Innovative Clinical Trial Designs Research Articles

Tuning CAR T-cell therapies for efficacy and reduced toxicity

Chimeric antigen receptor (CAR) T-cell therapies are a standard of care for certain relapsed or refractory B-cell cancers. However, many patients do not respond to CAR T-cell therapy or relapse later, short- and long-term toxicities are common, and current CAR T-cell therapies have limited efficacy for solid cancers. The gene engineering inherent in CAR T-cell manufacture offers an unprecedented opportunity to control cellular characteristics and design products that may overcome these limitations. This review summarises available methods to “tune” CAR T-cells for optimal efficacy and safety. The components of a typical CAR, and the modifications that can influence CAR T-cell function are discussed. Methods of engineering passive, inducible or autonomous control mechanisms into CAR T-cells, allowing selective limitation or enhancement of CAR T-cell activity are reviewed. The impact of manufacturing processes on CAR T-cell function are considered, including methods of limiting CAR T-cell terminal differentiation and exhaustion, and the use of specific T-cell subsets as the CAR T starting material. We discuss the use of multicistronic transgenes and multiplexed gene editing. Finally, we highlight the need for innovative clinical trial designs if we are to make the most of the opportunities offered by CAR T-cell therapies.

American College of Rheumatology and Food and Drug Administration Summit: Summary of the Meeting, May 17-18, 2022.

The American College of Rheumatology and the US Food and Drug Administration co-sponsored a public meeting in May 2022 about challenges in the clinical development of drugs for rheumatoid arthritis (RA) and psoriatic arthritis (PsA), focusing on innovative clinical trial designs, outcome measures, and data collection methods. Recommendations include early dose-ranging studies and use of active comparators. Challenges and opportunities in assessing long-term safety by leveraging real-world data from electronic health records (EHRs) and claims data are discussed, along with insights from European registries and the evolving role of real-world evidence and artificial intelligence in regulatory evaluations. Endpoints for assessing disease activity and outcome measures used in RA and PsA trials are explored, emphasizing challenges in defining remission, assessing clinical response, and evaluating structural progression. The need for outcome measures that better reflect treatment targets and the potential of advanced imaging in future trials are highlighted. Challenges with placebo-controlled trials in RA are discussed and use of non-inferiority clinical trial design, in which new drugs are evaluated with active comparators, is proposed. Pragmatic trials in RA and PsA, employing decentralized approaches, are highlighted for their real-world relevance and administrative efficiencies. Strategies for identifying at-risk populations for RA and the challenges of using EHRs and insurance claims data in drug development are discussed. Registry data and digital health technologies show promise in bridging the gap between clinical trials and real-world effectiveness.

555 Design Lab Methodology Supports Innovation in Clinical Trials

OBJECTIVES/GOALS: Since 2017, we have used the Design Lab methodology to support investigators taking innovative approaches to clinical effectiveness trial design. To date we have held 12 Design Labs and this year we are creating a handbook that will support dissemination of this approach across the Clinical and Translational Science Award consortium. METHODS/STUDY POPULATION: The Clinical Trial Design Lab brings together a multi-stakeholder group to consider innovative and impactful clinical trial designs. An investigative team is selected from a competitive pool of applicants, after which expert-led consultations support the investigator team to think about evidence generation in the context of the full treatment development pathway. Teams map the stakeholders at each step of this pathway (e.g. clinicians, patients, researchers, funders, industry experts, policy experts, regulatory experts, payers) and consider innovative design solutions. These consultations prepare investigators for an event that involves all stakeholders in a structured and facilitated discussion about trial designs that generate the best evidence and increase potential for health impact. RESULTS/ANTICIPATED RESULTS: The result of our work will be a set of Design Lab principles, a handbook with templates that support stakeholder mapping and structured discussions, and educational resources to accompany the handbook. The work is supported by a literature review that characterizes the multi-component processes included in the Design Lab, situates them within the larger context of team science interventions, and lays groundwork for the development of process metrics and impact evaluation criteria to assess the Design Lab method. In this poster presentation, we will share our multi-component broadly engaged team science approach, provide a brief outline of the principles and educational resources, and include an early version of the evaluation criteria. DISCUSSION/SIGNIFICANCE: Broadly engaged team science supports innovative thinking about study design and is especially important in the development of clinical trials. We have grown the Design Lab program of work over the past seven years and are now able to characterize our team science methodology and support others to use this approach to innovate for health impact.

Advancing randomized controlled trial methodologies: The place of innovative trial design in eating disorders research.

Randomized controlled trials can be used to generate evidence on the efficacy and safety of new treatments in eating disorders research. Many of the trials previously conducted in this area have been deemed to be of low quality, in part due to a number of practical constraints. This article provides an overview of established and more innovative clinical trial designs, accompanied by pertinent examples, to highlight how design choices can enhance flexibility and improve efficiency of both resource allocation and participant involvement. Trial designs include individually randomized, cluster randomized, and designs with randomizations at multiple time points and/or addressing several research questions (master protocol studies). Design features include the use of adaptations and considerations for pragmatic or registry-based trials. The appropriate choice of trial design, together with rigorous trial conduct, reporting and analysis, can establish high-quality evidence to advance knowledge in the field. It is anticipated that this article will provide a broad and contemporary introduction to trial designs and will help researchers make informed trial design choices for improved testing of new interventions in eating disorders. PUBLIC SIGNIFICANCE: There is a paucity of high quality randomized controlled trials that have been conducted in eating disorders, highlighting the need to identify where efficiency gains in trial design may be possible to advance the eating disorder research field. We provide an overview of some key trial designs and features which may offer solutions to practical constraints and increase trial efficiency.

Pediatric Cancer Drug Development: Leveraging Insights in Cancer Biology and the Evolving Regulatory Landscape to Address Challenges and Guide Further Progress.

The discovery and development of anticancer drugs for pediatric patients have historically languished when compared to both past and recent activity in drug development for adult patients, notably the dramatic spike of targeted and immune-oncology therapies. The reasons for this difference are multifactorial. Recent changes in the regulatory landscape surrounding pediatric cancer drug development and the understanding that some pediatric cancers are driven by genetic perturbations that also drive disparate adult cancers afford new opportunities. The unique cancer-initiating events and dependencies of many pediatric cancers, however, require additional pediatric-specific strategies. Research efforts to unravel the underlying biology of pediatric cancers, innovative clinical trial designs, model-informed drug development, extrapolation from adult data, addressing the unique considerations in pediatric patients, and use of pediatric appropriate formulations, should all be considered for efficient development and dosage optimization of anticancer drugs for pediatric patients.

Draft Guidance for Industry Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Related Dystrophinopathies - Developing Potential Treatments for the Entire Spectrum of Disease.

Duchenne muscular dystrophy (DMD) and related dystrophinopathies are neuromuscular conditions with great unmet medical needs that require the development of effective medical treatments. To aid sponsors in clinical development of drugs and therapeutic biological products for treating DMD across the disease spectrum by integrating advancements, patient registries, natural history studies, and more into a comprehensive guidance. This guidance emerged from collaboration between the FDA, the Duchenne community, and industry stakeholders. It entailed a structured approach, involving multiple committees and boards. From its inception in 2014, the guidance underwent revisions incorporating insights from gene therapy studies, cardiac function research, and innovative clinical trial designs. The guidance provides a deeper understanding of DMD and its variants, focusing on patient engagement, diagnostic criteria, natural history, biomarkers, and clinical trials. It underscores patient-focused drug development, the significance of dystrophin as a biomarker, and the pivotal role of magnetic resonance imaging in assessing disease progression. Additionally, the guidance addresses cardiomyopathy's prominence in DMD and the burgeoning field of gene therapy. The updated guidance offers a comprehensive understanding of DMD, emphasizing patient-centric approaches, innovative trial designs, and the importance of biomarkers. The focus on cardiomyopathy and gene therapy signifies the evolving realm of DMD research. It acts as a crucial roadmap for sponsors, potentially leading to improved treatments for DMD.

A multifaceted approach to global health

World Health Day underscores the scientific community's commitment to achieving health equity for all. It is paramount to eliminate bias in research that has traditionally focused on men, neglecting the specific needs of diverse populations. Innovative clinical trial designs are being developed with more inclusive enrollment. Ensuring equitable access to essential antibiotics, coupled with robust infection prevention and control measures, is vital to safeguarding public health. The pursuit of health equity extends beyond the realm of medicine. Investments in local food production and robust social safety nets are critical for mitigating the effects of climate change on access to healthy diets. Additionally, in times of polycrisis, prioritizing the unique needs of children and empowering community-led healthcare initiatives in conflict zones are essential steps. By taking these actions, we can move closer to realizing everyone's fundamental right to health.

Challenges in developing therapies in fragile X syndrome: how the FXLEARN trial can guide research.

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and the single-gene cause of autism, is caused by decreased expression of the fragile X messenger ribonucleoprotein protein (FMRP), a ribosomal-associated RNA-binding protein involved in translational repression. Extensive preclinical work in several FXS animal models supported the therapeutic potential of decreasing metabotropic glutamate receptor (mGluR) signaling to correct translation of proteins related to synaptic plasticity; however, multiple clinical trials failed to show conclusive evidence of efficacy. In this issue of the JCI, Berry-Kravis and colleagues conducted the FXLEARN clinical trial to address experimental design concerns from previous trials. Unfortunately, despite treatment of young children with combined pharmacological and learning interventions for a prolonged period, no efficacy of blocking mGluR activity was observed. Future systematic evaluation of potential therapeutic approaches should evaluate consistency between human and animal pathophysiological mechanisms, utilize innovative clinical trial design from FXLEARN, and incorporate translatable biomarkers.

Novel therapeutics and future directions for refractory immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder affecting approximately 1 in 20 000 people. While most patients with ITP are successfully managed with the current set of standard and approved therapeutics, patients who cannot be adequately managed with these therapies, considered to have refractory ITP, are not uncommon. Therefore, there remains an ongoing need for novel therapeutics and drug development in ITP. Several agents exploiting novel targets and mechanisms in ITP are presently under clinical development, with trials primarily recruiting heavily pretreated patients and those with otherwise refractory disease. Such agents include the neonatal Fc receptor antagonist efgartigimod, the Bruton tyrosine kinase inhibitor rilzabrutinib, the complement inhibitors sutimlimab and iptacopan and anti-CD38 monoclonal antibodies such as daratumumab and mezagitamab, among others. Each of these agents exploits therapeutic targets or other aspects of ITP pathophysiology currently not targeted by the existing approved agents (thrombopoietin receptor agonists and fostamatinib). This manuscript offers an in-depth review of the current available data for novel therapeutics in ITP presently undergoing phase 2 or 3 studies in patients with heavily pretreated or refractory ITP. It additionally highlights the future directions for drug development in refractory ITP, including discussion of innovative clinical trial designs, health-related quality of life as an indispensable clinical trial end-point and balancing potential toxicities of drugs with their potential benefits in a bleeding disorder in which few patients suffer life-threatening bleeding.

Comparison of the Latin America Regulation Landscape and International Reference Health Authorities to Hasten Drug Registration and Clinical Research Applications

IntroductionPromptly providing new drugs to fulfill unmet medical needs requires changes in drug development and registration processes. Health Authorities (HAs) considered as reference due to their experience and acknowledgement (Food and Drug Administration [FDA] among others) already consider innovative clinical trial (CT) designs and flexible approval procedures, but Latin America (LATAM) regulations are still far. A comparison was performed to identify gaps.Materials and MethodsCT requirements for drug Marketing Authorization Application (MAA) and CT approval regulations were compared between LATAM and reference HAs (FDA/European Medicines Agency [EMA]/Health-Canada/Swissmedic/Therapeutic Goods Administration [TGA]/Pharmaceuticals and Medical Devices Agency [PMDA]), as of August 2022. Procedure included reference HAs regulations review, item selection, identification in LATAM regulations, and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines (ICH-E6[R2]/ICH-E8[R1]) implementation revision.ResultsFor MAA, specific application requirements or ICH guideline M4(R4) on common technical document (CTD) adoption are generally stated, and phase-I/III performance is mandatory (explicitly/implicitly). Faster patient access procedures are infrequent: Priority-drug programs, conditional authorizations, or expedited procedures are scarce or non-existent. Regulatory reliance procedures are adopted through different pathways. Regarding CT approval, innovative/complex CT designs are not prohibited but usually omitted. Some countries implemented adapted CT conducting during the COVID-19 pandemic. Early scientific advice meetings (HA-sponsor) are occasionally considered. Most countries are not formally ICH-joined.ConclusionsLATAM regulations must adapt to new regulatory standards (FDA/EMA/ICH) through implementation of frequent updates, reliance/expedited procedures, early HA-sponsor interactions, innovative/complex CTs, mandatory phase-III reaching elimination, and decentralized elements for CT conducting.

Connected health in US, EU, and China: opportunities to accelerate regulation of connected health technologies to optimize their role in medicines development.

Connected health technology is playing an increasingly important role in healthcare. The power, complexity, functionality, and accessibility of connected health technologies are increasing rapidly, showing promise for improved and more equitable healthcare outcomes. They are integral to the lifecycle of medical products, from discovery and development to manufacturing and ultimately to the patient. The spectrum of integration between medical products and digital technologies ranges from non-drug specific solutions for supporting adherence or patient monitoring, which may or may not require regulatory approval, to digital therapeutics and software-containing combination products, which make claims supported by clinical evidence. The exponential increase and rapid evolution of connected health technologies - and the accompanying possibilities for innovative healthcare interventions, delivery systems, and clinical trial designs - pose new and complicated regulatory challenges. Currently, connected health may involve the use of regulated medical devices, including software as a medical device, or consumer products, such as wearables or apps, that fall under regulatory discretion. In this paper we examine how connected health technologies intersect with the development and lifecycle of medical products, how they are impacted by existing regulatory frameworks in the US, EU, and China, and propose future focus areas of activity.

Emerging Therapies for Ulcerative Colitis: Updates from Recent Clinical Trials.

Ulcerative colitis (UC) is a chronic and progressive inflammatory disorder that affects the colon. The advent of advanced therapies such as biologic agents and small molecules has revolutionized the management of UC. Despite the expanding therapeutic armamentarium of advanced therapies to treat UC, the overall net remission rates and durability of currently available agents are relatively low. This highlights the need for further drug development and more innovative clinical trial design. There are currently multiple emerging agents in the pipeline for the management of UC. This includes agents with alternative routes of administration such as oral or subcutaneous tumor necrosis factor inhibitors or novel mechanisms of action such as toll-like receptor 9 (TLR9) agonist cobitolimod and phosphodiesterase 4 inhibitor apremilast. In this review, we will highlight novel and emerging advanced therapies currently in the pipeline for the management of UC.

Model-Informed Approaches and Innovative Clinical Trial Design for Adeno-Associated Viral Vector-Based Gene Therapy Product Development: A White Paper.

The promise of viral vector-based gene therapy (GT) as a transformative paradigm for treating severely debilitating and life-threatening diseases is slowly coming to fruition with the recent approval of several drug products. However, they have a unique mechanism of action often necessitating a tortuous clinical development plan. Expertise in such complex therapeutic modality is still fairly limited in this emerging class of adeno-associated virus (AAV) vector-based gene therapies. Because of the irreversible mode of action and incomplete understanding of genotype-phenotype relationship and disease progression in rare diseases careful considerations should be given to GT product's benefit-risk profile. In particular, special attention needs to be paid to safe dose selection, reliable dose exposure response (including clinically relevant endpoints), or creative approaches in study design targeting small patient populations during clinical development. We believe that quantitative tools encompassed within model-informed drug development (MIDD) framework fits quite well in the development of such novel therapies, as they enable us to benefit from the totality of data approach in order to support dose selection as well as optimize clinical trial designs, end point selection, and patient enrichment. In this thought leadership paper, we provide our collective experiences, identify challenges, and suggest areas of improvement in applications of modeling and innovative trial design in development of AAV-based GT products and reflect on the challenges and opportunities for incorporating MIDD tools and more in rational development of these products.

WS05.04 Safety and efficacy of ivacaftor (IVA) in children aged 1 to

Objectives: To assess safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of IVA dosing for 24 weeks in infants with CF aged 1 to <4 months.

IBIS: identify biomarker-based subgroups with a Bayesian enrichment design for targeted combination therapy

BackgroundCombination therapies directed at multiple targets have potentially improved treatment effects for cancer patients. Compared to monotherapy, targeted combination therapy leads to an increasing number of subgroups and complicated biomarker-based efficacy profiles, making it more difficult for efficacy evaluation in clinical trials. Therefore, it is necessary to develop innovative clinical trial designs to explore the efficacy of targeted combination therapy in different subgroups and identify patients who are more likely to benefit from the investigational combination therapy.MethodsWe propose a statistical tool called ‘IBIS’ to Identify BIomarker-based Subgroups and apply it to the enrichment design framework. The IBIS contains three main elements: subgroup division, efficacy evaluation and subgroup identification. We first enumerate all possible subgroup divisions based on biomarker levels. Then, Jensen–Shannon divergence is used to distinguish high-efficacy and low-efficacy subgroups, and Bayesian hierarchical model (BHM) is employed to borrow information within these two subsets for efficacy evaluation. Regarding subgroup identification, a hypothesis testing framework based on Bayes factors is constructed. This framework also plays a key role in go/no-go decisions and enriching specific population. Simulation studies are conducted to evaluate the proposed method.ResultsThe accuracy and precision of IBIS could reach a desired level in terms of estimation performance. In regard to subgroup identification and population enrichment, the proposed IBIS has superior and robust characteristics compared with traditional methods. An example of how to obtain design parameters for an adaptive enrichment design under the IBIS framework is also provided.ConclusionsIBIS has the potential to be a useful tool for biomarker-based subgroup identification and population enrichment in clinical trials of targeted combination therapy.

Organizing precision medicine: A case study of Memorial Sloan Kettering Cancer Center's engagement in/with genomics

Recent decades have seen a dramatic rise of in the number of initiatives designed to promote precision oncology, a domain that has played a pioneering role in the implementation of post-genomic approaches and technologies such as innovative clinical trial designs and molecular profiling. In this paper, based on fieldwork carried out at the Memorial Sloan-Kettering Cancer Center from 2019 onwards, we analyze how a world-leading cancer center has adapted, responded, and contributed to the challenge of “doing” precision oncology by developing new programs and services, and building an infrastructure that has created the conditions for genomic practices. We do so by attending to the “organizing” side of precision oncology and to the nexus between these activities and epistemic issues. We situate the work that goes into making results actionable and accessing targeted drugs within the larger process of creating a precision medicine ecosystem that includes purpose-built institutional settings, thus simultaneously experimenting with bioclinical matters and, reflexively, with organizing practices. The constitution and articulation of innovative sociotechnical arrangements at MSK provides a unique case study of the production of a large and complex clinical research ecosystem designed to implement rapidly evolving therapeutic strategies embedded in a renewed and dynamic understanding of cancer biology.

RESTART trial design: two-stage seamless transition design with operational considerations

ABSTRACT Oncology/hematology is a competitive therapeutic area where the landscape is constantly evolving. With regulatory support, many drug developers have spent a lot of resources on the operationalization of innovative clinical trial designs, for example, adaptive Bayesian designs in confirmatory clinical trial settings. While overall survival is considered the gold standard in these designs, it is often not a viable choice in identifying treatment efficacy at a reasonable pace, especially for early-stage therapies. In recent years, several binary response surrogate endpoints have been used for accelerated or conditional approval of novel cancer therapies. Utilizing surrogate endpoints in the study design to predict objective clinical outcomes, such as overall survival, is particularly fundamental in cancer treatment clinical development. This manuscript will investigate logistic and statistical considerations of our proposed RESTART design, a new two-stage, seamless, single- to double-arm Bayesian design. This design could be used for single-arm dose expansion to a randomized confirmatory study. The operating characteristics of the RESTART design are evaluated based on simulations. Future directions and further modifications of this design will also be elaborated.

Biomarker‐based development for optimized ACI‐24, a novel candidate vaccine for the treatment and prevention of Alzheimer’s disease

AbstractBackgroundAmyloid plaques and neurofibrillary tangles are the neuropathologic hallmarks of Alzheimer’s disease (AD) with the key constituents being Amyloid Beta (Abeta) and Tau protein, respectively. However, the initiation and propagation of neurodegeneration and neurotoxicity in Alzheimer’s disease remains incompletely understood despite recent important progress in clinical trials. It is apparent that small aggregates such as Abeta oligomers or fragments such as Abeta 1‐42 and pyroglutamate Abeta3‐42 (pGlu‐Abeta3‐42)) are of key importance for disease initiation with significant implications for translational medicine and success in clinical trial development.MethodACI‐24 is a vaccine targeting Abeta for the treatment and prevention of AD. Initial clinical data have demonstrated safety and an initial pharmacodynamic response, both in sporadic AD and people with Down syndrome (DS), a specifically vulnerable population predisposed to developing AD. Preclinical data have recently demonstrated that a new, optimized formulation of ACI‐24 has significantly improved immunogenicity against key toxic species, i.e., Abeta oligomers, Abeta 1‐42 and pGlu‐Abeta3‐42. Recent clinical trial results in AD, specifically with monoclonal antibodies targeting Abeta, have successfully employed translational biomarkers, including Amyloid PET, as key decision markers and predictors of clinical benefit.ResultWe present an innovative translational clinical trial design to understand the immunogenic properties of optimized ACI‐24 in sporadic AD and in people with DS. The biomarker‐based design, including multiple interim analyses, will enable (I) assessment of early safety and immunogenicity, (II) dose selection for early and meaningful readouts on translational biomarkers including Amyloid PET, (III) the safe transition into the more vulnerable DS population and (IV) informed transition into pivotal studies.ConclusionThe Alzheimer’s disease field needs new treatments and clinical trial approaches. Vaccination is a proven approach to managing diseases affecting global populations. The field of biomarker‐based translational medicine has been mobilized by the recent understanding of how to clinically evaluate targeting of toxic Abeta fragments and aggregates in trials using monoclonal antibodies. Here, we demonstrate how we utilize these advances in an innovative clinical trial design for an efficient, evidence‐based translational medicine approach to test optimized ACI‐24 as a novel Abeta vaccine candidate.

EE499 Challenges of Health Economic Evaluations Alongside Innovative Clinical Trial Designs in Precision Oncology – Results of a Literature Review

EE499 Challenges of Health Economic Evaluations Alongside Innovative Clinical Trial Designs in Precision Oncology – Results of a Literature Review

Biobank for Translational Medicine: Standard Operating Procedures for Optimal Sample Management

Biobanks are key research infrastructures aimed at the collection, storage, processing, and sharing of high-quality human biological samples and associated data for research, diagnosis, and personalized medicine. The Biobank for Translational and Digital Medicine Unit at the European Institute of Oncology (IEO) is a landmark in this field. Biobanks collaborate with clinical divisions, internal and external research groups, and industry, supporting patients' treatment and scientific progress, including innovative diagnostics, biomarker discovery, and clinical trial design. Given the central role of biobanks in modern research, biobanking standard operating procedures (SOPs) should be extremely precise. SOPs and controls by certified specialists ensure the highest quality of samples for the implementation of science-based, diagnostic, prognostic, and therapeutic personalized strategies. However, despite numerous efforts to standardize and harmonize biobanks, these protocols, which follow a strict set of rules, quality controls, and guidelines based on ethical and legal principles, are not easily accessible. This paper presents the biobank standard operating procedures of a large cancer center.