merck brochure 2010 - version 2 - harvard university · case study: development of a herpes zoster...

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HARVARD SCHOOL OF PUBLIC HEALTHD e p a r t m e n t o f B i o s t a t i s t i c s

K r e s g e B u i l d i n g - S n y d e r A u d i t o r i u m , G 1 - 6 7 7 H u n t i n g t o n A v e , B o s t o n , M A

HSPH-MERCK WORKSHOP

Vaccines and the Control of Disease

Harvard School of Public Health - Kresge Building - Snyder Auditorium, G1 - 677 Huntington Ave, Boston, MA

HSPH-MERCK WORKSHOPVaccines and the Control of Disease

http://www.hsph.harvard.edu/merck-workshop/

HSPH-MERCK WORKSHOP

This workshop will assess the current status of, and future directions for, vaccine research and development; consider alternative and combined approaches to the prevention and control of communicable diseases; and discuss related regulatory and public health issues.

Since their inception vaccines have been important tools for improving health and controlling both endemic and epidemic disease. The possibilities for their use continue to expand, leading the Gates Foundation to declare this the 'Decade of Vaccines'. At the same time, there is much public concern about the need for and safety of vaccines as reflected, for example, in the declining use of childhood vaccines in developed countries and the discussions surrounding their use in the recent swine flu pandemic. Furthermore, vaccines have proven to be difficult to develop or only partly effective for certain communicable diseases, leading to a need to assess factors that affect the public health impact of partially effective vaccines in different communities, whether used single or in combination with other prevention modalities.

This symposium is dedicated to the memory of Stephen Lagakos, Professor of Biotatistics at Harvard School of Public Health, who was instrumental in establishing and sustaining this workshop series.

Vaccines and the Control of Disease

HARVARD SCHOOL OF PUBLIC HEALTHD e p a r t m e n t o f B i o s t a t i s t i c s


8:00 a.m. - Registration & Continental Breakfast

SESSION I - OVERVIEW & KEYNOTE LECTURE

8:45 Welcome and Introduction Victor DeGruttola Raymond Bain

9:00 Combating Global AIDS: Preventing Cell Gary J. Nabel Death and Primary Infection

10:00 Break

SESSION II - CASE STUDIESSession Chair: James Ware

10:15: Case Study: Development of a Herpes Zoster Paula Annunziato (HZ) Vaccine

11:00: The Thai HIV Vaccine Efficacy Trial: A Review Merlin L. Robb

11:45: Principles for Allocation of Limited Vaccines Marc Lipsitch During a Pandemic

12:30: Lunch (Sebastian’s Cafe)

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1:30 In Memoriam: Stephen Lagakos Marvin Zelen

SESSION III - EFFICACY & SAFETY Session Chair: Scott Evans

1:45: Evaluation of Preventive Vaccines: Phase 3 A. Dale Horne Clinical Trials

2:30: New Methods for Vaccine Safety Surveillance Robert L. Davis

3:15: Statistical Challenges Evaluating the Safety of Ivan S.F. Chan & Jie X. Chen Vaccines: A Case Study of Rotavirus Vaccines

4:00: Break

SESSION IV - ANALYSIS OF VACCINE TRIALSSession Chair: Tianxi Cai

4:15: Chop-Lump Tests for Vaccine Trials Dean Follmann

5:00: Bayesian Analysis of Vaccine Trials James Berger

5:45: RECEPTION (Sebastian’s Cafe)


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8:00 a.m. - Continental Breakfast

SESSION V - MODELING & DESIGNSession Chair: Ivan Chan

8:30: Different Aspects of Vaccine Efficacy: Evaluation and M.Elizabeth Halloran Implications for Transmission Dynamics

9:15: The HIV Vaccine Step Trial: A Case Study for Devan V. Mehrotra Test-of-Concept Trial Design

10:00: Panel Discussion: Victor DeGruttola Design and Analysis of Vaccine Trials

10:30: Break

Directly following the workshop, participants are invited to attend the 2010 Marvin Zelen Leadership Award lecture.

MARVIN ZELEN LEADERSHIP AWARD LECTURE

11:00: Measures of Heterogeneity, Diversity and Inequality Ingram Olkin

12:00: LUNCHEON RECEPTION (Sebastian’s Cafe)


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INTRODUCTION Victor DeGruttola, PhD Chair, Department of Biostatistics, HSPH

Raymond Bain, PhD Vice President of Biostatistics and Research Decision Sciences Merck Research Laboratories

SESSION II James Ware, PhD Frederick Mosteller Professor of Biostatistics Department of Biostatistics, HSPH

IN MEMORIAM Marvin Zelen, PhD Lemuel Shattuck Research Professor of Statistical Science Department of Biostatistics, HSPH

SESSION III Scott Evans, PhD Senior Research Scientist Department of Biostatistics, HSPH

SESSION IV Tianxi Cai, PhD Associate Professor of Biostatistics Department of Biostatistics, HSPH

SESSION V Ivan Chan, PhD Senior Director, Clinical Biostatistics Merck Research Laboratories ZELEN AWARD Richard Gelber, PhD Professor of Biostatistics & Computational Biology Dana-Farber Cancer Institute & HSPH



Gary J. Nabel, MD, PhDDirector, Vaccine Research Center, National Institute of Allergy and Infectious Diseases

Combating Global AIDS: Preventing Cell Death and Primary Infection

Advances in our basic scientific understanding of the immune system and mechanisms of HIV pathogenesis have provided the tools to prevent HIV-1 infection. We have investigated basic mechanisms of pathogenesis of HIV and have recently made progress in defining the molecular basis for CD4 cell killing/depletion by HIV. We have also utilized knowledge of HIV-1 Envelope structure to rationally design candidate vaccines for AIDS. Cross-reactive neutralizing antibodies (NAb) are found in the sera of many HIV-1 infected subjects, but the virologic basis of their neutralization remains poorly understood. We have used knowledge of HIV-1 Envelope (Env) structure to develop antigenically resurfaced glycoproteins specific for the structurally conserved site of CD4 receptor binding. These probes identified sera with such NAbs from infected donors, and enabled the isolation of B cells that recognize the CD4-binding site (CD4bs). By expressing immunoglobulin genes from individual B cells, we identified three monoclonal antibodies, including a pair of somatic variants that neutralized over 90% of circulating HIV-1 isolates. Exceptionally broad HIV-1 neutralization can be achieved with individual antibodies targeted to the functionally conserved CD4bs of gp120, an insight critical to the development of an AIDS vaccine.

Gary Nabel serves as Director of the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. He graduated from Harvard College, Massachusetts, USA, before continuing at Harvard, completing his PhD, and his MD 2 years later. Before his appointment at the VRC, he served as Henry Sewall Professor of Internal Medicine, Professor of Biochemistry and Howard Hughes Medical Institute Investigator at the University of Michigan in Ann Arbor, USA, where he pioneered gene therapy studies for cancer, developed a genetic vaccine for HIV and initiated his research programme to develop Ebola vaccines. As director of the VRC, he provides overall direction and scientific leadership of the basic, clinical and translational research activities of the VRC, and guides VRC development of novel vaccine strategies against HIV and other emerging and re-emerging infectious diseases, including Ebola and Marburg viral haemorrhagic fevers, influenza and chikungunya. Under his leadership, the VRC was able to initiate its first clinical trial, a Phase I study of an HIV/AIDS vaccine, within a year after opening. His laboratory has also developed novel strategies for immunization against Ebola and Marburg, and vaccines against these viruses are currently being tested in Phase I safety trials. Additional vaccine studies will begin soon. In recognition of his expertise at the forefront of virology, immunology, gene therapy and molecular biology, he was elected a member of the Institute of Medicine of the National Academy of Sciences in 1998. He is also an active member in the American Society for Microbiology, as well as a fellow of the American Association for the Advancement of Science.

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Paula Annunziato, MDSenior Director, Vaccines Clinical Research, Merck Research Laboratories

Case Study: Development of A Herpes Zoster (HZ) Vaccine

ZOSTAVAX™ was approved in 2006 for use in adults ≥60 years old for the prevention of HZ (also known as shingles). Licensure was largely supported by the demonstration of clinical efficacy and a favorable safety profile in a single placebo-controlled pivotal trial, The Shingles Prevention Study (SPS), conducted in collaboration between Merck, the Veterans Affairs Cooperative Studies Program (VACSP) and NIH. In the SPS, >38,000 subjects ≥60 years old were randomized to receive ZOSTAVAX™ or placebo and followed for up to ~4 years in order to identify HZ cases. Two sub-studies were included in the SPS study design to assess safety and immunogenicity. Critical to the design and successful implementation of this trial were the choice of appropriate efficacy, safety, and immunogenicity endpoints, development of study procedures that would be operationally feasible and sustainable over time for such a large number of study subjects, and utilization of sensitive and reproducible assays and patient reported outcome tools. The design and results of this trial will be discussed in detail.

Paula Annunziato, MD joined Merck Research Laboratories in August 2002 as Director, Biologics Clinical Research and is currently Senior Director, Vaccines Clinical Research. Her responsibilities include leading the ZOSTAVAX™ clinical research team and the inactivated VZV Product Development Team. She was recently named the Section Head for Pediatric Vaccine Clinical Research.

Prior to joining Merck, Dr. Annunziato served as Associate Professor Clinical Pediatrics at Columbia University College of Physicians and Surgeons. She received her Medical Degree from the University of Texas Health Science Center in San Antonio, TX, and completed her Pediatric residency at the Schneider Children's Hospital/Long Island Jewish Medical Center in New Hyde Park, NY. Dr. Annunziato completed her fellowship in Pediatric Infectious Diseases at the University of Rochester. She is board certified in Pediatric Infectious Diseases.



James Berger, PhDProfessor of Statistics, Duke University, and Director, Statistical and Applied Mathematical Sciences Institute

Bayesian Analysis of Vaccine Trials

While Bayesian statistical analysis has been somewhat slow to become adopted by regulatory agencies (the device side of the FDA being an exception), it is increasingly being used as a key scientific tool for understanding the scientific message from data and for decision making. It is particularly illuminating to look at vaccine trials from a Bayesian perspective, because the approach can directly address such questions as “What is the probability that the vaccine has no effect?” and “What is the probability that the vaccine efficacy is between 40% and 60%?” The Bayesian approach is also useful for addressing issues involved in multiple testing arising from repeated vaccine trials and subgroup analysis. These ideas will be illustrated with Bayesian analyses of part of the data from the RV144 and “Step” HIV vaccine trials.

Jim Berger received a PhD in mathematics from Cornell University in 1974. He was a faculty member in the Department of Statistics at Purdue University until 1997, at which time he moved to the Institute of Statistics and Decision Sciences (now the Department of Statistical Science) at Duke University, where he is currently the Arts and Sciences Professor of Statistics. He has also been Director of the national Statistical and Applied Mathematical Sciences Institute since 2002. Among the awards and honors Berger has received are Guggenheim and Sloan Fellowships, the COPSS President's Award in 1985, the Sigma Xi Research Award at Purdue University for contribution of the year to science in 1993, the Fisher Lectureship in 2001, election as foreign member of the Spanish Real Academia de Ciencias in 2002, election to the USA National Academy of Sciences in 2003, award of an honorary Doctor of Science degree from Purdue University in 2004, and the Wald Lectureship in 2007. Berger's research has primarily been in Bayesian statistics, foundations of statistics, statistical decision theory, simulation, model selection, and various interdisciplinary areas of science and industry, especially astronomy and the interface between computer modeling and statistics. He has supervised 31 PhD dissertations, published over 160 articles and has written or edited 14 books or special volumes.

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Ivan S.F. Chan, PhDSenior Director of Late Development Statistics, Merck Research Laboratories

Statistical Challenges Evaluating the Safety of Vaccines: A Case Study of Rotavirus Vaccines

Rotavirus is the leading cause of hospitalization and death from acute gastroenteritis among infants worldwide. The association of intussusception with a rhesus-human reassortant rotavirus tetravalent vaccine (RRV-TV, Rotashield, Wyeth) has drawn much attention since studies were first published by the CDC in 2001 showing an increased risk proximal to administration of the vaccine. This case study will be presented in two parts. The first will overview the design considerations for the Rotavirus Efficacy and Safety Trial (REST), a blinded, placebo-controlled study of a live pentavalent human-bovine reassortant vaccine (PRV, RotaTeq, Merck & Co.). REST was noteworthy because its primary objective was to evaluate the safety of PRV with regard to intussusception. The study involved approximately 70,000 infants and utilized an exact form of a generalized likelihood ratio test for sequential monitoring. The second part of the case study provides additional analyses of the original CDC case-control study data of RRV-TV. At issue is a controversial question about the existence of an age dependence on the risk of intussusception following RRV-TV vaccination. The data were fitted to a quadratic smoothing spline model and as expected, different forms of the model lead to different conclusions. The talk will conclude with a few remarks on the statistical challenges with the important problem of the ongoing safety evaluation of vaccines.

Ivan Chan received an MS in Statistics from The Chinese University of Hong Kong in 1991 and PhD in Biostatistics from the University of Minnesota in 1995. He joined Merck Research Laboratories in 1995 as a statistician supporting vaccine research. Currently Dr. Chan is Senior Director of Late Development Statistics, and he heads the statistics group supporting all vaccine clinical research programs at Merck. Dr. Chan’s research interests include methodologies for clinical trials in vaccines, design and analysis of noninferiority and equivalence trials, statistical inference using exact methods, and analysis of multiple endpoints. Professionally, Dr. Chan is active in multitudes of activities. He serves as Associate Editor for Biometrics, Journal of Biopharmaceutical Statistics, and Statistics in Biosciences. He also serves as a core member on a Clinical Trial Review Committee of the National Institutes of Health (NIH), as the Executive Director for the International Society for Biopharmaceutical Statistics, and the industry co-chair for the 2010 FDA/Industry Workshop on Applied Statistics. Dr. Chan is also a past Executive and Board member of the International Chinese Statistical Association (ICSA), and a past Program Chair for the Society for Clinical Trials.

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Jie X. Chen, PhDDirector of Statistics in Global Medical Services, Abbott Laboratories

Statistical Challenges Evaluating the Safety of Vaccines: A Case Study of Rotavirus Vaccines

Rotavirus is the leading cause of hospitalization and death from acute gastroenteritis among infants worldwide. The association of intussusception with a rhesus-human reassortant rotavirus tetravalent vaccine (RRV-TV, Rotashield, Wyeth) has drawn much attention since studies were first published by the CDC in 2001 showing an increased risk proximal to administration of the vaccine. This case study will be presented in two parts. The first will overview the design considerations for the Rotavirus Efficacy and Safety Trial (REST), a blinded, placebo-controlled study of a live pentavalent human-bovine reassortant vaccine (PRV, RotaTeq, Merck & Co.). REST was noteworthy because its primary objective was to evaluate the safety of PRV with regard to intussusception. The study involved approximately 70,000 infants and utilized an exact form of a generalized likelihood ratio test for sequential monitoring. The second part of the case study provides additional analyses of the original CDC case-control study data of RRV-TV. At issue is a controversial question about the existence of an age dependence on the risk of intussusception following RRV-TV vaccination. The data were fitted to a quadratic smoothing spline model and as expected, different forms of the model lead to different conclusions. The talk will conclude with a few remarks on the statistical challenges with the important problem of the ongoing safety evaluation of vaccines.

Jie Chen is a Director of Statistics in Global Medical Services, Abbott Laboratories, Abbott Park, IL, specializing in statistical practice and research in medical product safety signal detection. Before joining Abbott, he was an Associate Director with the Investigational Research Department of Merck Research Laboratories, Upper Gwynedd, Pennsylvania, US. Jie received an MD in 1984 from Shanghai First College of Medicine, an MPH in 1994 in biostatistics & epidemiology from the University of Oklahoma Health Science Center, Oklahoma City, and a PhD in 2003 in statistics from Temple University, Philadelphia, Pennsylvania. Jie has been with the biopharmaceutical industry for more than 14 years. His experience includes statistical methodology research for non-clinical, pre-clinical and clinical development, as well as post-approval safety surveillance. He currently collaborates with others from industry and academia to develop innovative statistical methods for early detection of safety signals. Jie is a co-organizer of the 4th international conference on MCP, a co-guest editor of a 2007 special issue of the Biometrical Journal and a 2009 special issue of Statistics in Biopharmaceutical Research, a co-founder of the International Society for Biopharmaceutical Statistics and a co-chair of the Executive Committee for the First International Symposium on Biopharmaceutical Statistics held from June 30 – July 2, 2008, in Shanghai, China. He is a member of the Current Index to Statistics (CIS) Management Committee.

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Robert L. Davis, MD, MPHDirector of Research, Kaiser Permanente Center for Health Research - Southeast

New Methods for Vaccine Safety Surveillance

In the United States, surveillance for vaccine safety occurs passively (via the Vaccine Adverse Event Reporting System) and actively (via the Vaccine Safety Datalink Project (VSD)). The VSD is a collaborative network between 8 health maintenance organizations and the Centers for Disease Control, and has begun to employ near real-time prospective surveillance methodologies in order to minimize the lag time between the occurrence and identification of vaccine adverse events. These methodologies include the maximized sequential probability ratio tests (maxSPRT), self-controlled case series analyses (SCCS), and temporal scan statistics. Each of these approaches are somewhat unique: the maxSPRT is repeatedly carried out on large groups of weekly cohorts to identify both pre-specified and unexpected signals of vaccine adverse events; the SCCS studies only vaccinated persons; and the temporal scan statistic looks for unusual clusters of events after vaccination. These analyses take advantage of the unique informatics and data infrastructure within the participating health plans, and have important implications for national drug safety surveillance efforts. In this talk I will discuss some of the challenges faced during the development of these techniques. I will also present examples of their use during times of substantial uncertainty in the course of new vaccine campaigns.

Bob Davis, senior investigator and director of the Kaiser Permanente Georgia, Center for Health Research/Southeast (CHR/SE), currently leads a team of investigators and staff in a portfolio of funded studies involving health services research, clinical trials of vaccines and pharmaceuticals, and prevention and epidemiology of chronic diseases. He began his career in medicine by earning an MD at UC San Diego. After his pediatrics residency at OHSU, Bob did a 2-year stint with the Centers for Disease Control as an epidemiology intelligence officer. He earned an MPH at the University of Washington and later joined its faculties of both Epidemiology in the School of Public Health and Pediatrics. Next, Bob was recruited back to the CDC to direct the CDC’s Immunization Safety Office. In 2007 he became the director of CHR/SE where he currently focuses on genetics research in diagnosis and treatment. Bob has published more than 110 articles and 8 book chapters, and serves as a reviewer for 14 journals, including JAMA and NEJM. He is a recipient of the National Research Award (1991-1993) and the CDC’s James H. Nakano Citation for an outstanding scientific paper.

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Dean Follmann, PhDAssistant Director for Biostatistics, National Institute of Allergy and Infectious Diseases

Chop-Lump Tests for Vaccine Trials

This talk proposes new tests to compare the vaccine and placebo groups in randomized vaccine trials when a small fraction of volunteers become infected. A simple approach that is consistent with the intent-to-treat principal is to assign a score, say W, equal to 0 for the uninfecteds and some post-infection outcome X>0 for the infecteds. One can then test the equality of this skewed distribution of W between the two groups. This Burden of Illness (BOI) test was introduced by Chang, Guess, and Heyse (1994). If infections are rare, the massive number of 0s in each group tends to dilute the vaccine effect, and this test can have poor power, particularly if the Xs are not close to zero. Comparing X in just the infecteds is no longer a comparison of randomized groups and can produce misleading conclusions. Gilbert, Bosch, and Hudgens (2003) and Hudgens, Hoering, and Self (2003) introduced tests of the equality of X in a subgroup—the principal stratum of those ‘doomed’ to be infected under either randomization assignment. This can be more powerful than the BOI approach, but requires unexaminable assumptions. We suggest new ‘chop-lump’ Wilcoxon and t-tests that can be more powerful than the BOI tests in certain situations. When the number of volunteers in each group are equal, the chop-lump tests remove an equal number of zeros from both groups and then perform a test on the remaining Ws which are mostly larger than zero. A permutation approach provides a null distribution. We show that under local alternatives, the chop-lump Wilcoxon test is always more powerful than the usual Wilcoxon test, provided the true vaccine and placebo infection rates are the same. We also identify the crucial role of the ‘gap’ between 0 and the Xs on power for the t-tests. The chop-lump tests are compared to established tests via simulation for planned HIV and malaria vaccine trials. A re-analysis of the first phase III HIV vaccine trial is used to illustrate the method.

Dean Follmann graduated from Carnegie Mellon University in 1985 with a PhD in statistics. He spent 3 years at the Center for Naval Analyses. He joined NIH in 1988 and spent 14 years at the National Heart Lung and Blood Institute where he was involved in the design and analysis of multi-center clinical trials. In 2002 he joined the National Institute of Allergy and Infectious Diseases to head and expand the Biostatistics Research Branch. He currently supervises a group of 15 statisticians as the Assistant Director for Biostatistics, NIAID. Current interests include counterfactual models, HIV vaccine development, crossover trials for survival endpoints, missing data, and re-sampling based methods.

Dr. Follmann is an Associate Editor of Biometrics, the Journal of Biopharmaceutical Statistics, and Statistics in Biopharmaceutical Research. He is an elected Fellow of the American Statistical Association. He is an author on over 120 papers and has served on a variety of boards including FDA Advisory Boards, Data Safety and Monitoring Boards, and Scientific Advisory Boards.dissertations, published over 160 articles and has written or edited 14 books or special volumes.

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M. Elizabeth Halloran, MD, MPH, DScProfessor of Biostatistics, School of Public Health, University of Washington

Different Aspects of Vaccine Efficacy: Evaluation and Implications for Transmission Dynamics

Vaccination can affect the probability of becoming infected upon exposure and the probability of developing disease or the severity of disease if a person becomes infected. An infected vaccinated person could also have a reduced probability of transmitting to another person compared to an infected unvaccinated person. The different aspects of vaccine efficacy require different study designs for their evaluation. They also have different implications for the dynamics of infection and the indirect and overall effects of vaccination strategies in a population. Here we discuss these different aspects of vaccine efficacy using influenza vaccines as an example. We demonstrate the importance of evaluating the different aspects of efficacy to understand and to simulate the effectiveness of vaccination strategies at the population level.

M. Elizabeth Halloran, MD MPH DSc, is a Professor of Biostatistics at the University of Washington and the Fred Hutchinson Cancer Research Center, in Seattle, Washington, USA. She held the Dr. Ross Prentice Professor of Biostatistics Endowed Chair during 2006-2007. She has her medical degree from the Freie Universitaet, Berlin, Germany (1983). She earned an MPH in Tropical Public Health (1985) and a DSc in Population Sciences (1989) from the Harvard School of Public Health. Professor Halloran’s main research interests are in developing novel designs, methods of statistical analysis, and interpretation of vaccine field studies and other interventions, and in causal inference. Her novel study designs and statistical methods have been used in studies of pertussis, malaria, and influenza, among others. Dr. Halloran has contributed extensively to dynamic transmission models, including influenza, malaria, chickenpox and tuberculosis. She is author or coauthor of over 100 scientific papers. She is Associate Editor of Biometrics, and on the Editorial Boards of Statistical Communications in Infectious Diseases and Epidemics. Previously, she was on the Editorial Boards of the American Journal of Epidemiology, Epidemiology, and Statistics in Medicine, and an Associate Editor of the Journal of the American Statistical Association. She is first author of the book Design and Analysis of Vaccine Studies (Springer). She is Director of the Summer Institute of Statistics and Modeling in Infectious Diseases at the University of Washington. Elizabeth Halloran is a Fellow of the American Association for the Advancement of Science, the American Statistical Association, and the Royal Statistical Society. She was featured in Vogue magazine as a Power Woman in March 2006.

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Amelia Dale Horne, DrPHChief, Vaccine Evaluation Branch, Division of Biostatistics , CBER, Food and Drug Administration

Evaluation of Preventive Vaccines: Phase 3 Clinical Trials

Although efficacy and safety are evaluated throughout product testing, this presentation focuses on assessments in Phase 3. Efficacy is directly measured via cases of clinical disease, although often it can only be indirectly inferred through measures of immune response. Safety is inherently more challenging to evaluate than efficacy, because of the difficulty in demonstrating the absence of a safety concern. Nevertheless, due diligence must be exercised in assuring that vaccines licensed for use in healthy humans are safe as well as effective.

Dr. Horne received a doctorate in biostatistics from the University of North Carolina at Chapel Hill in 1985. After working abroad for several years, she joined the FDA in 1991 as a statistical reviewer. In 2000 she was appointed Chief of the Vaccine and Blood Product Evaluation Branch within the Division of Biostatistics, Center for Biologics Evaluation and Research. Since 2003 she has been Chief of the Vaccine Evaluation Branch within the same Division.

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Marc Lipsitch, DPhilProfessor of Epidemiology & Director, Center for Communicable Disease Dynamics, HSPH

Principles for Allocation of Limited Vaccines during a Pandemic

Vaccination during an influenza pandemic has two goals: directly to protect those vaccinated against infection or severe outcomes, and indirectly to reduce transmission, slow the epidemic, and protect those not vaccinated by reducing their risk of infection. I will present results of recent mathematical modeling work that shows that under reasonably broad assumptions, allocating vaccine to the population stratum with the highest force of infection will maximally reduce transmission, and that a heuristic for distributing vaccine to several strata by "importance levelling" performs near-optimally (joint work led by Jacco Wallinga, also with Michiel van Boven). I will then shift to consider the 2009 pandemic and argue that the timing and limited supply of vaccine was such that transmission-reduction was not possible to any significant extent, so protecting those at highest risk directly was a more important goal. I will describe the evidence available at the time for identifying these groups, argue that adults with high-risk conditions should have been in the top priority group, and describe the needs to improve our real time data availability and analytic capacity for future pandemics (joint work in progress with Ed Goldstein).

Marc Lipsitch is Professor of Epidemiology and Director of the Center for Communicable Disease Dynamics at the Harvard School of Public Health. He is author of more than 100 peer-reviewed publications on antimicrobial resistance, mathematical modeling of infectious disease transmission, bacterial and human population genetics, and immunity to Streptococcus pneumoniae. His group produced one of the earliest estimates of transmissibility of the SARS virus in real time in 2003 and provided a key estimate of the transmissibility of 1918 pandemic influenza, which helped to support the possibility of the use of pharmaceutical and nonpharmaceutical interventions to control the spread of future pandemics. More recently, he has published studies of the impact of nonpharmaceutical interventions on the spread of 1918 influenza and models of the impact of antiviral use and resistance in control of future pandemics. Current work is focused on optimizing interventions for emerging infections (such as influenza) using limited data available as they emerge, seasonality of influenza, innate and acquired immune responses to Streptococcus pneumoniae, and the biological factors maintaining long-term coexistence of strains in bacterial pathogens. Dr. Lipsitch has received several outstanding young investigator awards and is on the editorial advisory boards/associate editor of PLoS Medicine, the Journal of Infectious Diseases, American Journal of Epidemiology, Epidemiology and Epidemics. He is a member of the World Economic Forum's Global Agenda Council on Pandemics and served on the President's Council of Advisors on Science and Technology Working Group on H1N1 Influenza, as well as CDC’s Team B for the 2009 H1N1 pandemic. He has provided advice on antimicrobial resistance, SARS and influenza to the Food and Drug Administration, World Health Organization, Centers for Disease Control, Congressional Budget Office, Defense Science Board, and the governments of Canada and Mexico. Dr. Lipsitch received his BA in philosophy from Yale University, completed his doctoral work in zoology at Oxford University as a Rhodes Scholar and did postdoctoral work at Emory University and at the CDC from 1995-1999. He joined the faculty of Harvard School of Public Health in 1999.

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Devan V. Mehrotra, PhDSenior Director & Head of Early Clinical Development Statistics, Merck Research Laboratories

The HIV Vaccine Step Trial: A Case Study for Test-of-Concept Trial Design

Almost all vaccine efficacy trials have evaluated vaccines designed to protect against clinical infection through antibody-based immunity. A new class of vaccines designed to induce cell mediated immunity (CMI) are being developed, which may protect primarily by lowering pathogen load after infection, translating to reduced disease progression and secondary transmission. The large uncertainty about the efficacy of such vaccines motivates conduct of relatively small test-of-concept (TOC) trials before qualifying them for large-scale licensure trials. We developed a novel TOC trial design and implemented it for the world's first efficacy trial of a CMI-based HIV vaccine (Step trial). The number of study participants and time needed to assess biological efficacy were minimized in two ways. First, by employing infection and post-infection pathogen load as dual primary endpoints, as opposed to a "traditional" approach of using a single burden-of-illness endpoint that assigns zero pathogen load to all uninfected subjects. Second, by conducting an interim analysis when the accrued number of infections provided adequate statistical power for the pathogen load endpoint, to either stop for futility if the results were convincingly negative for both endpoints, or to accelerate GO for phase III if they were convincingly positive for at least one endpoint. The Step trial was stopped for futility; however, while the vaccine failed, the trial was heralded as a success for delivering a timely NO GO decision. The proposed TOC trial design will enable efficient screening of candidate CMI-based vaccines for biological efficacy in a variety of disease areas, and is an important new tool for their expedient development worldwide. (Joint work with members of the Step team who will be acknowledged in the presentation.)

Dr. Devan Mehrotra is Senior Director and Head of Early Clinical Development Statistics at Merck Research Laboratories where he is responsible for the integrated statistical oversight of modeling and simulation, clinical pharmacology, experimental medicine and pharmacogenomics/genetics. He also has an Adjunct Scholar appointment at the University of Pennsylvania. During the past two decades, Devan has published extensively on various statistical topics, and has presented seminars at conferences and leading academic institutions. His professional activities have included serving as Associate Editor for The American Statistician, as President of the Philadelphia Chapter of the American Statistical Association (ASA), and on the Executive Committee of the ASA-Biopharmaceutical Section and the ASA Committee for Career Development. Devan is an elected Fellow of the ASA.

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Merlin L. Robb, MDDeputy Director for Clinical Research, Military HIV Research Program

The Thai HIV Vaccine Efficacy Trial: A Review of Design, Current Results and Future Plans and Impact on the HIV Vaccine Development Field

The Thai HIV vaccine efficacy trial (RV 144) evaluated a canary pox prime (ALVAC-1521, sanofi-pasteur) and an envelope sub-unit boost (AIDSVAX, GSID) compared to placebo for the prevention of infection and control of early viremia among incident HIV cases. The prime was not considered an optimal immunogen for induction of T cell responses and the boost was shown to be non-efficacious when used alone. The modest protective efficacy observed in RV 144 has significantly altered the landscape for HIV vaccine development even though it does not represent a product suitable for licensure. The absence of any effect on early viral load, the low frequency and amplitude of CD8 T cell immune responses have provoked a reassessment of the appropriate benchmarks for HIV vaccine development. Co-variates of gender, baseline risk level, and time were not significantly associated with efficacy outcome. However, further examination of these co-variates raises questions for future trial design. The Thai trial design, results and future plans will be reviewed in the context of the history and future of HIV vaccine development.

Dr. Merlin Robb has served as the HJF HIV Program Director for the U.S. Military HIV Research Program since 2002. From 1990 to 2002 he served in the MHRP and occupied a leadership role in the Department of Vaccine Development, MHRP, Division of Retrovirology/WRAIR since 1994. Dr. Robb is a retired Lieutenant Colonel from the United States Army Medical Corps. He is a board certified pediatric infectious disease specialist with research experience in molecular biology, neutralizing antibody assay development, perinatal and pediatric HIV research, HIV correlates of protection research, HIV immuno-therapeutic trials, the design and conduct of Phase I, II and III clinical trials and the strategic planning and organization of full vaccine development programs for a globally effective HIV vaccine. Dr. Robb was instrumental in developing MHRP’s vaccine development efforts in East Africa and contributed to the recently completed phase III HIV vaccine trial in Thailand as a member of the steering committee and head of the pharmacovigilance activity.

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W o r k s h o p S e r i e s


Every year the Biostatistics Department at the Harvard School of Public Health organizes a workshop dedicated to important and timely topics in the application of statistics to clinical trials. The event is intended for researchers from industry, academia, and the regulatory agencies, and provides a neutral ground for discussing important and potentially controversial issues related to the clinical development of drugs and devices.

The first workshop took place in 1993. Until 2009 the workshops were sponsored by the Schering-Plough Corporation. In late 2009 Merck & Co, Inc. acquired Schering-Plough and is now sponsoring the event.

2010 Vaccines and the Control of Disease2009 Global Trials: Challenges and Opportunities 2008 Benefits and Risks: Optimizing Decisions by Information Synthesis2007 Individualization of Medical Treatments2006 Assuring the Integrity of Reporting and Patient Safety in Therapeutic Trials2005 Statistical Issues in Drug Safety Monitoring2004 Development and Approval of Preventive and Therapeutic Products for Infectious Diseases: Impact of Statistics2003 Development and Approval of Oncology Drug Products: Impact of Statistics2002 Emerging Strategies in Designing and Monitoring Clinical Trials2001 Datamining with Applications in Genomics, Clinical Trials and Post-Marketing Drug Risk2000 Measurement and Analysis of Quality-of-Life Outcomes for Drug Development1999 Bayesian Methods in Clinical Trials1998 Monitoring of Clinical Trials1997 Contemporary Issues in Clinical Trials1996 Flexible Strategies for Clinical Trials1995 Statistical Methods for Multiple Events Data in Clinical Trials1994 Handling Dropouts in Longitudinal Clinical Trials1993 Interim Analysis of Clinical Trials: Beyond Stopping Rules

1 9 9 3 - 2 0 1 0 T o p i c s

Programs and video recordings of recent workshops are available at: www.hsph.harvard.edu/merck-workshop/series/


http://www.hsph.harvard.edu/merck-workshop/series/

http://www.hsph.harvard.edu/merck-workshop/series/

C r e d i t s


C O N F E R E N C E P L A N N I N G C O M M I T T E E

CHAIR: Victor DeGruttola Biostatistics, HSPH

MEMBERS: Tianxi Cai Biostatistics, HSPH Ivan Chan Merck Research Laboratories Kenneth Koury Merck Research Laboratories Marcello Pagano Biostatistics, HSPH Mathis Thoma Biostatistics, HSPH

C O N F E R E N C E C O O R D I N A T O R S Shaina Andelman Biostatistics, HSPH Artemis Moore Biostatistics, HSPH

C O N F E R E N C E B R O C H U R E Shaina Andelman Biostatistics, HSPH

With grateful acknowledgement to Merck Research Laboratories, the Department of Biostatistics, HSPH and the Program on Quantitative Sciences in Medicine.


Information


C O N F E R E N C E L O C A T I O N

Harvard School of Public Health Kresge Building - Synder Auditorium - G1 677 Huntington Ave. Boston, MA 02115 Breakfast and coffee breaks are served in the lounge outside the lecture hall. Lunches and the reception will be held in Sebastian’s Cafe, which is located on the ground floor of Kresge Building (1 floor up from the lecture hall).

P U B L I C T R A N S P O R T A T I O N

Green Line ‘E’ Train to Brigham Circle Stop Bus: 39 Bus to School of Public Health - 677 Huntington Ave.

T A X I I N F O R M A T I O N

Boston Cab: (617) 536-3200 or (617) 536-5010 Cambridge Cab: (617) 252-3333 or (617) 259-6668

C O O R D I N A T O R C O N T A C T I N F O R M A T I O N

Shaina Andelman: [email protected] (339) 927-4132

Artemis Moore: [email protected] (508) 320-3211


mailto:[email protected]





http://www.hsph.harvard.edu/merck-workshop/


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