Speaker Abstracts
The success of the health care system depends on the accuracy, correctness and trustworthiness of the information, and the privacy rights of individuals to control the disclosure of personal information. All participants in health care system (consumers and patients, health plans, and health care providers) need access to high quality information for informed decision making. At the same time, everyone must have confidence that information of a private nature is adequately protected.
Western society places a high value on individual rights, autonomous decision making, and the protection of the private sphere from governmental or other intrusion. The public believes that privacy rights are not adequately protected in the health care setting. Public fear and distrust of both technology and bureaucracy is likely to increase as collection, storage, and dissemination of information becomes even more automated.
Professor Gostin will discuss the privacy implications of a health care information infrastructure. He will discuss: (i) the automation of health information; (ii) health security ("smart") cards; (iii) unique identifiers (particularly social security numbers); (iv) patient-based longitudinal health records which record in electronic form a pre-birth to post-death account of a person's intimate health status; and health databases including genetic databases and registries for specific purposes (e.g., immunization) and diseases (e.g., cancer and HIV/AIDS).
Professor Gostin will also discuss the ethical and legal principles undergirding health information privacy. He will examine the trade-offs between the aggregate good derived from health information and the invasion of individual privacy.
Finally, Professor Gostin will suggest proposals for law reform based on the views of the Task Force on Health Information Privacy, a project chaired by Professor Gostin and supported by the Centers for Disease Control and Prevention. For the Model Public Health Information Privacy Act drafted as part of this CDC project, see
Distributed collaboration is an emerging technology that will significantly change how modeling and simulation is employed in 21st century organizations. Modeling and simulation (M&S) is already an integral part of how many organizations conduct business and, in the future, will continue to spread throughout government and industry enterprises across many domains from research and development to manufacturing to training to medicine. For example, in the Department of Defense, M&S allows organizations to do things that would otherwise be unaffordable (i.e., thousands of parametric sensitivity tests on new systems) or physically difficult to accomplish (evaluations of proposed systems in unusual or austere circumstances).
Advances in software and computer technology are making distributed collaborative environments with integrated M&S possible and affordable for the scientific and engineering process in government and industry research. Collaborative simulation is becoming a crucial means of information and knowledge sharing and systems integration for research and development.
Clinical trials using gene therapy products seems, at first blush, similar to the conduct of clinical trials with any FDA regulated drug or biologic. Certainly these trials incorporate fundamental concepts such as adherence to the agreed upon clinical protocol, timely reporting of adverse events, independent monitor of the trial, appropriate informed consent process and documentation. But Benjamin Franklin might note from Poor Richard's Almanac: "... for want of a nail, a shoe was lost; for want of a shoe, a horse was lost...", while Shakespeare might comment from Richard III "A horse! A horse! My kingdom for a horse!"
Gene therapy is complicated. Not as complicated as launching a space shuttle, but coordination of efforts, and communications of problems in a timely fashion becomes directly of importance to human subjects who may consider participation in a gene therapy clinical trial. No gene therapy product has been approved; the knowledge base of real and potential adverse events related to gene therapy products is still rapidly evolving. As a biological product, the active product may have toxicities but the manufacturing process may also contribute to adverse events. The numbers of human subjects treated is still relatively small, so that trends are not easily seen at this time. How will a potential human subject be able to realistically evaluate the risks of gene therapy trials? How will the sponsor of such a trial be able to realistically provide to the potential human subject enough information to be considered? Given the still small numbers of treated human subjects, how can we communicate and discuss adverse events, while protecting individual patient identity?
With an ever-increasing store of health information being developed and collected, consumers need protection. The advancing science of gene therapy poses new challenges to protect the privacy of confidential health information. If gene therapy is to be beneficial in helping to treat and prevent a host of diseases and health conditions, consumers must be assured that their valuable information is protected so that it cannot be used against them in a discriminatory manner (i.e., denial of health insurance or termination from employment). Further, consumers should be fully informed as to how their confidential medical records are to be used-who will have access to them, how will they be distributed. And more importantly, consumers should knowingly consent (opt in) to allow their medical records, which include sensitive genetic information, to be used by outside entities and researchers.
As a clinical investigator directly involved in gene therapy clinical trials (thus far numbering 16, including the first trial in September 1990), the speaker will respond to the presentations of Dr. Noguchi of the FDA and Ms. Golodner of the National Consumers League by explaining how investigators deal with the multitude of issues raised by gene therapy trials.
Computer-Assisted Trial Design (CATD) can be used to test a variety of "what if" scenarios related to specific trial design issues and drug characteristics. By using CATD, the drug development team can determine the range of plausible results a trial would produce prior to actually conducting the trial. A model of drug action and disease response that integrates current knowledge and assumptions is required to explore the different "what if" scenarios. The incorporation of CATD in the development process can result in better decision making on drug dosing and trial design because of better use of available knowledge and ability to explore the importance of a large amount of drug and trial design variables. For example, CATD can be used in drug development:
Biomedical research over the past decade has taken two directions: traditional hypothesis-generated research and the systematic collection of large data sets to build an information infrastructure for the future. During this time, databases and software tools have largely focused on enabling deep but narrow query capabilities to connect traditional laboratory investigations with genome-scale data. The outputs of functional genomics and proteomics technologies have fundamentally changed the ways in which investigators must interact with information resources. Traditional informatics approaches are now a bottleneck in a new era of discovery-driven research. Enabling higher bandwidths through this bottleneck is a major challenge for transforming complex data and information into knowledge and insights about human health and disease.
Computational fluid dynamics (CFD) is beginning to significantly impact the development of biomedical devices, in particular, rotary cardiac assist devices. The University of Pittsburgh's McGowan Center for Artificial Organ Development has extensively used CFD as the primary tool to analyze and design a novel axial flow blood pump having a magnetically suspended rotor. The blood-contacting surfaces of the pump were developed using a CFD-based design strategy that involved closely coupling an incompressible Navier-Stokes solver to a parameterized geometry modeler and advanced mesh movement techniques. CFD-based blood damage models for shear-induced hemolysis as well as surrogate functions describing thrombosis potential were employed to help guide design improvements. This CFD-based design approach resulted in the timely development of a pump subjected to five impeller blade refinements, three magnetic gap flow path refinements, and six aft stator blade refinementsall without building expensive physical prototypes and the associated testing for each design iteration. A physical prototype of the final improved pump was fabricated and experimentally analyzed using particle imaging flow visualization. The CFD predicted results correlated well with the experimental data including: pressure-flow (H-Q) performance, detailed flow field features, and particle residence times in the magnetic gap flow path. It is estimated that the present CFD-based design approach shortened the overall design time frame from an order of years to months.
Immunization registries are confidential, computerized information systems that contain information about immunizations and children. Registries remind parents when their child is due or overdue for a vaccination, assist providers in identifying their patients who require an immunization, and forecasting which immunization(s) a child may require. Registries also help assess immunization coverage and identify pockets of need. One of the greatest challenges in developing an immunization registry is balancing the need to gather and share information to protect the health of the public and provide clinical benefit to children, with the necessity of protecting the privacy of patients, providers, and other system users. Registry participants must feel confident that their health care information is protected from unauthorized access and disclosure, and that information will be used for the purposes for which it was disclosed. Legislation and technical security measures are not sufficient for protecting privacy. Written confidentiality policies protect the privacy of registry participants and the confidentiality of information contained in the registry.
This presentation offers a case study of the effects of legislation to protect the privacy of patient medical records on the ability to conduct public health research in the area of pharmacoepidemiology. Given the current lack of consensus regarding data privacy legislation across different states as well as intense interest at the federal level, the empirical findings of this study are of great relevance. The effect of study-specific informed consent requirements, as interpreted by one State, was dramatic and has policy implications. A post-marketing drug safety study of the relationship between tramadol and seizures in affiliated health plans required medical records for verification of case status (both cases (N=45) and matched non-cases (N=95) based on claims data). After two mailings of the consent form, 40% of the 140 members responded, with less than half of the respondents (just 16% of the total study population) agreeing to participate. After non-respondents were contacted by phone by health plan personnel, only 3 additional members agreed to participate, with a final participation rate of 19%. Those who experienced a seizure were slightly more likely to participate than non-cases. This case study illustrates the effect of study-specific consent on the ability to conduct pharmacoepidemiology research in a health plan setting and raises the policy question of how does society weigh the risk to privacy against the benefit of health research.
The scientific basis of pharmacology is based on the relationship between drug concentration and effect1. Clinical trials typically take a more empirical approach and study the dose-effect relationship. Dose and concentration may both be described as measures of drug exposure. There is no clearly accepted definition of exposure but it commonly refers either to the average dose or to the area under the concentration time curve (AUC). Both these approaches lead to loss of information because the time course of concentration in relation to effect is removed. Many drugs display schedule dependence i.e. the effect depends on the time course of concentration. This has been commonly observed in trials of cancer chemotherapy yet many still advocate AUC for trying to understand the exposure response relationship for these drugs. Clinical trial simulation offers a mechanism for describing how scientific knowledge relates to clinical outcome and can be used as a tool to determine what can be learned from different design choices2.
The distribution and disposition of a drug in the body result from a complex set of physiological processes and biochemical interactions. In principle it is possible to describe these processes and interactions in mathematical terms and, if sufficient data are available, to predict the time course of the drug and metabolite(s) in specific anatomical sites in the body. Allometric considerations have been employed in the development and application of physiological pharmacokinetic models. In fact the remarkable similitude of mammalian species forms the basis of much research in physiology, pharmacology and toxicology. Similitude is not equivalent to sameness. In biology as in engineering, the model system is never identical to the prototype. But appropriate use of model systems can provide considerable insight into basic principles, and these principles can be used in conjunction with other knowledge for a variety of pharmacologic applications. Some of these ideas are illustrated by a discussion of allometry, physiological pharmacokinetics, and the use of in vitro systems to predict drug metabolism in experimental animals and human subjects.
Hereditary breast cancer accounts for less than 5-10% of breast cancers diagnosed each year in the United States. Despite the low prevalence, inheritance of a gene mutation is associated with a high risk of developing breast and other cancers. Research into alterations of BRCA1 and BRCA2 as well as other breast cancer genes remains a high priority for scientists and for men and women who are potential carriers of a mutation. This research is important to understand the pathogenesis of breast cancer in this select population, to determine whether these findings may be applicable to women with familial or sporadic breast cancer, and to develop specific biologic or drug therapies targeted at the underlying causative mechanism. Certain mutations are more common in selected ethnic groups, which may also be important in assessing risk or developing new treatments. This presentation will summarize the current state of knowledge of the molecular biology of BRCA1 and BRCA2, the prevalence and penetrance of mutations in these genes, the technical aspects of genetic testing, and the current state of knowledge of drug therapy for these lesions.
The prediction of future weather and climate events relies heavily upon the use of mathematical models in which the physical laws governing the atmosphere are projected forward to the desired time. This is made possible by a fortunate characteristic of the real world, decades of scientific work, and modern computing technology. Such predictions would not be possible were it not for the fact that many of the enormous complications of the real world can be ignored in the mathematical model we use to represent it. Were it necessary to fully initialize and predict every turbulent eddy and sound wave in order to make useful predictions, we probably couldn't make any at all. In fact, however, we are able to approximate all but the largest scale motions and the gross character of the ocean and land surfaces in modeling weather and climate. From the early part of the 20th Century, scientists have continued to improve the realism of the models used, and current versions can predict weather to 7-10 days, and some aspects of climate for a year. Future progress is critically dependent on both scientific advances in modeling some of the less well understood aspects of the system and on continued advances in computational capability.
Learning in Silico: 21st Century Product Development
Jonathan C. Peck, Institute for Alternative Futures, Alexandria, Virginia
In this presentation forecasts will describe how artificial intelligence, eHealth, virtual organs and in silico biology can affect development and regulation over the next two decades. The focus will be on anticipating impacts from new knowledge and technology on pre-clinical, clinical and post-market studies for pharmaceuticals, biologics and devices. The thesis is that progress in multiple fields will enrich models and simulations with knowledge that will predict safety and efficacy issues with growing accuracy. Forecasts will describe new capabilities - from high-throughput screens using "androids" to implanted "biomems" sensors - emerging along with computer simulations to offer new ways to know when products will be safe and effective.
Lecture will include an overview of the "new" Air Force Medical Service Readiness/Science and Technology charter. Lecture will include new readiness focus coupled insertion of new technologies. Special attention will be given to new areas of research showing potential for quantum leaps in computer/communications capability.
This training program was initiated by Dr. Henney to develop courses with the regulated industry on emerging technologies as part of the overall objective of increasing the science base in FDA. The specific objectives of this training program are to bring scientific information about new technologies to the FDA and provide a forum for FDA field investigators, FDA headquarter scientists, and industry to discuss new technologies in a more informal setting. The training includes a hands-on demonstration of the technology in the facility where the technology is being uses. Specific FDA-regulated products are not discussed. It is hoped that this training will lead to a greater efficiency in the review of applications and in inspections for products using this technology. In the last year, five courses have been given under this program. They include the following topics: (1) Barrier Isolator Mechanisms; (2) New ELISA Technologies in Food Inspections; (3) Microarray Technology; (4) Nucleic Acid Amplification Testing and; (5) New Trends in Sterilization. The response to this program has been overwhelmingly positive from the FDA participants. The benefits to our FDA scientists have been (1) first class training and actual involvement in many new technologies; and (2) the opportunity to discuss these new technologies with scientists from other FDA Centers and the field, and with industry scientists.
Following the encouragement of Commissioner Jane Henney to develop training courses with the Regulated Indorse on emerging technologies of relevance to FDA, a program was designed for "Applications of ELISA Rapid Methods to FDA Field Investigations". The focus was pesticides and microbiological hazards at manufacturing facilities and port-of-entry settings. The program was implemented at the General Mills, Inc. Technical Center in Minneapolis under the direction of a working group of FDA, and industry scientists. The course was designed to include classroom, hands-on laboratory and roundtable discussion settings for optimum learning and exchange of ideas.
Anticipating future regulatory interest in new gene-chip microarray technologies, the Bay Area Bioscience Center co-sponsored a two-day symposium for Food and Drug Administration and industry professionals in May 2000. Critical elements of this successful training program included (1) extensive planning with both FDA and company participants involved; (2) holding the presentations on neutral ground, i.e. Stanford University campus; (3) framing the sessions as technical/scientific, not regulatory; (4) involving a number of manufacturers and users; (5) scheduling enough time for questions; and (6) bringing the first day's facts and figures together as individuals toured representative manufacturing facilities on the second and third days.
The Joint Institute for Food Safety and Applied Nutrition (JIFSAN) is a cooperative effort of the FDA's Center for Food Safety and Applied Nutrition (CFSAN) and Center for Veterinary Medicine (CVM) and the University of Maryland, College Park. The creation of a jointly-administered multidisciplinary research unit within the University was designed to foster the missions of FDA and the University through the creation of an intellectual partnership to increase the quality of research and public policy studies and to produce more efficient use of research resources. JIFSAN provides opportunities for undergraduate and graduate education in the form of internships, cooperative education, research experiences, and public service. JIFSAN also provides opportunities for professional and technical development and its expanding outreach and educational programs for industry and the public through the use of innovative technology. JIFSAN's activities include the formation of strategic alliances and partnerships with private industry and commodity groups and professional organizations to support research and development; and educational outreach.
To understand the mechanism of action of cytokines on immune cells and cancer cells we have discovered that a variety of solid tumor cell lines express chemical docking ports (receptors) for immune regulatory cytokines that attach to these receptors. These receptors are over expressed on cancer cells compared to normal immune cells. Therefore, we have designed and produced novel cancer therapeutics in which a toxin derived from a bacterium is fused to cytokines such as interleukin-4 and interleukin-13. These recombinant proteins were produced in large quantities in E.coli. These proteins (termed IL-13-PE and IL-4-PE) will only attach to cancer cells through their receptors. Once bound, the whole complex is taken inside the cell and cell gets tricked into intoxication and dies. This targeted approach can be very useful for cancer therapy. These two targeted agents have been licensed to Biotechnology Companies, and CBER has established CRADAs with these Companies. Under these CRADA agreements, preclinical safety, efficacy and mechanism of action studies are being performed for further clinical development
The Office of Pharmaceutical Science, Center for Drug Evaluation and Research (CDER) is directed to identify the best practices for the manufacturing of high quality pharmaceutical products. Achieving this directive became increasingly difficult in era of doing more with less. The Office had to create a mechanism to utilize external resources - both funding and drug development expertise - to get the job done. The mechanism emerged as a Product Quality Research Institute (PQRI) which is a collaborative process involving CDER, Industry and Academia. The mission of PQRI is to conduct research to generate scientific information to support regulatory policy. This initiative helps identify the types of product quality information that should be submitted in a regulatory filing to CDER. The outcomes of PQRI are focused on research projects whose results provide a continuing scientific basis for regulatory policy. The research may support reduction in regulatory burden by decreasing the amount of information needed for a submission and/or regulatory filing.
The Center for Devices and Radiological Health (CDRH) has been concerned about electromagnetic interference (EMI) with wireless medical telemetry for several years. This concern was heightened in March of 1998 when the telemetry systems in two Dallas hospitals were disrupted by the test broadcast of a nearby digital TV (DTV) signal. CDRH responded by issuing a Safety Alert and joining with the Federal Communications Commissioner (FCC) to reach out to medical telemetry users, TV broadcasters, and device manufacturers in an effort to coordinate and avoid more such incidents. CDRH partnered with the American Hospital Association (AHA) Task Group on Medical Telemetry (clinical and manufacturer members) and the FCC, to develop solutions. This group formulated recommendations for a new Wireless Medical Telemetry Service (WMTS) and petitioned FCC. With FDA support, the FCC formally established the WMTS in June 2000 that for the first time provides medical telemetry with its own spectrum and use rules designed to reduce the potential for EMI to these vital signals. The WMTS represents an opportunity to drastically reduce the risk of patient consequences from EMI with wireless medical telemetry.
FDA has more than 50 agreements with counterparts in other countries. Some of these go back more than 50 years, while others are quite recent. All are founded on the notion of leveraging: parties to these international cooperative agreements can, through their separate and collective actions, protect consumers in one or both of the partner countries.
The session will focus particularly upon issues with food and drug equivalence agreements, including the recent United States-European Union MRA.
International scientific, technical, and economic agreements and conventions have been established and implemented throughout history. The U.S.-E.C. Pharmaceutical Good Manufacturing Practices (GMPs) Mutual Recognition Agreement (MRA) finds its roots in the economic free trade theories of the late 19th century and is associated with the current free trade agreements and other initiatives. Implementation and institutionalization of MRAs and equivalency agreements rest on the harmonization and/or acceptance of scientific and technical standards and procedures. When fully implemented, the Pharmaceutical MRA will cover, human drugs, animal drugs, vaccines, therapeutic biologics, active pharmaceutical ingredients and finished dosage forms. The MRA was signed in December 1998 with a three-year transition period. The transition will include training, evaluations, and equivalence assessments. This presentation will focus on accomplishments to date, current and future concerns and issues, and industry's activities and role.
Consumer groups around the world are increasingly alarmed at the World Trade Organization's incursion into domestic regulatory matters. While a growing number of people are becoming familiar with how the WTO's controversial dispute resolution system can directly impact domestic law and regulation, what is less understood is that the WTO-promoted mechanisms of harmonization, mutual recognition and equivalency can have an equally significant impact. This presentation will discuss FDA's experience with harmonization and mutual recognition and the implications of these activities for open, democratic and accountable governance.
The WTO SPS Agreement requires importing member nations to accept other nations' different sanitary measures if they achieve an equivalent level of sanitary protection. The food industry recognizes the challenge of demonstrating equivalency but believes that equivalence agreements will facilitate trade and will enhance food safety standards globally as trading partners strive to achieve the necessary level of protection to gain access to key markets. Equivalence agreements can enable better allocation of limited resources based on risk assessment and result in decreased costs to industry, regulators and consumers. However, this is not as easy to assess as one would think, since one nation's equivalent level of sanitary protection may not be "equivalent" to that of another nation. Consequently, the question which must be addressed is, What is the scientific basis for these decisions/positions/agreements?