Clinical holds for cell and gene therapy trials: Risks, impact, and lessons learned.

The recent increase in cell and gene therapies being developed has been coupled with a disproportionate increase in Food and Drug Administration (FDA)-mandated clinical holds. Aiming to better understand causes and secondary effects of these clinical holds on biotechnology companies, we analyzed 33 clinical holds that were publicly announced from January 2020 to December 2022. Approximately 80% of the analyzed clinical holds were formally lifted by the close of our study after an average of 6.2 months, and several trials have had significant clinical success following a hold. CAR T cell therapies accounted for nine holds, Lentiviral and AAV-based gene therapies accounted for five and 15 holds, respectively, and other cell and gene therapies accounted for four holds. The most common trigger was an adverse event or patient death. To remove a hold, protocol amendments were the most requested resolution by FDA. While there is no way to guarantee a therapy will not be placed on clinical hold, especially following unexpected adverse events, some deficiencies are avoidable. Utilizing FDA-provided resources on regulations and expectations for cell and gene therapy investigational new drug applications, inclusion of an external safety monitoring board, and a proactive risk assessment plan may prevent a clinical hold or result in a shortened duration.

Implementation of a gene therapy education initiative by the ASGCT and Muhimbili University of Health and Allied Sciences.

There has been rapid growth in gene therapy development with an expanding list of approved clinical products. Several therapies are particularly relevant to patients in low- and middle-income countries. Moreover, investing in research and manufacturing presents an opportunity for economic development. To increase awareness of gene therapy, the American Society of Gene and Cell Therapy partnered with the Muhimbili University of Health and Allied Sciences, Tanzania, to create a certificate-bearing course. The goal was to provide faculty teaching in graduate and medical schools with the tools needed to add gene therapy to the university curriculum. The first virtual course was held in October of 2022, and 45 individuals from 9 countries in Africa completed the training. The content was new to approximately two-thirds of participants, with the remaining third indicating that the course increased their knowledge base. The program was well received and will be adapted for other under-resourced regions.

Global regulatory progress in delivering on the promise of gene therapies for unmet medical needs.

The rapid expansion of the gene therapy pipeline in recent years offers significant potential to treat diseases with great unmet medical need. However, the unique nature of these therapies poses challenges to regulating them within traditional frameworks, even when developing in a single country. Various factors exacerbate the issues in commercializing products across regions, including the lack of established regulatory frameworks for developing gene therapy products in many jurisdictions. While some countries have established separate regulatory frameworks for advanced therapies/regenerative medicine products, differences exist between them. Recommended solutions to overcome these hurdles include fostering convergence among countries with separate regulatory frameworks for these products and utilizing reliance and recognition for countries without such frameworks. Additionally, regulators who choose to establish new dedicated frameworks for regulating gene therapies should consider the inclusion of key elements such as expedited regulatory pathways that offer early engagement with regulators, innovative clinical trial design, and adequate post-market confirmatory studies. Increasing the alignment of regulatory pathways across countries will be crucial to facilitating the development of, and access to, gene therapies on a global scale.

Current state of biologic pharmacovigilance in the European Union: improvements are needed.

INTRODUCTION: Pharmacovigilance is essential to monitoring the safety profiles of authorized medicines. Compared with small-molecule drugs, biological drugs are more complex, more susceptible to structural variability due to manufacturing processes, and have the potential to induce immune-related reactions, underscoring the importance of safety monitoring for these products. Although highly similar to reference products, biosimilars are not expected to be structurally identical. For these reasons, proper reporting of potential adverse drug reactions (ADRs) using distinguishable names and batch numbers is essential for accurate tracing of all biological drugs. To address the need for robust pharmacovigilance, the European Parliament and Council of the European Union provided legislation regarding pharmacovigilance of biologics in 2010. AREAS COVERED: This narrative review examines the current state of pharmacovigilance for biologics in the European Union (EU) and discusses relevant information on pharmacovigilance of biosimilars, the current EU pharmacovigilance system, and areas that could be improved. EXPERT OPINION: Although steps have been taken to improve pharmacovigilance of biologics in the EU, several enhancements can still be made, including additional training for healthcare professionals on ADR reporting, the use of 2D barcodes that enhance traceability, and an open discussion of potentially missed opportunities in the pharmacovigilance of biosimilars.

Comparing student outcomes in traditional vs intensive, online graduate programs in health professional education.

BACKGROUND: Health professions' education programs are undergoing enormous changes, including increasing use of online and intensive, or time reduced, courses. Although evidence is mounting for online and intensive course formats as separate designs, literature investigating online and intensive formats in health professional education is lacking. The purpose of the study was to compare student outcomes (final grades and course evaluation ratings) for equivalent courses in semester long (15-week) versus intensive (7-week) online formats in graduate health sciences courses. METHODS: This retrospective, observational study compared satisfaction and performance scores of students enrolled in three graduate health sciences programs in a large, urban US university. Descriptive statistics, chi square analysis, and independent t-tests were used to describe student samples and determine differences in student satisfaction and performance. RESULTS: The results demonstrated no significant differences for four applicable items on the final student course evaluations (p values range from 0.127 to 1.00) between semester long and intensive course formats. Similarly, student performance scores for final assignment and final grades showed no significant differences (p = 0.35 and 0.690 respectively) between semester long and intensive course formats. CONCLUSION: Findings from this study suggest that 7-week and 15-week online courses can be equally effective with regard to student satisfaction and performance outcomes. While further study is recommended, academic programs should consider intensive online course formats as an alternative to semester long online course formats.

Design for success: Identifying a process for transitioning to an intensive online course delivery model in health professions education.

Intensive courses (ICs), or accelerated courses, are gaining popularity in medical and health professions education, particularly as programs adopt e-learning models to negotiate challenges of flexibility, space, cost, and time. In 2014, the Department of Clinical Research and Leadership (CRL) at the George Washington University School of Medicine and Health Sciences began the process of transitioning two online 15-week graduate programs to an IC model. Within a year, a third program also transitioned to this model. A literature review yielded little guidance on the process of transitioning from 15-week, traditional models of delivery to IC models, particularly in online learning environments. Correspondingly, this paper describes the process by which CRL transitioned three online graduate programs to an IC model and details best practices for course design and facilitation resulting from our iterative redesign process. Finally, we present lessons-learned for the benefit of other medical and health professions' programs contemplating similar transitions. ABBREVIATIONS: CRL: Department of Clinical Research and Leadership; HSCI: Health Sciences; IC: Intensive course; PD: Program director; QM: Quality Matters.

Improving Regulatory Education: Can We Reconcile Employers' Expectations With Academic Offerings?

BACKGROUND: The growing belief that an effective regulatory function is vital to the successful development of medical products has spurred initiatives in regulatory education. To help prepare highly skilled professionals, some academic institutions have begun to incorporate new competencies into their curricula and to offer innovative programs in the field of regulatory studies. METHODS: This study is the first national survey aimed at identifying the degree of adoption of an educational model based on well-defined professional competencies for graduate programs in regulatory studies. RESULTS: Respondents disclosed the challenges faced by faculty in implementing such a model. The study revealed the relevancy of this type of model and that a competency-based approach is largely perceived as a prerequisite for aligning a program's mission and vision with the skills that graduates need in the job market. Survey results show a strong general agreement regarding the suitability of a competency-based education model for regulatory studies. CONCLUSIONS: The challenges in implementing such a model, as described by survey participants, are significant but can be addressed. The barriers to implementation of regulatory curricula based on a competency-based education model should be better understood so that academic programs can educate highly skilled regulatory professionals. Such a workforce could best contribute to the delivery of high-quality, safe, and effective medical products.

Selective anion effects in chiral complexes of iridium via diffusion and HOESY data: relevance to catalysis.

1H and 19F Pulsed Gradient Spin Echo (PGSE) diffusion data, together with 1H, 19F-HOESY results are shown to distinguish between different types of anion/cation interactions in chiral dihydrido-P,N-complexes of Ir(III); in CD2Cl2 the diffusion coefficients, D, for the BArF and the Ir-cation suggest ion-pairing whereas the D-values for PF6-reveal independent motion; the PF6- approaches the cation via a specific pathway; the combined PGSE/HOESY approach offers a unique opportunity for exploring anion effects in organometallic/catalytic chemistry.