Speakers represent academia, industry and government agencies.

Additional talks/speakers are being confirmed.

Dr. Michelle Casey   Executive Director of Biostatistics, Pfizer

Dr. Michelle Casey Michelle Casey is an Executive Director of Biostatistics overseeing late phase development programs within hemophilia and rare cardiomyopathy conditions at Pfizer. She has been a practicing biostatistician for over 17 years holding multiple position supporting a variety of indications across rare disease and oncology. Michelle is a member of the industry working group for estimands in Oncology which is a special interest group of the European Federation of Statisticians in the Pharmaceutical Industry and a scientific working group of the Biopharmaceutical Section of the American Statistical Association. She received her Ph.D. from the Medical College of Virginia of Virginia Commonwealth University.

Gene Therapy: Opportunities and Challenges for the Treatment of Hemophilia


Hemophilia is a rare genetic disorder in which affected individuals have low levels of a protein (Factor VIII in the case of Hemophilia A and Factor IX in the case of Hemophilia B) necessary for blood clotting. Severe hemophilia can cause prolonged or spontaneous bleeding, particularly into the muscles, joints (hemarthrosis), or internal organs. Treatments for hemophilia are available; however, the implementation of prophylaxis beginning as early as the first year of life is associated with significant treatment burden and cost. Additionally, prophylaxis therapy does not eliminate bleeding events for all patients and therefore patients may still experience progressive joint disease or in some cases life threatening bleeding events.

Hemophilia A and Hemophilia B are ideal targets for gene therapy as the disorders are each caused by diminished function of a single protein (Factor VIII or Factor IX respectively) which in turn is caused by alteration of a single gene (F8 or F9 respectively). Gene therapy has the potential to provide long-term expression of the missing or abnormal clotting factor to reduce or even eliminate the need for prophylactic therapy.

Unlike some rare diseases, the natural history of hemophilia is well established, and annualized bleed rate (ABR) is a well-accepted endpoint for demonstrating efficacy. Additionally, recent clinical trials established a paradigm for one-way cross-over designs comparing treatment with standard of care during an observational phase to an active treatment phase in which participants receive experimental therapy.

Despite the advances in gene therapy research, the potential for benefits of gene therapy, and the history of clinical trial designs in hemophilia, challenges remain. Specifically, ABR alone does not distinguish the benefits of gene therapy, inter-laboratory variability in assays pose challenges for assessing factor activity levels which has long been established as a direct measure of severity of disease, and questions remain specific to the long-term efficacy and safety of gene therapy.

This presentation will focus on the challenges in design and analysis of gene therapy trials for hemophilia with a discussion on one-way cross-over designs vs. parallel study designs, prospective vs. retrospective collection of data on established standard of care therapy, endpoints specific to gene therapy, and requirements for long-term follow-up.

Dr. Margaret (Meg) Gamalo   Senior Director, Pfizer

Dr. Margaret (Meg) Gamalo Margaret (Meg) Gamalo, PhD is Senior Director – Biostatistics, Global Product Development – Inflammation and Immunology at Pfizer Innovative Health. She combines expertise in biostatistics, regulatory and adult and pediatric drug development. She recently was a Research Advisor, Global Statistical Sciences at Eli Lilly and Company and prior to that was a Mathematical Statistician at the Food and Drug Administration. Meg is an expert in pediatric extrapolation and leads the Pediatric Innovation Task Force at the Biotechnology Innovation Organization. She is also an active member of the European Forum for Good Clinical Practice – Children’s Medicine Working Party.

Lessons from Notable Applications of RWD/RWE as External Controls to Establish Efficacy of Therapeutic Interventions in New Marketing Applications


Externally controlled studies, wherein treatment in a study arm is assigned according to a protocol, and treatment in a control arm is observed using predefined "external" patient-level data, in successful regulatory submissions is growing. In rare diseases, aglucosidase alfa (2006), asfotase alfa (2015), cerliponase alfa (2017), fish oil triglycerides (2017) and triheptanoin (2020) used external controls to support demonstration of effectiveness. Similarly, blinatumomab (2014), defibrotide sodium (2016), avelumab (2017), axicabtagene ciloleucel (2017), erdafitinib (2018), selinexor (2019), tafasitamab (2020), in the oncology therapeutic area, all submitted data on external controls in their pre-market applications for their primary indications. While all these drugs were seeking indications considered as rare, the evidence threshold that the submissions were scrutinized has not changed. In that regard, it is informative to know what types of external data were submitted and how the external data was used in support of the indication/s, e.g., whether the proposed indication is wider than what the data supports. It is also helpful to know whether the data was the primary basis for approval for the indication sought or was it only supportive; and if the former, how the external control data was reflected in the label. These submissions also provide valuable lessons on scientific areas that need careful consideration and how these elements are factored in during the evaluation for effectiveness, e.g., design (e.g., finding the right comparators, finding the right/valid endpoints), data (e.g., prospective or retrospective, or concurrent) and extent of data including follow-up, minimization and analytic methods for adjusting confounding.

Dr. Steve Lake   Vice President of Biometrics, Wave Life Sciences

Dr. Steve Lake Steve Lake is the Vice President of Biometrics at Wave Life Sciences. Prior to joining Wave he work ed at Clementia Pharmaceuticals and spent 15 years at Genzyme and Sanofi. He holds a doctorate degree in Biostatistics from the Harvard School of Public Health.

Dr. Glen Laird   Head of Biostatistics Methodology and Innovation, Vertex

Dr. Glen Laird A practicing statistician for 20 years, Glen Laird is currently the head of Biostatistics Methodology and Innovation at Vertex Pharmaceuticals, having previously led the GMA Biostatistics group at Vertex. Prior to his 3 years at Vertex, Glen worked in oncology biostatistics at Novartis, BMS, and Sanofi, assuming roles with increasing responsibility across early and full development. Glen graduated with a PhD in Statistics from Florida State University and worked as a survey statistician for RTI International before joining the pharmaceutical industry.

Design and Analysis of Drop-the-Losers Studies Using Binary Endpoints in the Rare Disease Setting


The drop-the-losers design combines a phase 2 trial of k treatments and a confirmatory phase 3 trial under a single adaptive protocol, thereby gaining efficiency over a traditional clinical development approach. Such designs may be particularly useful in the rare disease setting, where conserving sample size is paramount, and control arms may not be feasible. We propose an unconditional exact likelihood (UEL) testing and inference procedure for these designs for a binary endpoint using small sample sizes, comparing its operating characteristics to existing methods. Additional practical considerations are evaluated, including the choice of stagewise sample sizes and effect of ties.

Dr. Chengxing (Cindy) Lu   Director of Biostatistics, Biogen

Dr. Cindy Lu Chengxing (Cindy) Lu, PhD, is currently a Director of Biostatistics in Biogen Inc, Cambridge, MA. Prior to Biogen, Cindy has cumulated various industry experiences from a few other leading pharmaceutical companies, Merck, Novartis and Bayer, in multiple disease areas, after receiving her Ph.D in Biostatistics from Emory University. She has led statistical related activities from early to late phases of clinical development, from marketing registration submissions to post-marking and reimbursement activities. Dr. Lu is currently the co-lead of master protocol design sub-team in ASA Biopharmaceutical Section Oncology Scientific Working Group, and the co-chair of DIA-ASA joint master protocol multidisciplinary Working Group. Her research interest is complex study designs in clinical trials, applications of real- world evidence in clinical development and HTA processes, and oncology/rare disease drug development strategy.

A Case Study Using Nature History Data to Understand Long-Term Disease Progression


Small patient population and limited natural history data on long term disease progression can be challenges in developing a therapeutic for a rare disease with slow progression. In this presentation, we share a case study of a gene therapy program to overcome these challenges. In this program, the randomized treated patients are followed for an extended period, while the untreated patients in the randomized trial and patients in a separate natural history study are only followed for a more limited duration of time. To understand the long-term disease progression in the untreated patients and potentially use them as a control to understand long-term treatment benefit, three steps were taken: 1) using meta-analysis to explore the impact of age on disease progression; 2) matching untreated patients from a natural history study with treated patients using propensity score matching method; 3) projecting long-term treated and matched untreated patients based on the short term trend, considering the age stratifications and utilizing findings from a meta-analysis. Although using external control in a formal marketing registration package was not recommended from regulatory for this program, this piece of work helps to frame the clinical development plan as well as market access strategies in terms of long-term efficacy in the context of a slowly progressive rare disease.

Dr. Sandeep Menon   Senior Vice President and Head of Early Clinical Development (ECD), Pfizer

Dr. Sandeep Menon Sandeep Menon is Senior Vice President and Head of Early Clinical Development (ECD) at Pfizer Inc. ECD works to drive and influence the early clinical development portfolio by partnering with key stakeholders across therapeutic areas to ensure scientific rigor, quantitative decision-making, innovation and operational excellence. Sandeep leads a multi-functional global team which includes experts in clinical study execution, biostatistics and bioinformatics, clinical pharmacology, precision medicine, digital medicine, translational imaging and early scientific planning and operations. He also sits on Pfizer’s Worldwide Research, Development and Medical Leadership Team.

During his ten years at Pfizer he has held several positions of increasing responsibility, most recently as Vice President and Head of ECD, Biostatistics. Prior to joining Pfizer, he held late-phase leadership roles at Biogen Idec and Aptiv Solutions (now ICON).

Sandeep has extensive experience with regulatory interactions, including with the FDA, EMA and PMDA (Japan Agency). He is internationally known for his technical expertise especially in the area of adaptive designs, translational biomarkers, multi-regional trials, and small populations. He has managed global multi-functional groups responsible for successfully delivering NDA’s, BLA’s and PMA’s.

Sandeep is an elected fellow of the American Statistical Association and was recently awarded the Young Scientist Award by the International Indian Statistical Association. Sandeep received his medical degree from Bangalore (Karnataka) University, India, and later completed his Masters and Ph.D. in Biostatistics at Boston University and research assistantship at Harvard Clinical Research Institute. He holds adjunct faculty positions at Boston University School of Public Health, Tufts University School of Medicine, and the Indian Institute of Management (IIM). He has received several awards for academic, teaching and research excellence.

Dr. Dionne Price   Director of the Division of Biometrics IV, FDA

Dr. Dionne Price Dionne Price, Ph.D. is the Director of the Division of Biometrics IV, Office of Biostatistics in the Office of Translational Sciences, Center for Drug Evaluation and Research, FDA. Dr. Price has provided statistical leadership across a broad variety of therapeutic areas including ophthalmology, anti-infectives, anti-virals, and rare diseases. She currently leads cross-cutting efforts across FDA to advance and facilitate the use of complex innovative trial designs. Dr. Price received her MS in Biostatistics from the University of North Carolina at Chapel Hill and a PhD in Biostatistics from Emory University. Dr. Price is an active member of the American Statistical Association (ASA) and the Eastern North American Region of the International Biometrics Society. She is a Fellow of the ASA and a Vice-President of the ASA.

Dr. Lee-Jen Wei   Professor of Biostatistics, Harvard University

Dr. L.J Wei L.J. Wei is a professor of Biostatistics at Harvard University. Before joining Harvard, he was a professor at University of Wisconsin, University of Michigan, and George Washington University. His main research interest is in the clinical trial methodology, especially in design, monitoring and analysis of studies. He has developed numerous novel statistical methods which are utilized in practice. He received the prestigious Wald Medal in 2009 from the American Statistical Association for his contribution to clinical trial methodology. He is a fellow of American Statistical Associating and Institute of Mathematical Statistics. In 2014, to honor his mentorship, Harvard School of Public Health established a Wei-family scholarship to support students studying biostatistics. His recent research area is concentrated on translational statistics, the personalize medicine under the risk-benefit paradigm via biomarkers and revitalizing clinical trial methodology. He has more than 200 publications and served on numerous editorial and scientific advisory boards. L. J. Wei has extensive working experience in regulatory science for developing and evaluating new drugs/devices.

Dr. Ying Yuan   Bettyann Asche Murray Distinguished Professor and Deputy Chair in the Department of Biostatistics, University of Texas MD Anderson Cancer Center

Dr. Ying Yuan Ying Yuan, PhD, is a Bettyann Asche Murray Distinguished Professor and Deputy Chair in the Department of Biostatistics at the University of Texas MD Anderson Cancer Center. Dr. Yuan has published over 100 statistical methodology papers on innovative Bayesian adaptive designs, including early phase trials, seamless trials, biomarker-guided trials, and basket and platform trials. The designs and software (www.trialdesign.org) developed by Dr. Yuan’s lab have been widely used in medical research institutes and pharmaceutical companies. Dr. Yuan is the Chair of Data Safety Monitoring Board (DSMB) at MD Anderson Cancer Center, overseeing over 140 randomized clinical trials. Dr. Yuan wrote book "Bayesian Designs for Phase I-II Clinical Trials" published by Chapman & Hall/CRC.

Dr. Marie-Laure Névoret   Senior Clinical Development Lead, REGENXBIO

Dr. Marie-Laure Névoret is the Senior Clinical Development Lead for the CNS programs at REGENXBIO where she oversees the company's clinical programs of gene therapy products for rare pediatric genetic neurodegenerative disorders. Prior to that, Dr. Névoret served in progressive roles at Helixmith (formerly ViroMed/VM BioPharma), leading the global clinical development programs of their lead gene therapy VM202. Before Helixmith, Dr. Névoret was the Medical Director, North America for Impeto Medical, heading medical affairs and clinical development of an innovative sudomotor function device for the detection of small fiber impairment. Earlier in her career, she worked at PPD in pharmacovigilance and at Eastern Virginia Medical School in clinical research on diabetes, diabetic neuropathy, and neuroendocrinology. After completing her bachelor’s degree at Duke University, Dr. Névoret received her M.D. from Loyola University Chicago Stritch School of Medicine. She went on to complete a residency in general surgery at Loyola as well and practiced general surgery in Massachusetts. Dr. Névoret has been working in diabetes and neurodegenerative clinical research and development for over a decade.

Dr. John Zhong   Vice President, Head of Biometrics, REGENXBIO

Dr. John Zhong Dr. John Zhong is the Vice President of Biometrics at REGENXBIO, a leading AAV gene therapy company. Before joining REGENXBIO, John was a Biostatistics Group Head at Biogen, leading his teams to provide statistical strategy and support to all phases of clinical development for Immunology and Rare Diseases as well Early Development for all assets. He also led the Innovative Analytics group and played a critical role in the use of innovative clinical trial designs, statistical methods and analytical approaches in Biogen’s research and drug development. Prior to Biogen, John was a Senior Director of Biostatistics at Human Genome Sciences, accountable for statistical strategy and support to all phases of clinical development in autoimmune disease and infectious disease areas. John has 20 years of industry experience and played pivotal roles in multiple successful drug development programs, bringing efficacious treatments to patients with serious unmet needs. In the industry, John actively promoted statistical innovation in drug development and brought industry’s voice to regulatory innovation. John was an invited expert panelist at the FDA Public Meeting on "Promoting the Use of Complex Innovative Designs in Clinical Trials". He made a positive impact on the design of FDA’s Complex Innovative Designs Pilot program. Currently, John is a Rapporteur at the ICH, leading the E20 Expert Working Group to develop an international regulatory guideline on Adaptive Clinical Trials. John received his PhD in Mathematical Statistics from the University of Maryland at College Park. He has coauthored over 50 manuscripts in peer reviewed medical and statistical journals and more than 100 presentations.

Opportunities and Challenges in Gene Therapy Clinical Development – Some Clinical and Statistical Perspectives

By Marie-Laure Névoret, MD and John Zhong, PhD


Gene therapy has attracted increasingly greater interest and resulted in several approved products to benefit patients with serious unmet needs in recent years. These successes were largely resulted from a better scientific understanding of the diseases, the safety profile of gene therapy, and refined manufacturing processes. In this talk, we will provide an overview of gene therapy. Gene therapy and its application in MPS II will be reviewed to exemplify some of the challenges and opportunities for innovation in rare pediatric diseases where protracted clinical development is inappropriate but difficult to overcome, especially in rare neurodegenerative diseases. MPS II is a rare, X-linked recessive disease caused by a deficiency in the lysosomal enzyme iduronate-2-sulfatase (IDS) leading to an accumulation of glycosaminoglycans (GAGs) in tissues which ultimately results in cell, tissue, and organ dysfunction. In severe MPS II, neurodevelopmental delay due to GAG accumulation in the brain appears in early childhood and progresses unrelentingly. Gene therapy administered to the CNS has the potential to be curative; however, demonstrating neurodevelopmental efficacy of a study drug in severe pediatric MPS II is highly challenging due to the rarity of the disease, the heterogeneity of the population, the lack of early childhood natural history data, and the disease’s prolonged progression. In addition to clinical perspectives, we will discuss some opportunities in the current innovative environment and statistical approaches to address the clinical development challenges.