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Center of Excellence in Regulatory Science and Innovation

Substitutability of Generic Drugs: Perceptions and Reality

Bios and Abstracts


Renata Albrecht, MD, is the Director of the Division of Transplant and Ophthalmology Products in the Center for Drug Evaluation and Research at FDA. Her division regulates the immunosuppressants used for the prevention of rejection in solid organ transplantation.  


Dr. Alexander is an Associate Professor of Epidemiology and Medicine at the Johns Hopkins Bloomberg School of Public Health, where he serves as founding co-Director of the Center for Drug Safety and Effectiveness and Principal Investigator of the Johns Hopkins Center of Excellence in Regulatory Science and Innovation. He is a practicing primary care physician and pharmacoepidemiologist and the author of over 200 scientific articles examining prescription drug utilization, safety and effectiveness. Dr. Alexander received his B.A. cum laude from the University of Pennsylvania, an MD from Case Western Reserve University, and a Master of Science from the University of Chicago.


Rita R. Alloway, Pharm.D., FCCP is Research Professor in the College of Medicine at the University of Cincinnati and Director of Transplant Clinical Research.  She also serves as Director of the Transplant Pharmacy Residency and Fellowship where since 1994, she has trained over 30 pharmacy residents and fellows in solid organ transplantation with a focus on clinical research. Dr. Alloway’s practice areas include kidney, liver and pancreas solid organ transplantation.  Her work in transplantation pharmacotherapy has generated over 200 peer-reviewed publications and over 150 invited lectures to present specific research results and overviews of transplant immunosuppression.  Her individual research efforts focus on the goal of individualizing immunosuppressive regimens in the transplant patient. Dr. Alloway is an elected member of the American College of Clinical Pharmacy (ACCP) and American Society of Transplantation (AST).  As a member of the AST, she previously served as Councilor at Large on the AST Board, Chair of the Transplant Pharmacy Community of Practice, and member of the Public Policy and Governance Committees. Her long-standing mentoring and training efforts in transplantation were recognized by AST when she was awarded the 2013 AST Mentoring Award. In 2014, she was awarded the Russell R. Miller Award presented in recognition of substantial contributions to the literature of clinical pharmacy, thereby advancing both clinical pharmacy practice and rational pharmacotherapy.  In 2007 she was elected as a Fellow of the American College of Clinical Pharmacy and recognized locally as a “Leading Woman of Cincinnati in Research and Technology”.  


The Most Different Generic Products of the Narrow Therapeutic Index Immunosuppressant Tacrolimus are Bioequivalent to Each Other and the Brand Product in Kidney and Liver Transplant Patients:  A Randomized, Controlled Trial.
Rita R. Alloway, PharmD; Alexander A. Vinks, PharmD, PhD; Tsuyoshi Fukuda, PhD; Tomoyuki Mizuno, PhD; Eileen C. King, PhD; Yuanshu Zou, PhD; Wenlei Jiang, PhD; E. Steve Woodle, MD; Simon Tremblay, PharmD; Jelena Klawitter, PhD; Jost Klawitter, PhD; Uwe Christians, MD, PhD

Background: Although the United States Food and Drug Administration’s (FDA) generic drug approval process has a long-term successful track record, concerns remain for approval of narrow therapeutic index generic immunosuppressants, such as tacrolimus, in transplant recipients.  Several professional transplant societies and publications have generated skepticism of the generic approval process. Three areas of concern are that pharmacokinetic properties of generic and brand products in healthy volunteers may not reflect those in transplant recipients, bioequivalence between generic and brand may not ensure bioequivalence between generics, and high-risk patients may have specific bioequivalence concerns.  While this study tests tacrolimus, the novel trial design and results may globally impact regulatory considerations and strategies, not only for the approval of immunosuppressants but also for other narrow therapeutic index/ critical dose drugs. Methods:To address such concerns, an appropriately powered, prospective, fully replicated, partially blinded, randomized, 3-treatment, 6-period crossover bioequivalence study was conducted in kidney (n=35) and liver transplant (n=36) recipients comparing the most disparate tacrolimus generics on the United States market with 1) the innovator’s tacrolimus and 2) with each other. Patients were genotyped for CYP3A5, CYP3A4, POR, and ABCB1 polymorphisms. Bioequivalence of major tacrolimus metabolites was also assessed. Results: Average bioequivalence (ABE) and scaled average bioequivalence (SCABE) acceptance criteria were met for all product comparisons for AUC, Cmax, and Cmin in both kidney and liver transplant subjects. Intra-individual variability was similar for all products. SCABE was also observed for the major tacrolimus metabolite. In general, all subgroup analyses fell within ABE limits with most meeting SCABE criteria. Renal function or any other safety parameter were not affected by the 6 product switches over 42 days. Conclusions: Using an innovative bioequivalence study design, these results demonstrate equivalence between tacrolimus brand and generic and between generic products in kidney and liver transplant recipients.


Lucinda (Cindy) Buhse, Ph.D., Director, FDA Office of Testing and Research, joined DPA in 2001 as Deputy Director of the Division of Pharmaceutical Analysis for Center for Drug Evaluation and Research in the FDA. She was promoted to Division Director in June, 2004 and has been Director for Office of Testing and Research since June 2013. Dr. Buhse received a B.A. in Chemistry from Grinnell College and a Ph.D. in Physical Chemistry from the University of California, Berkeley under the direction of John H. Clark and George C. Pimentel. Before joining FDA, Dr. Buhse worked in management positions in Production, Validation and Analytical Services at Sigma Aldrich Corporation and as a Senior Research Scientist for Rohm and Haas Company. She leads a laboratory based office in the Center for Drug Evaluation and Research (CDER) responsible for supporting FDA review, investigation and enforcement actions and for conducting research programs to advance the science needed to regulate the quality of human drugs. 


Robert M. Califf, MD, MACC, is the Food and Drug Administration's commissioner of food and drugs. As the top official of the FDA, Dr. Califf is committed to strengthening programs and policies that enable the agency to carry out its mission to protect and promote the public health. Previously, Dr. Califf served as the FDA’s Deputy Commissioner for Medical Products and Tobacco from February 2015 until his appointment as commissioner in February 2016. In that capacity, he provided executive leadership to the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, the Center for Devices and Radiological Health, and the Center for Tobacco Products. He also oversaw the Office of Special Medical Programs and provided direction for cross-cutting clinical, scientific, and regulatory initiatives, including precision medicine, combination products, orphan drugs, pediatric therapeutics, and the advisory committee system.

Prior to joining the FDA, Dr. Califf was a professor of medicine and vice chancellor for clinical and translational research at Duke University. He also served as director of the Duke Translational Medicine Institute and founding director of the Duke Clinical Research Institute. A nationally and internationally recognized expert in cardiovascular medicine, health outcomes research, healthcare quality, and clinical research, Dr. Califf has led many landmark clinical trials and is one of the most frequently cited authors in biomedical science, with more than 1,200 publications in the peer-reviewed literature.

Dr. Califf has served on the Institute of Medicine (IOM) committees that recommended Medicare coverage of clinical trials and the removal of ephedra from the market, as well as on the IOM Committee on Identifying and Preventing Medication Errors and the IOM Health Sciences Policy Board. He has served as a member of the FDA Cardiorenal Advisory Panel and FDA Science Board’s Subcommittee on Science and Technology. Dr. Califf has also served on the Board of Scientific Counselors for the National Institutes of Health and the National Library of Medicine, as well as on advisory committees for the National Cancer Institute, the National Heart, Lung, and Blood Institute, the National Institute of Environmental Health Sciences and the Council of the National Institute on Aging. While at Duke, Dr. Califf led major initiatives aimed at improving methods and infrastructure for clinical research, including the Clinical Trials Transformation Initiative (CTTI), a public-private partnership co-founded by the FDA and Duke. He also served as the principal investigator for Duke’s Clinical and Translational Science Award and the NIH Health Care Systems Research Collaboratory coordinating center. Dr. Califf is a graduate of Duke University School of Medicine. He completed a residency in internal medicine at the University of California, San Francisco and a fellowship in cardiology at Duke.


Dr. D'Cunha is presently the Director, Global Medical Affairs at Apotex Inc.,responsible for Medical Affairs activities within the group. Prior responsibilities included Pharmacovigilance. Dr. D’Cunha has over 16 years experience in public health at both the local and provincial levels of government. He has held senior positions including Chief Medical Officer of Health, Commissioner of Public Health and Assistant Deputy Minister, Ontario, Chief Occupational Medical Officer, Manitoba and Medical Officer of Health, Scarborough. He has actively participated in national population health matters. Dr. D'Cunha graduated in medicine from the University of Bombay, and obtained his Masters of Health Science from the University of Toronto. He is also a fellow of the Royal College of Physicians and Surgeons of Canada in Community Medicine. His academic background includes an Adjunct Professor appointment at the University of Toronto, and is Past Chair of the Specialty Committee in Community Medicine at the Royal College of Physicians and Surgeons of Canada.


Rishi J Desai, MS, PhD, is an Instructor of Medicine at Harvard Medical School and an Associate Epidemiologist in the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital. His research focuses on generating high-quality evidence for comparative safety and effectiveness of drug treatments for chronic diseases, especially in patient populations typically underrepresented in clinical trials, including pregnant women, the elderly, and patients with multiple chronic conditions. His research projects have mainly concentrated on rheumatology and cardiology; where he has extensively used observational study designs as well as systematic reviews to answer clinically important research questions related to drug effects on a variety of health outcomes. He also has a special interest in applied methodological research aimed at improving confounding control in observational studies. Dr. Desai received his research doctorate in Pharmaceutical Sciences from the University of North Carolina at Chapel Hill and his Master’s in Pharmacy Administration from the University of Houston. He is clinically trained with a Bachelor’s degree in Pharmacy from the Sardar Patel University, Gujarat, India.


Assessing the Post-marketing Safety of Authorized Generic Drug Products

Importance: Authorized generics (AGs), which are brand-name products sold as generics, provide a unique opportunity to conduct comparative evaluations between generics and brand-name products unaffected by potential bias arising from negative perception of generics. Objective: To compare clinical outcomes between AGs, generics, and brand-name versions of 8 selected drug products- alendronate tablets, amlodipine tablets, amlodipine-benazepril capsules, calcitonin salmon nasal spray, escitalopram tablets, glipizide extended-release tablets, quinapril tablets, and sertraline tablets. Design: Observational cohort study. Setting and participants: Enrollees of private health insurance programs in the US (2004-2013). Exposure for observational studies: Prescription fills for AGs, generics, or brand-name products of interest with censoring on discontinuation, switching, or administrative endpoints. Main outcome measures: Among brand-name users who switch to either AG or a generic version upon generic market entry, we evaluated switchback to the brand-name version. Among AG or generic switchers and among AGs, generics, or brand-name initiators, we compared following clinical endpoints using Cox proportional hazards regression after 1:1 propensity-score matching: a composite cardiovascular endpoint (amlodipine, amlodipine-benazepril, quinapril), a composite non-vertebral fracture endpoint (alendronate and calcitonin), psychiatric hospitalization (sertraline and escitalopram), and insulin initiation (glipizide). Inverse variance meta-analytic methods were used to pool the adjusted hazard ratios (HR) across all drug products. Results: The rates of switchback to the brand-name version were consistently lower among AG users compared to generic users (pooled HR-0.72, 95% confidence interval (CI) 0.64-0.81). In the AGs versus generics initiator and switching analysis, none of the comparisons showed statistically significant differences in the risk of clinical outcomes (pooled HR, 95% CI 1.03, 0.98-1.09 and 1.07, 0.99-1.15, respectively). Results from the analyses comparing initiators of AGs or generics with brand-name versions were also consistently non-significant (pooled HR, 95% CI 0.99, 0.90-1.10 and 0.97, 0.89-1.05, respectively). Conclusion and relevance: AG use was associated with significantly lower brand-switchbacks compared with generics, which may be attributable to similar pill characteristics such as color, shape, and size between AGs and brands. No significant differences were noted in clinical outcomes across the three versions. This study adds to mounting evidence that generics are associated with clinical benefit comparable to brand-name products.


Ida-Lina Diak received a Doctor of Pharmacy degree in 2002 from the University of the Sciences- Philadelphia College of Pharmacy.  Following graduation, she joined the U.S. Public Health Service and worked as a clinical pharmacist and outpatient chief of pharmacy at Fort Defiance Indian Hospital before transferring to the FDA. Since joining FDA in 2007, Ida-Lina served as a Safety Evaluator and then a Safety Evaluator Team Leader in the Division of Pharmacovigilance I, where she currently leads a team in their mission of detecting and assessing postmarketing safety signals with the psychiatry and dermatology drug products.  In 2012, Ida-Lina received a Master’s of Science degree in Pharmaceutical Outcomes and Policy with a concentration on Patient Safety and Medication Risk Management from the University of Florida. 


Richard A. Hansen, RPh, PhD, FAPhA is the Sandra Kent Gilliland and David Louie Gilliland Endowed Professor and Head of the Department of Health Outcomes Research and Policy at Auburn University.  Dr. Hansen is a registered pharmacist with a bachelor’s degree in pharmacy from the University of Wisconsin, and a PhD in Social, Administrative, and Clinical Pharmacy from the University of Minnesota.  Prior to joining Auburn University he was Associate Professor of Pharmaceutical Outcomes and Policy in the Eshelman School of Pharmacy at the University of North Carolina, Chapel Hill.  Dr. Hansen’s research focuses on population-level assessment of the benefits and risks of drug treatments.  His work has been funded by numerous organizations, including the National Institutes of Health, the Agency for Healthcare Research and Quality, the Foundation for the National Institutes of Health, the National Pharmaceutical Council, and the U.S. Food and Drug Administration.  He has worked extensively in the area of comparative effectiveness research and drug safety, and since moving to Auburn University he has applied these areas of expertise to studying generic drugs.  Dr. Hansen is a Fellow of the American Pharmacists Association and the University of North Carolina Cecil G. Sheps Center for Health Services Research.  


Post-market Authorized Generic Evaluation

Background: Authorized generics are identical in formulation to brand drugs, manufactured by the brand company but marketed as a generic. Generics, marketed by generic manufacturers, are required to demonstrate pharmaceutical and bioequivalence to the brand drug, but repetition of clinical trials is not required. Objectives: This retrospective cohort study compared healthcare utilization and medication use patterns following a switch from a brand to a corresponding generic drug.  The primary comparison was between patients switching to a generic vs. an authorized generic, conceptualizing the authorized generic as a proxy for the brand in the sense that it is pharmaceutically identical to the brand but is subject to the same public perception biases as other generics. Methods: A retrospective cohort study was conducted using claims and electronic health records data from a regional U.S. healthcare system. Ten drugs with authorized generics and generics marketed between 1999 and 2014 were evaluated. Eligible adult patients received a brand drug during the 6 months preceding generic entry, and then switched to a generic or authorized generic.  Patients in this cohort were followed for up to 12 months from the index switch date to evaluate health services utilization and medication discontinuation, and followed up to 30 months from the index switch date to evaluate occurrence of generic-to-brand switchbacks. Multivariable models adjusted for age, sex, Charlson comorbidity score, pre-index drug use characteristics, and pre-index healthcare utilization. Results:  During the 12-months following the brand-to-generic switch, patients using authorized generics vs. generics had a similar likelihood of all-cause hospitalization (OR=1.14; 95% CI 0.91-1.43) and medication discontinuation (OR=0.95; 95% CI 0.80-1.12), but a slightly higher likelihood of emergency department visits (OR=1.33; 95% CI 1.11-1.61). Overall switchback rates were similar for authorized generics compared with generics (HR=0.86; 95% CI 0.65-1.15). Conclusions: Overall healthcare utilization and medication use patterns were similar between authorized generic and generic drug users, indirectly supporting similar efficacy and tolerability profiles for brand and generic drugs. These data suggest that generics were clinically no worse than their proxy brand comparator. 


Ilene Harris is Managing Director and Principal Research Scientist at IMPAQ International, a health and social science research firm. She served as Principal Investigator on the FDA-sponsored cooperative agreement, Post-marketing Surveillance of Generic Drug Usage and Substitution Patterns (U01FD004855) that funded the research being presented today. Her research interests and expertise in preventing adverse health outcomes in older adults by optimizing medication use and adherence stem from her training and experience in pharmacy, geriatrics, and epidemiology. She currently is co-Principal Investigator on two FDA-sponsored cooperative agreements:  Educating Groups Influencing Generic Drug Use (U01FD005486) and Generic Drug Substitution in Special Populations (U01FD005875); both of these are collaborations with Auburn University. Additionally, Ilene is Project Director on a CMS contract to provide technical implementation support for the Center for Medicare & Medicaid Innovation’s Part D Enhanced Medication Therapy Management Model. Prior to joining IMPAQ, Ilene was on the faculty at the University of Maryland School of Pharmacy, where she served as co-investigator on Decision Science, Outcomes Research, and Other Disciplines to Support Decision Making, as well as an investigator in the Center for Excellence in Regulatory Science and Innovation (CERSI), both funded by the FDA. Ilene received her PharmD and PhD in Epidemiology from the University of Maryland, Baltimore. 


Postmarketing Surveillance of Generic Drug Usage and Substitution Patterns
Ilene Harris, PharmD, PhD, IMPAQ International (Presenter); Christine Franey, MPH, IMPAQ International; Zippora Kiptanui, MPH, IMPAQ International; Wenlei Jiang, Ph.D., U.S. Food and Drug Administration; Sarah Dutcher, PhD, U.S. Food and Drug Administration; Françoise Pradel, PhD, University of Maryland School of Pharmacy; James Polli, PhD, University of Maryland School of Pharmacy

Generic drugs typically go through the Abbreviated New Drug Application (ANDA) process. This process determines whether the generic products are therapeutically equivalent to the brand name drugs. Bioequivalence studies of generic drugs, as well as branded drugs undergoing post-approval changes, are typically conducted in vivo. However, the standard bioequivalence procedures may not always be appropriate or preferred, for example due to site of drug action. For this reason, in vitro or alternative in vivo methods to establish bioequivalence are employed. This is the case for acarbose tablets, calcitonin salmon nasal spray, and others. The objectives of this study are to estimate brand and generic drug use and switchback rates, and investigate medical service use associated with generic switching. Medicare administrative data for years 2006 through 2011 were used as the data source for the patient-level information to determine utilization of brand and generic products, including time to switch to generics, time to switchback to brand and impact of switching on health outcomes. Users of brand products of interest were identified by linking the manufacturer’s Application Number to the National Drug Codes in Medicare Part D prescription drug event files. We evaluated time to switching to generic products and time to switching away from generic products and compared these to controls (i.e., drugs with or without known or suspected generic product issues). We found an increase in generic prescription fills with a corresponding decrease in the number of brand product prescription fills, once the generic drug was available, with a few exceptions. When examining the likelihood of switching to generic, the individual drugs were the factor that most strongly determined the likelihood. The likelihood of switching back to brand varied across the positive and negative controls. When examining the impact of time-varying switch and switchback on outcomes, the results varied by drug. In post-hoc analyses, the composite outcome of time to switching away from generic and back to brand, other dosage forms, other drugs in class, or generic discontinuation provided preliminary evidence to support this composite outcome as a possible claims-based measure to detect safety concerns with generic drugs. The findings from this analysis highlight the need for additional research to further validate claims-based metrics/indicators to identify potential safety concerns with generic drugs.


Dr. Wenlei Jiang is currently a Senior Science Advisor in the Office of Research and Standards (ORS)/Office of Generic Drugs (OGD)/Center for Drug Evaluation and Research (CDER). She is mainly responsible for coordinating post-market generic drug safety investigation and research, representing ORS on OGD’s new international harmonization activities, and developing opportunities for scientific outreach. Previously she served as Acting Deputy Director of ORS, where she provided oversight on Generic Drug User Fee Act (GDUFA) regulatory science research programs. Her regulatory research interest has been focused on bioequivalence standards development for generic complex drug products containing nanomaterials, solid oral modified release drug products, and narrow therapeutic index drugs, as well as post-market surveillance of generic drug. In the area of post-market surveillance, she initiated and managed research studies ranging from surveillance method development, brand-to-generic switching studies in patients, to physician and patient perceptions of generic drug products. She also worked as a chemistry reviewer in the Division of Chemistry, OGD to review chemistry, manufacturing, control (CMC) section of abbreviated new drug application (ANDA). Prior to joining FDA, she was at Novartis Pharmaceutical Corporation where her responsibilities included formulation development of conventional liquid and solid dosage forms, as well as advanced parenteral drug delivery systems. She received her PhD in Pharmaceutics and Pharmaceutical Chemistry from The Ohio State University in 2001.


Post-market Surveillance Lab Investigation

When the FDA approves generic drugs, we promise to the public that they will be of high quality and provide equivalent safety and efficacy to patients as the reference listed drug (RLD). In 2014, the market penetration of generic drugs reached 84% of prescriptions in the US. Given the high rate of generic utilization, it is important that the FDA has the process and up-to-date tools available to monitor marketed generic drugs to ensure they have the same safety and efficacy profile as their RLD. This presentation will provide an overview about the post-market research of generic drugs with a focus on FDA lab investigation. Case examples will be discussed to illustrate the investigation process and highlight the contribution of FDA lab investigation to the generic drug post-market surveillance. 


Gregory Krauss, MD focuses on the evaluation and treatment of seizures and epilepsy. He has a particular interest in treating medically-resistant epilepsy, evaluating unexplained seizure-like episodes, treating seizures associated with tumor and systemic illnesses and family planning counseling for patients with epilepsy. Dr. Krauss also evaluates patients who have failed standard medical therapies for possible treatment with epilepsy surgery, investigational medications or vagal nerve stimulation.  Dr. Gregory Krauss received his medical degree from Oregon Health Sciences University. He then completed an internship in medicine at Greenwich Hospital. He went on to complete both a residency in neurology and a fellowship in epilepsy and electrophysiology at The Johns Hopkins Hospital. 


Robert Lionberger, Ph.D. serves as Director of the Office of Research and Standards (ORS) in the Office of Generic Drugs (OGD).  Dr. Lionberger leads OGD’s implementation of the GDUFA science and research commitments including internal research activities and external research grants and collaborations to ensure the therapeutic equivalence of generic drug products. ORS provides pre-submission advice on complex generics through pre-ANDA meetings, product specific guidance and correspondence responses. He received his undergraduate degree from Stanford University in Chemical Engineering, and a PhD from Princeton University in Chemical Engineering. After his Ph.D., he conducted post-doctoral research in Australia in the Department of Mathematics and Statistics at the University of Melbourne. Prior to joining the FDA 13 years ago, he was an Assistant Professor of Chemical Engineering at the University of Michigan. 


Michael D. Nguyen, MD is the FDA Sentinel Program Lead in the Office of Surveillance and Epidemiology at the Center for Drug Evaluation and Research (CDER). He oversees the day to day management of the Sentinel Program for the Agency and coordinates scientific operations, routine safety analyses, and data infrastructure development. He previously served as the Deputy Director of the Division of Epidemiology in the Center for Biologics Evaluation and Research (CBER), where he led CBER’s Sentinel Program and was involved in postmarketing safety surveillance of vaccines, blood components, and blood-derived products.  Prior to working at the FDA, he completed his training in pediatrics at Washington University in St. Louis, and served as an officer in the Epidemic Intelligence Service at the Centers for Disease Control and Prevention.


James Osterhout, PhD has worked at the FDA as a pharmacologist since 2003. Dr. Osterhout’s 13 years of FDA experience have been with the Office of Generic Drugs, first in the Division of Bioequivalence, then the Division of Clinical Review and most recently in the Immediate Office’s Clinical Safety and Surveillance Staff as the Data Review Team Leader. Prior to joining the FDA, Dr. Osterhout completed a post-doctoral fellowship at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, in Bethesda, Maryland where he researched G-protein signaling in mast cells. Dr. Osterhout received his PhD in Pharmacology and Physiology at the University of Rochester School of Medicine and Dentistry in Rochester, New York. His industry experience includes positions in the fields of pharmacokinetics and drug metabolism at Proctor & Gamble, Astra Zeneca, and Fisons Pharmaceuticals.


Office of Generic Drug Surveillance Practice

Postmarketing surveillance of generic drugs in CDER’s Office of Generic Drugs (OGD) involves a multi-disciplinary effort that reviews potential inequivalence or safety issues identified during surveillance of spontaneous MedWatch reports submitted to the FDA, as well as from other external sources. The potential signal is confirmed or refuted after a thorough scientific investigation that can involve several Offices within the OGD along with CDER’s Office of Surveillance and Epidemiology. Disposition of the potential signal can result in removal of the product from the market, downgrade of the therapeutic equivalence rating for the product, or a manufacturing change to correct the defect. These surveillance efforts assure that only safe, effective, and equivalent generic drugs are available to the American public.


Angela Ostrom is the Vice President of Public Policy & Advocacy for the Epilepsy Foundation.  Ms. Ostrom has spent the last 15 years working in disability and health policy.  Prior to joining the Foundation, Ms. Ostrom was Assistant Director of Advocacy for the National Osteoporosis Society and worked for over five years at the National Multiple Sclerosis Society as Senior Director of Public Policy & Advocacy Research. At the Foundation Angela oversees advocacy efforts on federal and state public policy and heads the legal advocacy efforts of the Foundation’s Legal Defense Fund.  She serves as Co- Chair of the National Health Council FDA Issue Team and as a Steering Committee Member for the Partnership to Improve Patient Care. Angela earned her Bachelor of Arts degree from The Ohio State University in 1996 and her law degree from the University of Maryland School of Law in 1999.  Upon graduation, Ms. Ostrom was selected as a Presidential Management Fellow.  Through this federal program she worked for the Social Security Administration Office of Public Policy, Office of the General Counsel and Office of Disability Policy.   Angela completed her fellowship program in the office of United States Representative Stephanie Tubbs Jones (Ohio).   She is a member of the Maryland Bar.


John R. Peters, MD served as a Family and Emergency Physician in Minnetonka, MN following his Residency at University of MN. He later entered the US Army to teach in the residency program at DeWitt Army Hospital, Ft Belvoir and Uniformed Services University of Health Science. In the Army he served as Chief of Emergency Medicine and Chief of Primary until joining the residency program of Georgetown University School of Medicine at Providence Hospital in Washington, DC. He also served as Chief of Managed Care for the Virginia Medical Associates and Associate Director of Managed Care for a large health insurer until returning to practice as Chief of Primary Care and Director of Emergency Services at Kimbrough Army Medical Center. His practice experience spanned over 35 years. DR. Peters came to the FDA in 2006 as a medical reviewer in CDER’s Office of Antimicrobial Products, and he joined the OGD in 2009 where he served as a primary clinical reviewer, Director of the Division of Clinical Review, and Director of the Office of Bioequivalence. He is currently the Deputy Director of the Office of Generic Drugs. Dr. Peters received his BA degree, cum laude with honors in Biology from New York University and is a graduate of the George Washington University School of Medicine. He is a Family Physician and is also certified in Forensic Medicine with a Certification in Public Health from Georgetown University. He is trained in Utilization and Quality Review, Root Cause Analysis, Team Development, Psychology, and Psychoanalysis. All of my experience has been in the integrative, interdisciplinary and collaborative approach to medical care.


Dr. James E. Polli is Professor and Ralph F. Shangraw/Noxell Endowed Chair in Industrial Pharmacy and Pharmaceutics at the University of Maryland School of Pharmacy. His two main research interests are 1) maximizing oral bioavailability through formulation and chemical approaches and 2) developing public quality standards for oral dosage forms. He teaches pharmacy students and has served as advisor to 19 Ph.D. graduates. His is an Associate Editor of Pharmaceutical Research.


Bioequivalence in Epilepsy Patients and Assessment of Generic Brittleness
Jim Polli, Ph.D. and Tricia Ting, M.D.

This presentation will summarize BioEquivalence in Epilepsy Patients (BEEP) study findings and ongoing BEEP2 (Generic Brittle Epilepsy Patient Characterization) study results.  BEEP was a randomized, double-blind, fully replicated, multiple-dose BE study comparing generic lamotrigine to brand-name LAMICTAL in “generic-brittle” (GB) epilepsy patients (n=34). Generic demonstrated BE to brand. The WSV of generic and brand were also similar. Individual patient pharmacokinetic ratios for generic-vs-brand, were similar but not identical, just as for brand-vs-brand when subjects were re-challenged with same product. In BEEP2 study, designed to explore factors that may contribute to generic-brittleness in epilepsy patients, an objective was to determine the frequency of generic brittleness (GB) in epilepsy patients. A working definition of GB was determined by clinical history and patient opinion about generic medication. N=148 epilepsy patients completed.  N=60 subjects were GB (40.5%), and n=88 were not GB (59.5%).  The most common scenario to be GB was where subject had intractable seizures or an adverse event due to an AED, opined generics problematic, and on a current generic AED. Of the n=60 subjects who were GB, n=41 subjects had a prior switch problem; the problems collectively involved n=32 brand-generic switch problems and n=10 generic-generic switch problems.


Tonya Saffer, Senior Health Policy Director at the National Kidney Foundation (NKF) leads the organization’s efforts to identify, develop, and advance legislative and federal regulatory policies to improve health outcomes and opportunities for kidney patients and enhance health professionals' abilities to prevent, identify and treat chronic kidney disease. Tonya has a career history of leading health policy development for non-profits.  Her primary focus has been on healthcare payment, value based purchasing, and patient advocacy with a concentration on chronic kidney disease. Prior to joining NKF, Tonya also worked at Avalere Health in the company’s Reimbursement and Product Commercialization practice where she advised healthcare companies and non-profits on how to incorporate policy and market dynamics into their business planning.  In 2013, Tonya was appointed by the County Executive to serve her local community for a three-year term as an adviser on the Montgomery County, MD Commission on Health. She earned a M.P.H. in Health Policy from the George Washington University School of Public Health and Health Services and graduated from Arizona State University with honors and a B.A. in Political Science. 


Ameet Sarpatwari is an Instructor in Medicine at Harvard Medical School, an Associate Epidemiologist at Brigham and Women’s Hospital, and Assistant Director of the Program On Regulation, Therapeutics, And Law (PORTAL) within the Division of Pharmacoepidemiology and Pharmacoeconomics. His research draws upon his interdisciplinary training as an epidemiologist and lawyer and focuses on the effects of laws and regulations on therapeutic development, approval, use, and related public health outcomes. Among other projects, he is currently examining the public health impact of risk evaluation and mitigation strategies, the comparative safety and effectiveness of authorized and non-authorized generics, and the effect of variation in state drug product selection laws on generic drug prescribing. Dr. Sarpatwari completed his undergraduate studies at the University of Virginia, where he was a Jefferson Scholar. He studied epidemiology at the University of Cambridge, where his doctoral work centered on uncovering disease progression, treatment effectiveness, and co-morbid burden among adults patients with primary immune thrombocytopenia. He subsequently studied law at the University of Maryland as a John L. Thomas Leadership Scholar. Dr. Sarpatwari is currently the Principal Investigator on a Greenwall Foundation Making a Difference in Real-World Bioethics Dilemmas grant and a Faculty Affiliate with the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School and the Behavioral Insights Group at the Harvard Kennedy School. He teaches an annual course on Public Health Law at the Harvard T.H. Chan School of Public Health.  


Changing Physician and Patient Perceptions About Generic Drugs

Background: Over 85% of all prescriptions in the United States are dispensed with generic drugs. However, generic drug use remains controversial, with recent widely publicized concerns over the quality and substitutability of select generic products. Objectives: To survey physicians’ and patients’ perceptions and use of generic drugs and to evaluate possible predictors thereof. Methods: We randomly selected 300 clinically active internists and 900 specialists in endocrinology, hematology, and infectious diseases from a master list of American Board of Internal Medicine diplomates and invited them to participate in an online survey via email with the offer a $50 honorarium. We used the CVS Advisor Panel—a national database of 124,621 CVS customers—to randomly select 1,450 patients with self-reported chronic conditions who filled at least one prescription in the prior three months. For both surveys, we collected basic demographic information, used 5-point Likert scales to probe skepticism about generic drug safety and effectiveness, and queried physicians and patients about the frequency with which they prescribed and requested brand-name drugs, respectively. Chi-square tests and two-sample t-tests were used to assess associations. Results: Among 718 physician respondents (62% response rate), 35% reported brand-name-only prescribing more than 5% of the time, with higher rates among physicians who last learned about generic drugs from pharmaceutical representatives (51% vs. 30). Generic drugs were widely favored: 89% perceived them as effective and 91% perceived them to be as safe as their brand-name counterparts, while 73% agreed that they do not cause more adverse effects and 70% preferred prescribing generic over brand-name drugs. Generic skeptics—defined as answering neutral or negative to whether generic drugs were as safe and effective as brand-name drugs, or answering neutral or positive to whether generic drugs cause more adverse effects—showed no significant variation in demographic or practice characteristics. Of 933 patient respondents (65% response rate), a majority (54%) said they had not asked their physicians to prescribe a brand-name drug over a generic in the past year. Most respondents considered generic drugs to be as effective (87%) and safe (88%) as their brand-name counterparts, and to have the same side effects (80%) and active ingredients (84%). Non-Caucasians were more likely than Caucasians to request a brand-name drug over a generic (56% vs. 43%, p<0.01), and were also more skeptical of generic drugs’ clinical equivalence (43% vs. 29%, p<0.01). Conclusions: We found a substantial shift towards more physicians and patients having positive views of generic drugs, but lingering negative perceptions will have to be overcome to ensure continued cost-savings and improved patient outcomes from generic drugs. Targeted educational outreach to non-Caucasian patients and physicians receiving information from pharmaceutical representatives could in particular prove beneficial.


Does Variation in the Physical Characteristics of Generic Drugs Affect Patients’ Experiences?  Results from a National Survey of Pharmacists and Patients

Background: Medication non-adherence is estimated to add $12 billion annually in avoidable US health care costs. Changes in pill appearance (color, shape, size, and markings) between different manufacturers of the same drug may contribute to this problem. In prior studies, we found that changes in cardiovascular and antiepileptic pill appearance significantly increased the odds of non-persistence among a commercially-insured population. Objectives: To compare pharmacists’ and patients’ preferences for, perceptions of, and responses to changes in pill appearance. Methods: We randomly selected 2,161 licensed pharmacists practicing in independent, franchise, and chain settings from a master file maintained by the commercial marketer SK&A. Each pharmacist was given $5 and sent up to four postal mailings inviting them to complete our survey online or via paper. To identify patients, we randomly dialed 16,243 household phone numbers (mobile and landline) from a Survey Sampling International sample. Eligible callers had to be 50 years or older and take generic drugs for epilepsy, diabetes, hypertension, hyperlipidemia, depression, or HIV. Both surveys included demographic questions, used Likert scales to probe preferences and perceptions with regard to generic drugs and pill appearance changes, and queried respondents as to their actions in responses to pill appearance changes. Chi-square tests and two-sample t-tests were used to assess associations, and one-way ANOVAs were used to evaluate trends. Results: Of 719 pharmacist respondents (33% response rate), 52% worked in a chain setting. Over 95% perceived generic drugs as safe and effective as their brand-name counterparts, but only 35% preferred that both products have the same appearance. This preference was directly associated with years in practice (<10 years=24%, 10-19 years=24%, 20-29 years=39%, >30 years=44%; p<0.001). When pill changes occurred, 77% of pharmacists reported commonly or always informing patients verbally, in person or on the phone, and 88% reported doing so using a sticker on the prescription bottle. A total of 1006 patients (30% response rate) completed the survey. More than half (53%) reported usually or always relying on pill appearance to make sure they take the correct medication, and more than a third “definitely” preferred that their refill pills have the same color (41%), shape (40%), and size (43%), and markings (37%). Over 80% of patients expressed a desire to be notified about pill appearance changes by their pharmacy—most commonly verbally (44%). However, 62% and 50% report not being notified verbally or via a sticker, respectively, when their pills did change appearance.  In response to pill appearance changes, 29% of patients thought they received the wrong medication, 25% asked their pharmacist about the appearance changes, and 12% stopped using their pills or used them less frequently. Conclusions: We found discrepancies between pharmacists’ and patients’ preferences and recollection of notification practices with regard to pill appearance changes. Given the reliance of many patients on pill appearance and the public health consequences of non-adherence, standardized pharmacy notification practices and/or generic pill appearance requirements should be explored.  


 Alex Secora is an epidemiologist and drug safety analyst in the Office of Surveillance and Epidemiology at the U.S. Food and Drug Administration.  Alex is also a 2nd year doctoral student at Johns Hopkins University in Epidemiology, with a specific focus on Pharmacoepidemiology.  Prior to FDA and his doctoral work, Alex received his Masters degree from Hopkins in Epidemiology and Biostatistics, and spent over 6 years at Columbia University running pharmacotherapy trials for people with addiction.  His work at FDA has been primarily focused on products with the potential for abuse, and he has authored several methodological papers related to studying the abuse of prescription drugs using surveillance data.  His doctoral work is focused on the inappropriate use of renally-cleared drugs in patients with compromised kidney functioning. 


Jodi B. Segal, MD, MPH is a Professor of Medicine at the Johns Hopkins University School of Medicine, where she practices general internal medicine. She also has faculty appointments in the Bloomberg School of Public Health in the Departments of Health Policy and Management and in Epidemiology. She has been involved in the field of evidence generation and synthesis for the past 18 years. She was an associate director of the Johns Hopkins’ Evidence-based Practice Center funded by the Agency for Healthcare Quality and Research and has been involved in large scale systematic reviews since 1998. She has been a leader in comparative effectiveness research nationally and developed the first course offered in the U.S. in the field. She was awarded a PhRMA Foundation award to develop a Center of Excellence in Comparative Effectiveness Research at Johns Hopkins.  She is an associate director of the Center for Health Services and Outcomes Research, where she works closely with students and faculty doing outcomes research using large datasets including Medicare data and commercial claims data, and serves on the (Medicare Evidence Development and Coverage Advisory Committee (MEDCAC). As a pharmacoepidemiologist, she co-directs the Center for Drug Safety and Effectiveness at Johns Hopkins and has done numerous projects on behalf of the U.S. Food and Drug Administration (FDA) including developing methodologies to help the FDA in their comparative effectiveness and safety evaluations.  


Determinants of Generic Drug Use
Jodi B. Segal, MD, MPH, Oluwadamilola Onasanya, MD, MPH, Matthew Daubresse, MHS, Chia-Ying Lee, MHS, Mischka Moechtar, MHS , Xia Pu, PhD, Sarah K. Dutcher, PhD,  Robert J. Romanelli, PhD, MPH

We sought to identify the determinants of generic drug substitution for branded products among commercially-insured patients in the United States (US). We used MarketScan Commercial Claims data, which has pharmacy and medical claims from patients who are representative of commercially-insured patients in the US. The generic substitution rates (GSRs) for most classes exceeded 90%, but some were lower, including thyroid hormones (67%), androgens (31%), estrogens (34%), and topical/inhaled adrenal hormones (10%).  The determinants of generic substitution varied markedly across the therapeutic classes, both in bivariate and multivariate analyses. Patients using a mail order pharmacy had less generic substitution than patients filling at retail pharmacies for half of the studied classes. If the prescription fill was a refill, it was less likely to be filled with a generic than if it was a new prescription in three-quarters of the evaluated classes. Given the high cost of healthcare, it is increasingly important to encourage the use of safe, effective and typically lower cost generic drugs, when available, but this may need to be addressed on a class-by-class basis. 


Andrew Sperling is the Director of Federal Legislative Advocacy for NAMI, the National Alliance on Mental Illness.  In this position, he leads NAMI’s legislative advocacy initiatives in Congress and before federal agencies. Mr. Sperling works on issues affecting the mental health community with a focus on improving the lives of people with severe mental illnesses. Since 1994, Mr. Sperling has also served as Co-Chair of the Consortium for Citizens with Disabilities (CCD) Housing Task Force. Prior to joining NAMI, Mr. Sperling held the position of deputy director of government relations for the National Community Mental Healthcare Council and was a legislative assistant for U.S. Representative Dick Swett (D-NH). Mr. Sperling earned his BA from Tulane University.  After graduating from Tulane, Sperling attended George Washington University where he received a Masters of Arts, and in 1992, he earned a law degree from the Franklin Pierce Law Center.


Timothy E Welty MA PharmD FCCP BCPS is Professor and Chair of Clinical Science in the College of Pharmacy and Health Sciences at Drake University. Previously, he was Professor of Pharmacy Practice at the University of Kansas, School of Pharmacy and Adjunct Professor in the Department of Neurology at the University of Kansas Medical Center. Dr Welty obtained his BS in Pharmacy from Butler University, completed a PharmD and research fellowship in neuropharmacology and pharmacokinetics at the University of Minnesota, and holds a Master of Arts from Trinity International University. He has served on the faculties of Samford University, the University of Alabama Birmingham, the University of Cincinnati, North Dakota State University, and Purdue University. In addition to his academic experience, Dr Welty has extensive experience in hospital and ambulatory pharmacy practice. An active practitioner, educator, and researcher in neuropharmacotherapy, Dr Welty has focused his research and practice in epilepsy. He has published multiple research articles and book chapters on epilepsy, antiepileptic drugs, neurology, and pharmacy practice. Internationally, he has been a visiting lecturer in China, Thailand, Japan, and Korea. He served on the Continuing Pharmacy Education Commission for the Accreditation Council on Pharmacy Education and is active in the American Epilepsy Society, American College of Clinical Pharmacy, Christian Pharmacists Fellowship International, and American Association of Colleges of Pharmacy.


Pharmacokinetic Studies of Epileptic Drugs in Patients [EQUIGEN], Multiple-dose Studies and Single Dose Studies 

The Equigen study group designed 2 studies to address specific questions surrounding generic substitution. One study considered the appropriateness of FDA bioequivalence standards as they relate to switching between generic lamotrigine products taken chronically. In this study, patients with epilepsy taking lamotrigine with other antiepileptic drugs were randomized to switch between 2 disparate generic lamotrigine products. The second study was designed to use a single dose bioequivalence study design in patients with epilepsy, but not taking lamotrigine. The design was a replicate study using 2 disparate generic lamotrigine products and the branded product. Primary outcomes for both studies were peak concentration and area under the curve. These parameters were compared in accordance with FDA standards for bioequivalence. In both studies, lack of bioequivalence was not detected, and all comparisons fell well within FDA standards for bioequivalence. With replicate design, we detected inter- and intra-product variability. Details of the studies and implications for future studies will be presented.


John J. Whyte, MD, MPH is currently the Director of Professional Affairs and Stakeholder Engagement at the Center for Drugs Evaluation and Research at the U.S.  Food and Drug Administration.  In this role, Dr. Whyte works with health care professionals, patients, patient advocates, and others involved in the use of medicines. His office provides them with a focal point for advocacy, enhanced two-way communication, and collaboration, and assists them in navigating the FDA on issues concerning drug development, review, and drug safety. He also oversees the Safe Use program and supports the ongoing partnerships and activities under the Safe Use Initiative.

Previously, Dr. Whyte served as the Chief Medical Expert and Vice President, Health and Medical Education at Discovery Channel, the leading non-fiction television network. In this role, Dr. Whyte developed, designed and delivered educational programming that appeals to both a medical and lay audience.  This included television shows as well as online content. Prior to Discovery, Dr. Whyte was in the Immediate Office of the Director at the Agency for Healthcare Research Quality.  He served as Medical Advisor/Director of the Council on Private Sector Initiatives to Improve the Safety, Security, and Quality of Healthcare. Prior to this assignment, Dr. Whyte was the Acting Director, Division of Medical Items and Devices in the Coverage and Analysis Group in the Centers for Medicare & Medicaid Services (CMS). In his role at CMS, Dr.Whyte made recommendations as to whether or not the Medicare program should pay for certain procedures, equipment, or services

Dr. Whyte is a board-certified internist and continues to see patients.  He completed an internal medicine residency at Duke University Medical Center as well as earned a Masters of Public Health (MPH) in Health Policy and Management at Harvard University School of Public Health.  Prior to arriving in Washington, Dr. Whyte was a health services research fellow at Stanford and attending physician in the Department of Medicine.  He has written extensively in the medical and lay press on health policy issues. His book Is This Normal? The Essential Guide to Middle Age and Beyond  has won numerous awards. His most recent book, AARP New American Diet:  Lose Weight, Live Longer is a national best-seller.


Dr. Xinyuan (Susie) Zhang is currently a Scientific Lead in the Division of Quantitative Methods and Modeling (DQMM)/ Office of Research and Standards (ORS)/ Office of Generic Drugs (OGD)/ Center for Drug Evaluation and Research (CDER). Her main responsibility is implementing modeling and simulation in various generic drug review processes, such as Abbreviated New Drug Application (ANDA) review, response to consult request, response to controlled correspondences, and bioequivalence guidance development. She received her Ph.D. from the Department of Pharmaceutical Sciences, the University of Michigan, Ann Arbor.


Bioequivalence and Characterization of Generic Drugs

When not stored properly, some drug products may undergo physicochemical changes that may have impact on in vivo performance. Physicians and patients question whether brand and generic drug will be substitutable under such stressed conditions. Physiologically based pharmacokinetic (PBPK) and absorption modeling is a valuable tool to assess the in vivo pharmacokinetic risk associated with the in vitro performance change. In this study, warfarin, a narrow therapeutic index drug, lost isopropyl alcohol (IPA) and showed slow dissolution in acidic pH. We conducted PBPK absorption modeling and simulation to bridge the in vitro test results and in vivo PK performance of the drug product. Sensitivity analyses indicated that warfarin PK was not sensitive to solubility, particle size and density, or dissolution rate in pH 4.5, but affected by dissolution rate in pH 6.8, and potency. Virtual bioequivalence (BE) studies suggested that stressed warfarin sodium tablets (i.e.,  in an open bottle in 40°C/75% RH for 24 hours)  with slow dissolution rate in pH 4.5 but similar dissolution rate in pH 6.8 would be bioequivalent to the unstressed warfarin sodium tablets (i.e., in a tight closed container under  a controlled room temperature). A four-way crossover single-dose BE study in healthy subjects was conducted to test the same hypothesis and confirmed the simulation conclusion.