Day 2 :
Keynote Forum
Soma Ghosh
Food and Drug Administration, USA
Keynote: Regulatory considerations for In Vitro diagnostics in oncology
Biography:
Soma Ghosh continued her training in Molecular Biology at the National Institutes of Health (NIH/NICHD), Bethesda, MD, where her work dealt with the mechanisms that regulate cellular DNA replication during animal development; after completing her Doctoral degree from the School of Life Sciences at Jawaharlal Nehru University, New Delhi, India. Her focus then shifted to development of sequencing-based assays to support clinical decision making in cancer therapy and management, an area she pursed as a Molecular Geneticist at the Sidney Kimmel Comprehensive Cancer Center in Johns Hopkins Medical Institute. Currently, she is a Regulatory Scientist at the FDA where she is actively involved in the review and approval of companion diagnostic devices.
Abstract:
Advancements and innovation in the development of in vitro diagnostic (IVD) devices are important for the success of personalized medicine. At FDA, the development of targeted therapies and the associated diagnostics have been a priority since the first companion diagnostic and corresponding drug were approved in 1998. Since this time, there has been a dramatic increase in biomarker-targeted drug development programs. In 2013, approximately 45% of new drug approvals were for targeted therapies, and there are currently upwards of 25 approved companion diagnostic devices. When a device is considered for marketing authorization, FDA relies upon valid scientific evidence to determine whether there is reasonable assurance that a device is safe and effective for its intended use. During my presentation, I will provide an overview of the regulatory framework for IVDs and discuss validation considerations for IVDs. In addition, I will highlight challenges and strategies related to the use of diagnostics in biomarker-driven clinical trials, and I will summarize recent FDA approvals of diagnostic devices for cancer therapeutics.
Keynote Forum
David I Smith
Mayo Clinic, USA
Keynote: Mate-Pair Sequencing (MP-Seq) as a powerful clinical tool for the management of cancer patients
Biography:
David I Smith completed his PhD from the University of Wisconsin in Madison and then did his Post-doctoral studies at the University of California in Irvine. Since 1996, he has been a Professor at the Mayo Clinic in the Department of Laboratory Medicine and Pathology. He is also the Chairman of the Technology Assessment Group for the Center for Individualized Medicine at the Mayo Clinic. His laboratory studies include the common fragile sites and the role that these regions of instability play in the development of cancer. His group also studies the different ways that HPV can contribute to the development of different cancers. He has published over 200 papers in reputed journals and serves on the Editorial Board of a number of journals.
Abstract:
Advances in DNA sequencing based upon massively parallel sequencing (Next Generation Sequencing- NGS) have dramatically increased sequence output. The Illumina sequencing platform is now capable of producing billions of simultaneous DNA sequences and this facilitates a number of different ways of characterizing nucleic acids. The most powerful use of NGS is for whole genome sequencing (WGS), but there are a number of limitations of utilizing WGS for the management of cancer patients, including the total cost and difficulties in interpreting the resulting data. A powerful alternative to WGS is the construction of mate-pair libraries and the sequencing of libraries of DNA fragments that were originally kilobases apart. We have been utilizing MP-Seq to characterize oropharyngeal squamous cell carcinomas (OPSCC) which are cancers that are increasingly caused by human papillomavirus. We will describe how MP-Seq can characterize the physical status of HPV in HPV-positive OPSCCs and the clinical significance of this characterization. This work has demonstrated that HPV plays different roles in the development of OPSCCs and many of these are quite distinct from HPVs role in the development of cervical cancer. In addition, MP-Seq can characterize genomic changes in each cancer and these can be used to develop cancer-specific markers, which can be used to monitor an individual patient response to therapy. Thus, MP-Seq could be a powerful and yet affordable tool that can be used as a clinical tool for the management of cancer patients.
Keynote Forum
John Michael Sauer
University of Arizona College of Medicine, USA
Keynote: The predictive safety testing consortium: Qualification of translational safety biomarkers for use in drug development
Biography:
John Michael Sauer is a Toxicologist by training with over 20 years of experience in drug discovery and development. He has been responsible for leading multiple functional areas across several pharmaceutical companies. He received his Doctorate degree in Pharmacology and Toxicology from The University of Arizona. Currently, he is working as the Program Officer of Biomarker Programs and the Executive Director of the Predictive Safety Testing Consortium at the Critical Path Institute, as well as an Adjunct Research Professor in the Department of Pharmacology at the University of Arizona, College of Medicine.
Abstract:
The use of novel safety biomarkers in clinical trials has the potential to profoundly impact the ability of drug development innovators and health authorities to evaluate and improve patient safety. Many of the biomarkers currently being used to evaluate clinical safety suffer from a lack of sensitivity or specificity for detecting drug induced organ injury. Therefore, several groups including the Critical Path Institute’s Predictive Safety Testing Consortium (PSTC) have been working towards the regulatory qualification of novel safety biomarkers with the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and Japanese Pharmaceuticals and Medical Devices Agency (PMDA) to gain scientific and regulatory endorsement of these biomarkers. However, these efforts have been hampered by the lack of well-defined scientific and regulatory expectations or evidentiary criteria. Therefore, the objective of this presentation is to discuss and align the expectations for qualification of novel safety biomarkers to be applied during drug development. Furthermore, the general approach to the regulatory qualification of translational safety biomarker will be discussed using several case studies focusing on safety biomarkers.
Keynote Forum
Nikolai V Ivanov
Philip Morris International Research & Development, Switzerland
Keynote: Pre-clinical and clinical studies in COPD and cardiovascular areas and the role of biomarkers
Biography:
Nikolai V Ivanov currently holds the position of Manager of the Research Technologies Department at Philip Morris International R&D Innovation Cube, Philip Morris Products S A in Neuchatel, Switzerland. In this role, he is responsible for setting the strategic direction of the department and leading genome sequencing, gene expression, proteomics, high performance computing and quality management systems projects. He received his MSc in Mathematics and Computer Science in 2001 and his PhD in Biochemistry in 2002 from Emory University (Atlanta, USA). In 2015, he was awarded a title of Privat Docent by the University of Neuchatel (Switzerland). He has published more than 40 manuscripts primarily in the area of Systems Toxicology.
Abstract:
Cigarette smoking causes serious diseases including chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD). ApoE-deficient mice are prone to developing premature atherosclerosis and emphysema making it an ideal model in which both pathologies can be assessed simultaneously. We evaluated the effects of cigarette smoke (CS) from a cigarette (3R4F) and aerosol from tobacco heating system 2.2 (THS2.2), a candidate modified risk tobacco product. ApoE-/- mice were exposed for up to eight months to the test aerosol for three hours/day, five days/week to a target nicotine concentration of 30 µg/l. After two months of exposure to CS, cessation and switching groups were further exposed for up to six months to fresh air, or THS2.2, respectively. Multiple markers of disease progression were investigated including atherosclerotic plaque formation, pulmonary inflammation, pulmonary function and lung emphysema. Exposure to CS induced time-dependent molecular, physiological and inflammatory pulmonary responses in ApoE-/- mice consistent with emphysematous changes. Significant changes in the lung transcriptome and proteome of ApoE-/- mice were observed in response to CS-exposure compared to sham-exposed mice. Smoking cessation and switching to THS2.2 resulted in lower activation levels compared to continuous exposure to CS. Both, smoking cessation and switching to the THS2.2 halted the rate of disease development as assessed by histopathological and molecular endpoints. At the same time, a clinical study reported as part of a global clinical program for THS was designed to demonstrate sustained exposure reduction to selected HPHCs and to provide first insight on changes in clinical risk endpoints (CREs) in smokers pre-dominantly using tobacco sticks menthol variant (mTHS) for five days in confinement followed by an ambulatory period of 85 days, compared to subjects continuing to smoke menthol cigarettes (mCC) and those who abstained from smoking. Biomarkers of exposure (BoExp) to 16 HPHCs and nicotine were measured to provide an assessment of human uptake of a set of representative toxicants contained in tobacco products. Selected CREs associated with cardiovascular and respiratory diseases and genotoxicity as well as subjective effects to investigate mTHS acceptance compared to mCC were assessed.
Keynote Forum
Lowe Leroy
Lancaster University, UK
Keynote: Tackling heterogeneity in advanced cancers with personalized combination therapeutics
Biography:
Leroy J Lowe is the President and Cofounder of Getting to Know Cancer, a Canadian Non-Profit Organisation that is focused on the advancement of cancer research. His PhD is from Lancaster University in the UK and he is the Key Architect of the Halifax Project (2011-2015), a global initiative that involved more than 350 cancer researchers in 31 countries. He is currently focused on the Broadspec Clinical Trials, a multi-institution case-series that will encompass prophylactic trials for myelodysplastic syndrome patients who are at high risk of developing acute myeloid leukemia and therapeutic trials for patients with advanced-stage ovarian cancer, pancreatic ductal adenocarcinoma or glioblastoma multiforme.
Abstract:
Tackling heterogenity in advanced cancers will require personalized therapeutic protocols customized for an array of molecular targets unique to each patient. However, many existing therapies are highly toxic and approved for only a limited subset of cancers, so the range of therapeutic combinations for a given cancer is often limited. Recently, a multinational taskforce of 180 researchers collaborated to put forward a design for a broad-spectrum therapeutic approach to prevent high-risk cancers, treat refractory cancers and prevent disease relapse. In doing so, they identified a great number of natural health products and re-purposed pharmaceuticals that could be used in conjunction with existing standard of care to reach many targets simultaneously. The approach leverages our understanding of the molecular biology of the hallmarks of cancer and combines it with the principles of precision medicine and network pharmacology. The goal now is to use genomic and proteomic information to provide physicians with complementary, low-toxicity protocols that can be developed dynamically, individualized, and then used to support cancer patients who are already undergoing traditional modes of treatment. Several challenges exist, but clinical trials are now being initiated to validate key assumptions. It will necessitate concurrently administered combinations of many agents using metronomic dosing regimens specifically designed and managed to ensure patient safety. This is a logical next step forward in personalized cancer therapeutics and it will help us take advantage of next generation sequencing information. The future will most certainly make use of broad-spectrum protocols to enhance anti-cancer synergies and improve patient outcomes.