National landscape assessment of academic medical center support for expanded access to investigational products.

Expanded access (EA) provides a pathway for the clinical use of investigational products (drugs, biologics, and medical devices) for patients who are without satisfactory therapeutic options and for whom a clinical trial is not available. Academic medical centers (AMCs) are likely to encounter EA requests, but it is unknown what support is available at these institutions for physicians seeking EA for patients. METHODS: A landscape assessment was conducted at AMCs, focused on those within the Clinical and Translational Science Awards (CTSA) consortium. RESULTS: Forty-seven responses were evaluated including 42 CTSA hubs. The large majority (43 of 47 respondents) reported using single-patient EA, while 37 reported multi-patient industry sponsored EA and 37 reported multi-patient investigator-initiated EA. Only half reported central tracking of EA requests. Support was available at 89% of sites for single-patient EA but less often for multi-patient EA. Types of support varied and were focused largely on the initial submission to the FDA. CONCLUSION: Use of and support for EA is widespread at AMCs, with support focused on single-patient requests. Gaps in support are common for activities after initial submission, such as FDA reporting and data collection.

Translation of Digital Health Technologies to Advance Precision Medicine: Informing Regulatory Science.

The proliferation of digital technologies and the application of sophisticated data analysis techniques are increasingly viewed as having the potential to transform translational research and precision medicine. While digital technologies are rapidly applied in innovative ways to develop new diagnostics and therapies, the ultimate approval and adoption of these emerging methods presents several scientific and regulatory challenges. To better understand and address these regulatory science gaps, a working group of the Clinical and Translational Science Awards Program convened the Regulatory Science to Advance Precision Medicine Forum focused on digital health, particularly examining gaps in the use, validation, and interpretation of data from sensors that collect and tools that analyze digital biomarkers. The key findings and recommendations provided here emerged from the Forum and include the need to enhance areas related to data standards, data quality and validity, knowledge management, and building trust between all stakeholders.

The integration of emerging omics approaches to advance precision medicine: How can regulatory science help?

Building on the recent advances in next-generation sequencing, the integration of genomics, proteomics, metabolomics, and other approaches hold tremendous promise for precision medicine. The approval and adoption of these rapidly advancing technologies and methods presents several regulatory science considerations that need to be addressed. To better understand and address these regulatory science issues, a Clinical and Translational Science Award Working Group convened the Regulatory Science to Advance Precision Medicine Forum. The Forum identified an initial set of regulatory science gaps. The final set of key findings and recommendations provided here address issues related to the lack of standardization of complex tests, preclinical issues, establishing clinical validity and utility, pharmacogenomics considerations, and knowledge gaps.

Regulatory interfaces surrounding the growing field of additive manufacturing of medical devices and biologic products.

Rapidly advancing technology often pulls the regulatory field along as it evolves to incorporate new concepts, better tools, and more finely honed equipment. When the area impacted by the technological advancement is regulated by the Food and Drug Administration (FDA), a gap develops between the technology and the guidelines that govern its application. Subsequently, there are challenges in determining appropriate regulatory pathways for evolving products at the initial research and developmental stages. Myriad factors necessitate several rounds of iterative review and the involvement of multiple divisions within the FDA. To better understand the regulatory science issues roiling around the area of additive manufacturing of medical products, a group of experts, led by a Clinical and Translational Science Award working group, convened the Regulatory Science to Advance Precision Medicine at the Fall Forum to discuss some of the current regulatory science roadblocks.

Advancing a Vision for Regulatory Science Training.

Regulatory science, a complex field which draws on science, law, and policy, is a growing discipline in medical-related applications. Competencies help define both a discipline and the criteria to measure high-quality learning experiences. This paper identifies competencies for regulatory science, how they were developed, and broader recommendations to enhance education and training in this burgeoning field, including a multifaceted training approach.

Access to Investigational Drugs: FDA Expanded Access Programs or "Right-to-Try" Legislation?

PURPOSE: The Food and Drug Administration Expanded Access (EA) program and "Right-to-Try" legislation aim to provide seriously ill patients who have no other comparable treatment options to gain access to investigational drugs and biological agents. Physicians and institutions need to understand these programs to respond to questions and requests for access. METHODS: FDA EA programs and state and federal legislative efforts to provide investigational products to patients by circumventing FDA regulations were summarized and compared. RESULTS: The FDA EA program includes Single Patient-Investigational New Drug (SP-IND), Emergency SP-IND, Intermediate Sized Population IND, and Treatment IND. Approval rates for all categories exceed 99%. Approval requires FDA and Institutional Review Board (IRB) approval, and cooperation of the pharmaceutical partner is essential. "Right-to-Try" legislation bypasses some of these steps, but provides no regulatory or safety oversight. CONCLUSION: The FDA EA program is a reasonable option for patients for whom all other therapeutic interventions have failed. The SP-IND not only provides patient access to new drugs, but also maintains a balance between immediacy and necessary patient protection. Rather than circumventing existing FDA regulations through proposed legislation, it seems more judicious to provide the knowledge and means to meet the EA requirements.

Recommendations from the Investigational New Drug/Investigational Device Exemption Task Force of the clInical and Translational Science Award Consortium: developing and implementing a sponsor-investigators training program.

OBJECTIVE: The objective of this study was to provide recommendations for provision of training for sponsor and investigators at Academic Health Centers. BACKGROUND: A subgroup of the Investigational New Drug/Investigational Device Exemption (IND/IDE) Task Force of the Clinical and Translational Science Award (CTSA) program Regulatory Knowledge Key Function Committee was assembled to specifically address how clinical investigators who hold an IND/IDE and thus assume the role of sponsor-investigators are adequately trained to meet the additional regulatory requirements of this role. METHODS: The participants who developed the recommendations were representatives of institutions with IND/IDE support programs. Through an informal survey, the task force determined that a variety and mix of models are used to provide support for IND/IDE holders within CTSA institutions. In addition, a CTSA consortium-wide resources survey was used. The participants worked from the models and survey results to develop consensus recommendations to address institutional support, training content, and implementation. RECOMMENDATIONS: The CTSA IND/IDE Task Force recommendations are as follows: (1) Institutions should assess the scope of Food and Drug Administration-regulated research, perform a needs analysis, and provide resources to implement a suitable training program; (2) The model of training program should be tailored to each institution; (3) The training should specifically address the unique role of sponsor-investigators, and the effectiveness of training should be evaluated regularly by methods that fit the model adopted by the institution; and (4) Institutional leadership should mandate sponsor-investigator training and effectively communicate the necessity and availability of training.

Production and characterization of mammalian virus-like particles from modified vaccinia virus Ankara vectors expressing influenza H5N1 hemagglutinin and neuraminidase.

Several studies have described the production of influenza virus-like particles (VLP) using a variety of platform systems. These VLPs are non-replicating particles that spontaneously self-assemble from expressed influenza virus proteins and have been proposed as vaccine candidates for both seasonal and pandemic influenza. Although still in the early stages of development and evaluation as influenza vaccines, influenza VLPs have a variety of other valuable uses such as examining and understanding correlates of protection against influenza and investigating virus-cell interactions. The most common production system for influenza VLPs is the baculovirus-insect cell expression which has several attractive features including the ease in which new gene combinations can be constructed, the immunogenicity elicited and protection afforded by the produced VLPs, and the scalability offered by the system. However, there are differences between the influenza VLPs produced by baculovirus expression systems in insect cells and the influenza viruses produced for use as current vaccines or the virus produced during a productive clinical infection. We describe here the development of a modified vaccinia virus Ankara (MVA) system to generate mammalian influenza VLPs containing influenza H5N1 proteins. The MVA vector system is flexible for manipulating and generating various VLP constructs, expresses high level of influenza hemagglutinin (HA), neuraminidase (NA), and matrix (M) proteins, and can be scaled up to produce VLPs in quantities sufficient for in vivo studies. We show that mammalian VLPs are generated from recombinant MVA vectors expressing H5N1 HA alone, but that increased VLP production can be achieved if NA is co-expressed. These mammalian H5N1 influenza VLPs have properties in common with live virus, as shown by electron microscopy analysis, their ability to hemagglutinate red blood cells, express neuraminidase activity, and to bind influenza specific antibodies. Importantly, these VLPs are able to elicit a protective immune response in a mouse challenge model, suggesting their utility in dissecting the correlates of immunity in such models. Mammalian derived VLPs may also provide a useful tool for studying virus-cell interactions and may have potential for development as pandemic vaccines.

A roadmap for academic health centers to establish good laboratory practice-compliant infrastructure.

Prior to human clinical trials, nonclinical safety and toxicology studies are required to demonstrate that a new product appears safe for human testing; these nonclinical studies are governed by good laboratory practice (GLP) regulations. As academic health centers (AHCs) embrace the charge to increase the translation of basic science research into clinical discoveries, researchers at these institutions increasingly will be conducting GLP-regulated nonclinical studies. Because the consequences for noncompliance are severe and many AHC researchers are unfamiliar with Food and Drug Administration regulations, the authors describe the regulatory requirements for conducting GLP research, including the strict documentation requirements, the necessary personnel training, the importance of study monitoring, and the critical role that compliance oversight plays in the process. They then explain the process that AHCs interested in conducting GLP studies should take before the start of their research program, including conducting a needs assessment and a gap analysis and selecting a model for GLP compliance. Finally, the authors identify and analyze several critical barriers to developing and implementing a GLP-compliant infrastructure at an AHC. Despite these challenges, the capacity to perform such research will help AHCs to build and maintain competitive research programs and to facilitate the successful translation of faculty-initiated research from nonclinical studies to first-in-human clinical trials.

Smallpox vaccines induce antibodies to the immunomodulatory, secreted vaccinia virus complement control protein.

Vaccination with Dryvax elicits a broad humoral response against many viral proteins. Human vaccinia immune globulin was used to screen the secreted proteins from cells infected with Dryvax or the candidate smallpox vaccine LC16m8 to determine whether the protective humoral response included antibodies against secreted viral proteins. Many proteins were detected, with the primary band corresponding to a band of 28 or 30 kDa in cells infected with Dryvax or LC16m8, respectively. This was identified as the vaccinia virus complement protein (VCP), which migrated more slowly in LC16m8-infected cells due to post-translational glycosylation. Vaccinia virus deleted in VCP, vVCPko, protected mice from a lethal intranasal challenge of vaccinia Western Reserve strain. Mice vaccinated with purified VCP demonstrated a strong humoral response, but were not protected against a moderate lethal challenge of vaccinia virus, suggesting that the humoral response against VCP is not critical for protection.

Optimizing viral protein yield of influenza virus strain A/Vietnam/1203/2004 by modification of the neuraminidase gene.

The preparation of high-yield prepandemic influenza virus H5N1 strains has presented a challenge to both researchers and vaccine manufacturers. The reasons for the relatively low yield of the H5N1 strains are not fully understood, but it might be partially dependent on the interactions between the hemagglutinin (HA) or neuraminidase (NA) surface glycoprotein and other influenza virus proteins. In this study, we have constructed chimeras between the A/Puerto Rico/8/34 (PR8) NA gene and the A/Vietnam/1203/2004 (VN1203) NA gene that have resulted in an increase in the virus yield of the reassortant viruses without a significant loss of NA activity. By combining the amino terminus of NA from the PR8 strain with the carboxy terminus of NA from VN1203, the surface epitopes unique to the H5N1 VN1203 NA glycoprotein are maintained. This reassortant virus had a higher titer and total protein yield in eggs, grew to a higher titer, produced large plaques on MDCK cells, and retained NA activity. This work describes a novel recombinant technique designed to increase the yields of vaccine candidates for the production of pandemic influenza virus vaccines. The relationship between the infectivity and protein yield of the reassortants also is discussed.

Human cytomegalovirus TRS1 protein is required for efficient assembly of DNA-containing capsids.

The human cytomegalovirus tegument protein, pTRS1, appears to function at several discrete stages of the virus replication cycle. We previously demonstrated that pTRS1 acts during the late phase of infection to facilitate the production of infectious virions. We now have more precisely identified the late pTRS1 function by further study of a mutant virus lacking the TRS1 region, ADsubTRS1. We observed a significant reduction in the production of capsids, especially DNA-containing C-capsids, in mutant virus-infected cells. ADsubTRS1 exhibited normal cleavage of DNA concatemers, so the defect in C-capsid production must occur after DNA cleavage and before DNA is stably inserted into a capsid. Further, the normal virus-induced morphological reorganization of the nucleus did not occur after infection with the pTRS1-deficient mutant.