this gender disparity in authorship contributes to the many barriers women face in advancing their career in the field of IBD.

P487 Automated Scoring of Patient Endoscopy Videos Using Deep Learning Techniques: A Promising Approach for Clinical Trials in Inflammatory Bowel Disease

Abstract Background Accurate assessment of patient endoscopy videos is crucial for various clinical trials, including those related to inflammatory bowel diseases (IBD). However, manual scoring by trained local and central readers can lead to discrepancies, inconsistencies, and logistical challenges. To address these issues, we devised a novel approach utilizing deep learning techniques to automate the analysis, parsing, and scoring of patient endoscopy videos. Our objectives were to reduce human error/variability, accelerate endoscopic scoring by enhancing read accuracy, and lower clinical trial cost. Methods We developed and trained deep learning models using a large dataset of labeled patient endoscopy images. The models were designed to predict the Mayo endoscopic score (MES), which serves as a standardized measure of disease severity in IBD. Our approach developed convolutional neural networks (CNNs) to extract features from raw video data and processed them into meaningful patterns. The models were optimized using transfer learning and validated on external endoscopy video datasets through rigorous testing protocols. Results Using an iterative process, we developed two sets (total 4) of proof-of-concept (POC) Artificial Intelligence (AI) models using frame level datasets from endoscopy videos. First, quality was assessed by the blur detection model, currently performing at > 90% accuracy, and the bowel preparation model, performing at > 95% accuracy compared to the labels provided by human annotators. Second, MES sub-score prediction currently performs with >75% accuracy for 4-level Mayo sub-score prediction and >90% accuracy in predicting advanced MES scores (2 or higher compared with consensus score derived from 3 annotators). Conclusion The presented study highlights the potential of deep learning techniques in revolutionizing the assessment of patient endoscopy videos in clinical trials for IBD. Automating the endoscopic scoring process enables faster, more accurate, and cost-efficient evaluations, ultimately leading to better detection of patient outcomes. Future research directions involve further refining the models to enhance their performance and expand their application to other gastrointestinal diseases.

P1013 Placebo rates in Crohn's disease: An individual patient data meta-analysis from multiple randomised controlled trials

Abstract Background Estimating placebo rates and their determinants is essential for designing efficient randomised clinical trials (RCTs) in inflammatory bowel disease. We conducted an individual patient data (IPD) meta-analysis of placebo data from RCTs in Crohn’s disease (CD). Methods MEDLINE, Embase, and CENTRAL were searched from 01/2010 to 01/2020 for contemporary phase 2 and 3 placebo-controlled RCTs of biologics in moderate-to-severe CD. De-identified IPD from eligible trials that were available through the Vivli and Yale University Open Data Access data-sharing platforms were obtained. Primary outcomes were placebo clinical response and remission. Pooled placebo rates and 95% CIs were estimated using a 2-stage meta-analytical approach. Significant patient-level factors (P<0.05) associated with placebo rates were identified using regression analyses. Results Placebo IPD were available from 8 induction (n=1147) and 4 maintenance trials (n=524). Pooled placebo clinical response and remission rates varied based on outcome definition and prior biologic exposure (Figure). In induction trials, overall placebo response and remission rates were 27% (95% CI 23-32%) and 10% (95% CI 8-14%), respectively. Among bio-exposed patients, placebo response and remission rates were 27% (95% CI 16-40%) and 9% (95% CI 6-15%), respectively, compared with 29% (95% CI 24-34%) and 11% (95% CI 8-15%) for bio-naïve patients. Overall placebo response and remission rates in maintenance trials were 32% (95% CI 23%-42%) and 22% (95% CI 14-33%), respectively. Corresponding placebo response and remission rates for bio-exposed patients were 21% (95% CI 8-46%) and 17% (95% CI 11-25%), and 36% (95% CI 28-44%) and 24% (95% CI 15-36%) for bio-naïve patients. Placebo rates were lowest when response was defined as a ≥100-point decrease from baseline in the Crohn's Disease Activity Index (CDAI) score, and when remission was defined using stool frequency (≤1.5) and abdominal pain (≤1) subscores. Higher baseline C-reactive protein concentrations were associated with lower odds of placebo response and remission, while higher baseline albumin levels increased the odds of these outcomes (Table). Increased baseline CDAI and 2-item patient-reported outcome (PRO2) scores predicted higher odds of placebo response in induction trials, yet this reduced the odds of remission in induction trials and of both outcomes in maintenance trials. Prior failure to tumour necrosis factor (TNF) antagonist therapy was more predictive than prior TNF antagonist/biologic exposure for reducing the odds of placebo response and remission. Conclusion Placebo rates and the patient-level factors influencing them vary according to study design, clinical outcome measure and outcome definitions.

The Clinical Interpretation of Noninferiority Trials.

Noninferiority trials are designed to demonstrate that a new treatment is not unacceptably worse than a standard treatment, considering an allowable difference termed the noninferiority margin. We highlight that selection of noninferiority margins at the time of study design can be biased toward wider margins that favor noninferiority claims. We discuss a clinically oriented approach to interpretation of results with a focus on confidence intervals and recommend that readers base their judgments regarding noninferiority on margins reflecting patient values and preferences rather than those set by investigators. We provide examples from trials in inflammatory bowel diseases.

Use of external control arms in immune-mediated inflammatory diseases: a systematic review

ObjectivesExternal control arms (ECAs) provide useful comparisons in clinical trials when randomised control arms are limited or not feasible. We conducted a systematic review to summarise applications of ECAs in...

The Use of Placebo in Clinical Trials of Inflammatory Bowel Disease.

Lay Summary We review concerns regarding use of placebo in clinical trials of inflammatory bowel disease. We propose alternate designs to overcome ethical issues, while providing data that are clinically relevant.

Washout Periods in Inflammatory Bowel Disease Trials: A Systematic Literature Review and Proposed Solutions

Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), impose a substantial burden. Despite many effective molecules, significant numbers of patients do not achieve clinical remission at 1 year1 and undergo surgery during their lives, revealing an important unmet need and therapeutic gap. Multiple randomized controlled trials (RCTs) are ongoing or planned to develop more effective and tolerable therapies. In parallel, a dramatic decline in recruitment rates has been observed. A multitude of factors have contributed to poor recruitment rates, including a long washout period between the investigational drug and prior advanced therapies (ie, biologic or small molecule drug).2,3 This study aims to review the different washout periods with prior advanced therapies or immunosuppressants in phase 3 RCTs for UC and CD and to propose potential solutions to ultimately improve the design of clinical studies and patient enrollment in future trials.

The State of Clinical Trials in Pediatric Inflammatory Bowel Disease.

The gap between available biologic and small molecule therapy for inflammatory bowel disease for children and adults remains large. At present only 2 anti-TNF agents are licensed for pediatric use compared with multiple other agents with different mechanisms of action being used in adults. The reasons are many but largely revolve around the inadequate acceptance of adult efficacy data to children, and the reluctance of industry to commit to early pediatric drug development for fear of inadequate return on investment. We suggest common sense steps that need to be taken to improve this situation.

Review article: Externally derived control arms-An opportunity for clinical trials in inflammatory bowel disease?

One of the greatest challenges in the current IBD clinical trial landscape is, perhaps, the recruitment and retention of eligible participants. Seamless testing of promising investigational compounds is paramount to address unmet needs, but this is hindered by a number of barriers, particularly patient concerns of placebo assignment. To review the use of novel trial designs leveraging externally derived data to synthetically create control groups or augment existing ones, and to summarise the regulatory position on the use of external controls for market authorisation. We conducted a PubMed literature search without restriction using search terms such as 'external controls' and 'historical controls' to identify relevant articles. External controls are increasingly being used outside the context of cancer and rare diseases, including IBD, and increasingly recognised by regulatory bodies. Such designs, particularly in earlier phase trials, can inform key nodes in drug development and permit evaluating efficacy of interventions without combating the ethical and numerical enrolment challenges described. However, the lack of randomisation and blinding subjects them to significant bias. Groups require robust statistical and computational approaches to ensure patient-level data across groups are adequately balanced. While this approach has several pitfalls, and is not robust enough to replace traditional randomised, placebo-controlled trials, it may offer a compromise to address key research questions at a more rapid pace, with fewer patients, and lower cost.

Geographic Inequities in Access to Phase 3 Clinical Trials for Inflammatory Bowel Disease in the United States

Randomized controlled trials (RCTs) are an important mode of access to treatments for patients with inflammatory bowel diseases (IBDs) (eg, Crohn's disease [CD], ulcerative colitis [UC]), and a critical step in the regulatory process toward the approval of new therapies. Prior studies examining disparities in RCT participation for patients with IBD have importantly focused on racial and age-related disparities.1,2 Lack of geographic access to trials may be an important barrier to participation and a source of inequity. The aim of our study was to geographically map access to phase 3 clinical trials in IBD within the United States, and identify the impact of rural residence and socioeconomic status on access to trials.

Enhancing Regulatory T Cells to Treat Inflammatory and Autoimmune Diseases.

Regulatory T cells (Tregs) control immune responses and are essential to maintain immune homeostasis and self-tolerance. Hence, it is no coincidence that autoimmune and chronic inflammatory disorders are associated with defects in Tregs. These diseases have currently no cure and are treated with palliative drugs such as immunosuppressant and immunomodulatory agents. Thereby, there is a great interest in developing medical interventions against these diseases based on enhancing Treg cell function and numbers. Here, we give an overview of Treg cell ontogeny and function, paying particular attention to mucosal Tregs. We review some notable approaches to enhance immunomodulation by Tregs with therapeutic purposes including adoptive Treg cell transfer therapy and discuss relevant clinical trials for inflammatory bowel disease. We next introduce ways to expand mucosal Tregs in vivo using microbiota and dietary products that have been the focus of clinical trials in various autoimmune and chronic-inflammatory diseases.

Anti-β7 integrin treatment impedes the recruitment on non-classical monocytes to the gut and delays macrophage-mediated intestinal wound healing.

Closing mucosal defects to reach mucosal healing is an important goal of therapy in inflammatory bowel disease (IBD). Among other cells, monocyte-derived macrophages are centrally involved in such intestinal wound healing. We had previously demonstrated that the anti-α4β7 integrin antibody vedolizumab blocks the recruitment of non-classical monocytes as biased progenitors of wound healing macrophages to the gut and delays wound healing. However, although important for the interpretation of disappointing results in recent phase III trials in IBD, the effects of the anti-β7 antibody etrolizumab on wound healing are unclear so far. We analyzed the expression of etrolizumab targets on human and mouse monocyte subsets by flow cytometry and assessed their function in adhesion and homing assays. We explored wound-associated monocyte recruitment dynamics with multi-photon microscopy and compared the effects of etrolizumab and vedolizumab surrogate (-s) antibodies on experimental wound healing and wound-associated macrophage abundance. Finally, we investigated wound healing macrophage signatures in the large intestinal transcriptome of patients with Crohn's disease treated with etrolizumab. Human and mouse non-classical monocytes expressed more αEβ7 integrin than classical monocytes and were a target of etrolizumab-s, which blocked non-classical monocyte adhesion to MAdCAM-1 and E-Cadherin as well as gut homing in vivo. Intestinal wound healing was delayed on treatment with etrolizumab-s along with a reduction of peri-lesional wound healing macrophages. Wound healing macrophage signatures in the colon of patients with Crohn's disease were substantially down-regulated on treatment with etrolizumab, but not with placebo. Combined blockade of αEβ7 and α4β7 with etrolizumab seems to exceed the effect of anti-α4β7 treatment on intestinal wound healing, which might help to inform further investigations to understand the recent observations in the etrolizumab phase III trial program.

Declining Enrolment and Other Challenges in IBD Clinical Trials: Causes and Potential Solutions.

Rates of enrolment in clinical trials in inflammatory bowel disease [IBD] have decreased dramatically in recent years. This has led to delays, increased costs and failures to develop novel treatments. The aim of this work is to describe the current bottlenecks of IBD clinical trial enrolment and propose solutions. A taskforce comprising experienced IBD clinical trialists from academic centres and pharmaceutical companies involved in IBD clinical research predefined the four following levels: [1] study design, [2] investigative centre, [3] physician and [4] patient. At each level, the taskforce collectively explored the reasons for declining enrolment rates and generated an inventory of potential solutions. The main reasons identified included the overall increased demands for trials, the high screen failure rates, particularly in Crohn's disease, partly due to the lack of correlation between clinical and endoscopic activity, and the use of complicated endoscopic scoring systems not reflective of the totality of inflammation. In addition, complex trial protocols with restrictive eligibility criteria, increasing burden of procedures and administrative tasks enhance the need for qualified resources in study coordination. At the physician level, lack of dedicated time and training is crucial. From the patients' perspective, long washout periods from previous medications and protocol requirements not reflecting clinical practice, such as prolonged steroid management and placebo exposures, limit their participation in clinical trials. This joint effort is proposed as the basis for profound clinical trial transformation triggered by investigative centres, contract research organizations, sponsors and regulatory agencies.