Bruce K. Burnett

Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis

OBJECTIVE Osteoarthritis (OA) is a chronic and slowly progressive disease for which biomarkers may be able to provide a more rapid indication of therapeutic responses to therapy than is currently available; this could accelerate and facilitate OA drug discovery and development programs. The goal of this document is to provide a summary and guide to the application of in vitro (biochemical and other soluble) biomarkers in the development of drugs for OA and to outline and stimulate a research agenda that will further this goal. METHODS The Biomarkers Working Group representing experts in the field of OA biomarker research from both academia and industry developed this consensus document between 2007 and 2009 at the behest of the Osteoarthritis Research Society International Federal Drug Administration initiative (OARSI FDA initiative). RESULTS This document summarizes definitions and classification systems for biomarkers, the current outcome measures used in OA clinical trials, applications and potential utility of biomarkers for development of OA therapeutics, the current state of qualification of OA-related biomarkers, pathways for biomarker qualification, critical needs to advance the use of biomarkers for drug development, recommendations regarding practices and clinical trials, and a research agenda to advance the science of OA-related biomarkers. CONCLUSIONS Although many OA-related biomarkers are currently available they exist in various states of qualification and validation. The biomarkers that are likely to have the earliest beneficial impact on clinical trials fall into two general categories, those that will allow targeting of subjects most likely to either respond and/or progress (prognostic value) within a reasonable and manageable time frame for a clinical study (for instance within 1-2 years for an OA trial), and those that provide early feedback for preclinical decision-making and for trial organizers that a drug is having the desired biochemical effect. As in vitro biomarkers are increasingly investigated in the context of specific drug treatments, advances in the field can be expected that will lead to rapid expansion of the list of available biomarkers with increasing understanding of the molecular processes that they represent.

Cell Therapy for Lung Diseases. Report from an NIH–NHLBI Workshop, November 13–14, 2012

The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health convened the Cell Therapy for Lung Disease Working Group on November 13-14, 2012, to review and formulate recommendations for future research directions. The workshop brought together investigators studying basic mechanisms and the roles of cell therapy in preclinical models of lung injury and pulmonary vascular disease, with clinical trial experts in cell therapy for cardiovascular diseases and experts from the NHLBI Production Assistance for Cell Therapy program. The purpose of the workshop was to discuss the current status of basic investigations in lung cell therapy, to identify some of the scientific gaps in current knowledge regarding the potential roles and mechanisms of cell therapy in the treatment of lung diseases, and to develop recommendations to the NHLBI and the research community on scientific priorities and practical steps that would lead to first-in-human trials of lung cell therapy.

Support for investigator-initiated clinical research involving investigational drugs or devices: the Clinical and Translational Science Award experience.

Purpose Investigator-initiated research involving investigational drugs and devices is key to improving health. However, this requires the investigator to serve as a “sponsor–investigator,” which can be complex and overwhelming. The Investigational New Drug/Investigational Device Exemption (IND/IDE) Taskforce of the Clinical and Translational Science Award (CTSA) consortium carried out a survey to examine how academic health centers (AHCs) assist sponsor–investigators with regulatory responsibilities. Method The 24 CTSA centers existing in 2008 were surveyed regarding regulatory oversight and support for sponsor–investigators. Responses were analyzed by descriptive statistics. The evaluation of survey responses yielded three models of institutional support/oversight. Results Nineteen centers and one affiliate responded. Eleven (55%) reported having an IND/IDE support office, increased from five (25%) prior to their CTSA award. The volume of investigator-initiated IND/IDE research was highly variable (measured by numbers of investigators, IND/IDE applications, and studies). Oversight, if done, was provided by either the IND/IDE office or elsewhere in the institution. Most IND/IDE offices assisted with IND/IDE submissions and preparation for external audits. Half reported advanced training for sponsor–investigators. Almost all reported a goal to increase IND/IDE research. Important issues include the need for robust training of investigator/staff, appropriate determination of IND-exempt research, and sufficient support for preparing IND/IDE applications. Conclusions Investigator-initiated research involving IND/IDEs is essential, but complex. AHCs should examine how they support sponsor–investigators in meeting the complex requirements. A model of either expert consultation/support or full service will minimize risks to participants and institutions, and regulatory noncompliance.

Preparation and Analysis of Peanut Flour Used in Oral Immunotherapy Clinical Trials

BACKGROUND Oral immunotherapy (OIT) is an investigational therapeutic approach for the treatment of food allergies. Characterization of the drug product used in oral immunotherapy trials for peanut allergy has not been reported. OBJECTIVE To quantify relative amounts of the major peanut allergens and microbial load present in peanut flour used in OIT trials and assess whether these parameters change over a 12-month period. We also anticipate that this report will serve as a guide for investigators seeking to conduct OIT trials under Food and Drug Administration-approved Investigational New Drug applications. METHODS Densitometric scanning of Ara h 1 and Ara h 2 resolved on SDS-PAGE gels was used to assess allergen content in peanut flour extracts. Microbial testing was conducted on peanut flour under US Pharmacopeia guidelines for the presence of Escherichia coli, salmonella, yeast, mold, and total aerobic bacteria. In addition, aflatoxin was quantified in peanut flour. Reported results were obtained from 4 unique lots of peanut flour. RESULTS Relative amounts of the major peanut allergens were similar between different lots of peanut flour and remained stable over a 12-month period. E coli and salmonella were absent from all lots of flour. Yeast, mold, total aerobic bacteria, and aflatoxin were within established US Pharmacopeia guidelines on all lots tested and remained within the criteria over a 12-month period. CONCLUSIONS Peanut flour used as a drug product contains the major peanut allergens and has low levels of potentially harmful microbes. Both these parameters remain stable over a 12-month period.

Co-delivery of antigen and IL-12 by Venezuelan equine encephalitis virus replicon particles enhances antigen-specific immune responses and antitumor effects.

We recently demonstrated that Venezuelan equine encephalitis virus-based replicon particle (VRPs) encoding tumor antigens could break tolerance in the immunomodulatory environment of advanced cancer. We hypothesized that local injection of VRP-expressing interleukin-12 (IL-12) at the site of injections of VRP-based cancer vaccines would enhance the tumor-antigen-specific T cell and antibody responses and antitumor efficacy. Mice were immunized with VRP encoding the human tumor-associated antigen, carcinoembryonic antigen (CEA) (VRP-CEA(6D)), and VRP-IL-12 was also administered at the same site or at a distant location. CEA-specific T cell and antibody responses were measured. To determine antitumor activity, mice were implanted with MC38-CEA-2 cells and immunized with VRP-CEA with and without VRP-IL-12, and tumor growth and mouse survival were measured. VRP-IL-12 greatly enhanced CEA-specific T cell and antibody responses when combined with VRP-CEA(6D) vaccination. VRP-IL-12 was superior to IL-12 protein at enhancing immune responses. Vaccination with VRP-CEA(6D) plus VRP-IL-12 was superior to VRP-CEA(6D) or VRP-IL-12 alone in inducing antitumor activity and prolonging survival in tumor-bearing mice. Importantly, local injection of VRP-IL-12 at the VRP-CEA(6D) injection site provided more potent activation of CEA-specific immune responses than that of VRP-IL-12 injected at a distant site from the VRP-CEA injections. Together, this study shows that VRP-IL-12 enhances vaccination with VRP-CEA(6D) and was more effective at activating CEA-specific T cell responses when locally expressed at the vaccine site. Clinical trials evaluating the adjuvant effect of VRP-IL-12 at enhancing the immunogenicity of cancer vaccines are warranted.

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.

ClinicalTrials.gov Reporting: Strategies for Success at an Academic Health Center

The Food and Drug Administration Amendments Act of 2007 (FDAAA 2007, US Public Law 110-98) mandated registration and reporting of results for applicable clinical trials. Meeting these registration and results reporting requirements has proven to be a challenge for the academic research community. Duke Medicine has made compliance with registration and results reporting a high priority. In order to create uniformity across a large institution, a written policy was created describing requirements for clinical trials disclosure. Furthermore, a centralized resource group was formed with three full time staff members. The group not only ensures compliance with FDAAA 2007, it also acts as a resource for study teams providing hands-on support, reporting, training, and ongoing education. Intensive resourcing for results reporting has been crucial for success. Due to implementation of the institutional policy and creation of centralized resources, compliance with FDAAA 2007 has increased dramatically at Duke Medicine for both registration and results reporting. A consistent centralized approach has enabled success in the face of changing agency rules and new legislation.

Comprehensive Hands-on Training for Influenza Vaccine Manufacturing: A WHO-BARDA-BTEC Partnership for Global Workforce Development.

The critical need for enhancing influenza pandemic preparedness in many developing nations has led the World Health Organization (WHO) and the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services (HHS), to develop an international influenza vaccine capacity‐building program. Among the critical limitations faced by many of these nations is lack of access to training programs for staff supporting operations within vaccine production facilities. With support from BARDA, the Biomanufacturing Training and Education Center (BTEC) at North Carolina State University has addressed this need for training by developing and delivering a comprehensive training program, consisting of three courses: Fundamentals of cGMP Influenza Vaccine Manufacturing, Advanced Upstream Processes for Influenza Vaccine Manufacturing, and Advanced Downstream Processes for Influenza Vaccine Manufacturing. The courses cover process design, transfer, and execution at manufacturing scale, quality systems, and regulations covering both manufacturing and approval of pandemic vaccines. The Fundamentals course focuses on the concepts, equipment, applicable regulations, and procedures commonly used to produce influenza vaccine. The two Advanced courses focus on process design, scale up, validation, and new technologies likely to improve efficiency of vaccine production. All three courses rely on a combination of classroom instruction and hands‐on training in BTECs various laboratories. Each course stands alone, and participants may take one or more of the three courses. Overall participant satisfaction with the courses has been high, and follow‐up surveys show that participants actively transferred the knowledge they gained to the workplace. Future plans call for BTEC to continue offering the three courses and to create an online version of several modules of the Fundamentals course.