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C2 – Real World Evidence Framework in Clinical Development

Chair: Hong Tian (BeiGene)
Vice Chair: Freda Cooner (Eli Lilly)

Laura Fernandes, PhD (COTA)
Freda Cooner, PhD (Eli Lilly)

Course Description:

Real-world data (RWD) and real-world evidence (RWE) have historically played an important role in drug development and patient access.  In PDUFA VI that has been in effect since October 2017, “exploring the use of real world evidence for use in regulatory decision-making” is specified to enhance regulatory science and expedite drug development, for both effectiveness and safety evaluations.  Since then, there is a surge of innovative trial designs and methodologies that incorporate RWE in clinical setting.  The COVID-19 pandemic also sheds a unique light on alternative data sources usage in understanding the virus and disease, including off-label use of drugs in COVID-19 treatment.  In the last quarter of 2021, the FDA published a series of four guidance documents on RWD utilization standards and strategies in fulfillment of the mandate under section 505F of the FD&C Act.

This short course will start by defining RWD and RWE and then present the FDA framework for using RWD in clinical development.  We will take a closer look into the FDA guidance documents.  Each guidance has its specific purpose, ranging from electronic health records (EHRs) and medical claims (“Real-World Data: Assessing Electronic Health Records and Medical Claims Data To Support Regulatory Decision-Making for Drug and Biological Products”), to registries (“Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products Guidance for Industry”) in support of submissions for drug and biologic approval, including data standards specific to RWD (“Data Standards for Drug and Biological Product Submissions Containing Real-World Data”) and other considerations (“Considerations for the Use of Real-World Data and Real-World Evidence To Support Regulatory Decision-Making for Drug and Biological Products”) in regulatory decision-making.  We will also define the process of evaluating a fit for purpose database that is relevant and applicable to the research question.

The next section will focus on the different types of systemic biases: selection, information and confounding, and the methods that can be used to mitigate their effects.  Different types of external controls, e.g., historical control, external control, synthetic control, pragmatic, and hybrid control, will be presented along with their pros and cons.  Special focus will be given on the different biases that come in play when using these external controls in a clinical trial and the ways to mitigate them.

Finally clinical trial designs and Bayesian statistical methodologies that leverage external clinical trial data will be introduced.  Methods to borrow patient-level and study-level data into a clinical trial design will be discussed.  Special considerations in the incorporation of RWD into the various stages of clinical trials, Phase 1 through Phase 4, will also be presented.  Multiple case examples will be used throughout the course to illustrate the trial designs and statistical methodologies.


Laura Fernandes, Ph.D.
Senior Statistical Director
COTA, Inc.

Laura FernandesLaura Fernandes is a senior statistical director at COTA, a real world data company specializing in curating cancer electronic health records (EHR) data for clinical research. She has been involved in clinical trials and research for over 20 years spanning academia, the industry and regulatory agency. She has presented at several international conferences and workshops and published in many peer-reviewed journals. Her research interest includes real world endpoints in oncology, use of RWD in clinical trials as external controls and oncology clinical trial design.

Dr. Fernandes received her PhD in biostatistics from the University of Michigan in Ann Arbor. Her thesis focused on the adaptive phase I clinical trial designs in oncology.  She worked part-time supporting clinical research at the cancer center during her graduate studies.

Dr. Fernandes also worked at the US-FDA for over 7 years as a statistical reviewer supporting the Oncology Center of Excellence (OCE) for oncology and hematology drug applications. She was part of over 20 different drug approvals and has reviewed several hundred clinical trial protocols covering different stages of development. She was involved in several working groups and in formulating several guidance documents. She is a recipient of several excellency awards from CDER and worked on many research publications and presentations. Dr. Fernandes also worked in the satellite offices of GlaxoSmithKline (GSK) in Bangalore, India in the biometrics team as a statistical programmer and was responsible for executing analysis of clinical trial data that would eventually be submitted to the regulatory agencies.

Freda Cooner, Ph.D.
Senior Director – Statistics
Eli Lilly

Freda CoonerDr. Freda Cooner is currently a Senior Director, Statistics in Eli Lilly and Company. Prior to that, she was a Statistics Director in Amgen, leading the prostate cancer statistics program and exploration of innovative designs for several oncology and non-oncology products, including master protocols and seamless trials. Before joining Amgen late 2018, she was an Associate Director in Sanofi leading several diabetes products and studies. Prior to Sanofi, Dr. Cooner worked in FDA for over 10 years, where she reviewed hundreds of products in multiple therapeutic areas and led several working groups. She obtained her Ph.D. in Biostatistics from School of Public Health, University of Minnesota.

Her research interests include Bayesian statistics, adaptive design, small sample size trials, pediatric studies, multiple testing procedures, missing data imputation, mater protocols, real-world evidence, safety evaluation and endpoints selection. She has multiple publications in Bayesian statistics and its application in oncology trials, pediatric clinical development and rare diseases. She also has extensive real case experiences in real-world data (RWD) and real-world evidence (RWE) utilization in multiple oncology and hematology clinical programs. She has published research work on RWD/RWE in pediatrics and more recently COVID-19 pandemic.

Dr. Cooner has more than 16 years of clinical trial experience with an extensive regulatory and trial conduct background. Her regulatory experience includes serving as the statistician on the pediatric review committee (PeRC), managing a statistical review team and overseeing all rare disease and pediatric applications. She also made contributions in multiple guidance drafting and advisory committee meetings while at FDA. Her industry experience includes diabetes, oncology, hematology and dermatology products.

Dr. Freda Cooner has been an active member in ASA Biopharmaceutical Section (BIOP) and DIA.  She has been an executive committee and Regulatory-Industry Statistics Workshop (RISW) steering committee member since 2015. She has numerous presentations and session organization in professional meetings, including JSM, DIA and RISW. She is currently serving as an associate editor for Statistics in Biopharmaceutical Research (SBR) journal. Within DIA, she is the chair of DIA Bayesian Scientific Working Group (BSWG) and leading an oncology subteam under DIA Innovative Design Scientific Working Group (IDSWG). In addition, she is a key advisor on the executive committee of DIA Statistics and Data Science Community.