The National Vaccine Advisory Committee (NVAC)

Transcript of the Proceedings of the April 11, 2008 Meeting of the Vaccine Safety Working Group of the National Vaccine Advisory Committee

Note: Intermittent technical difficulties with the recording equipment at this meeting resulted in the loss of brief portions of the audio, which are indicated in this transcript by "(Inaudible)" or by underscores.

DR. CORNELIA DEKKER: - professor of pediatrics and infectious diseases at Stanford. I'm a ____ member. I'm a PI for our ____ site at Stanford. My research in vaccine clinical trials is funded by NIH and through CDC I have to ___ funding for the vaccine safety - immunization safety assessment centers. Thank you.

DR. CARMEN COLLAZO-CUSTODIO: Good morning, my name is Carmen Collazo. I am at the Food and Drug Administration Office of Vaccine.

DR. FLORENCE HOUN: Florence Houn, Food and Drug Administration Office of Vaccine.

DR. ROBERT BALL: Food and Drug Administration Office of Biostatistics and Epidemiology.

DR. BENJAMIN SCHWARTZ: I'm Ben Schwartz. I'm in the National Vaccine Program Office as the Senior Science Advisor.

(INAUDIBLE)

MS. TAWNY BUCK: Good morning, I'm Tawny L. Buck and I am the one with the very short bio in the program. By profession, I'm a high schoolteacher, but I believe I'm here because I am the parent of a vaccine-injured child. I have three children and my oldest daughter was injured by Pertussis vaccine in 1995. I am also the Vice-Chair of the Advisory Commission on Childhood Vaccines.

DR. STEVEN GOODMAN: Hi, I'm Steven Goodman, I'm the acting director of the Division of Biostatics in the Johns Hopkins Oncology Center. I was trained as a pediatrician but then become an epidemiologist and biostatistician. I have joint appointments in the Department of Pediatrics, Epidemiology, and Biostatics and I was also a member of the IOM Immunization Safety Review Committee that Dr. McCormick so ably chaired.

DR. DANIEL SALMON: Good morning, I'm Dan Salmon, I'm a vaccine safety specialist with the National Vaccine Program Office.

DR. ANDREW PAVIA: And we have additional members who aren't able to join us in person who should be on the phone and if you are able to, I would like you to go ahead and introduce yourself; otherwise, I'll mention who is on the phone link.

DR. ELIZABETH MILLER: (INAUDIBLE)

DR. PAVIA: We can hear you very well, thanks.

DR. MILLER: Okay, I'm part of the Immunization Department of the Health Protection Agency in London. Our responsibility is monitoring the National Vaccination Program, looking at the efficacy of vaccine. ______ for monitoring safety, but my department does ____ where there is a problem identified ____ or other methods. And we are funded via the government and ___ sponsorship. And previously, I had been a member of the London ____ Advisory Committee on Vaccine Safety.

DR. PAVIA: Thanks.

MS. TRISH PARNELL: (INAUDIBLE) of infectious diseases and ____

DR. PAVIA: Thank you Trish.

UNKNOWN MALE VOICE: (INAUDIBLE) ____ I'm chairman of the _____ for Vaccine Safety.

DR. PAVIA: Thank you very much.

DR. RENATA ENGLER: (INAUDIBLE)

UNKNOWN MALE VOICE: Thanks. And you've got a lot of static on your line so if you could mute when you're not speaking, that would be helpful.

DR. ENGLER: Okay.

DR. PAVIA: Is there is anyone else who needs to introduce themselves who's on the phone bridge? Well good. Again, thank you very much everyone for participating, for your interest, and for the work you're going to do. I think as you can see, we're all getting to know each other. This is the beginning of a process. We are going to be working out exactly how we are going to proceed with writing our report after today's session. In today's session, we are going to hear from the CDC about their five year safety agenda from the Office of Immunization Safety and we are going to hear about more of that in detail. I think, ____, can people hear me? It's probably a good time to mention that this meeting is going to be transcribed so that it is available for everyone to review the records of what happened in the future. There are a number of other mechanisms for taking public input so if there are moments when the sound system fails us, you can go back and find out what was said, but hopefully we'll work smoothly from here. What I think you're seeing is that in putting together the working group so far, we have assembled members of ____ and by charter that includes representative - of industry representatives of the public and a variety of academic interest, but we've also brought in expertise in areas that are quite broad including but not limited to genetics, drug safety, immunology, statistics, ethics and law. Dr. Gosta is not on the phone with us and we've also included very purposely experts from systems outside of the U.S. so we can get an independent perspective on how to do things best and we're very grateful to Drs. Miller and Lambert for joining us in this effort. As I have said, the process today for this working group is predominantly to hear about the long term five year strategy that has been put together by CDC's Office of Immunization Safety. It will become very clear as we talk about things that that is one piece of the puzzle and the machinery that's involved in determining vaccine safety. And we're very cognizant about it, so we are charging this working group with two tasks.

The first, and there is - I'll read it just so that we're a little more clear cut. The first is to undertake and coordinate a scientific review of the ISO's five year agenda and there are specific questions that we are going to try and address and we will offer up additional questions as well. But these include, are the topics on the agenda appropriate, are there other topics that should be answered - that should be included, and we've been asked to try and come up with a sense of priority, that is which of these questions are most important and should be the ones that receive the greatest amount of resources. I think it's very incumbent on us to also think about where extra resources may be needed in the future. We're going to look at possible scientific barriers to ___ research agenda and to the degree that we can come up with suggestions to CDC for how to implement these. Karen is going to explain the process at CDC but they will take our advice as well as input from a broad range of public participants and use that to refine their scientific agenda as they go forward.

But what I wanted to mention briefly is the second task that we are asking the working group to undertake which I think is a larger one but perhaps even more important and that is to review the current status of the vaccine safety research efforts and to work on creating a what I've called the white paper for lack of a better term, but a report on the system and where it should be moving in the 21^st century to get the best possible science and that will be an effort to identify gaps and opportunities and the kinds of resources and the kinds of partners that need to be brought in going forward.

I want to talk a little bit about our expected outcomes. We are not going to leave here with a report on the safety agenda. We are really going to be here to hear about it and to listen to vast questions. The committee will then - the working group will then go forward and do its work and perhaps a report. Now, advice to the government has to come through the NVAC, so the working group's report will go back to the NVAC that will vote on it and then it gets presented to the government from there. But the second piece of what we're doing today is to try and begin what I hope is a long and much better process of improving transparency, improving communication, and public trust. There's been a lot of anger and a lot of distrust over issues of vaccine safety and what's needed in my opinion and I think we'll hear a great deal more is a very comprehensive and thoughtful way for different voices to be engaged and to do that we have asked a panel of people representing different voices and different expertise at 2 o' clock to speak to that specific issue. What are some of the mechanisms that can be used and that will work to make sure there is real public dialogue ___ engagement that people's voices are heard? We then have about an hour for public comments. That's quite limited, I know. We have asked people to register in advance and to limit the comments to five minutes but there are going to be many other opportunities for comment here. I want to make that clear from the front. One is since we are in the modern era, one is electronically. Written comments that come to NVPO working group will be posted on the NVPO website so that we will all have a chance to review them but they will be there for the public to see. So, if you have material to submit please be aware that it is going to be in the public domain but we would appreciate that. This meeting is being transcribed and I hope that what comes out of the session this afternoon are some novel ideas for how to move forward and from that a commitment I think for ways in which this working group can hear from the public, but probably much more importantly since we are independent outside people that the government scientist and physicians who are responsible for vaccines and vaccine safety, have much better ways to interact with the public and have meaningful dialogues.

I think with that, I am just going to ask members of the working group if they have questions or comments they want to make at this point - one thing that I do want to throw out to the working group for us to think about as we go forward is have we done an adequate job of constituting this working group? Do we have all the experts around the table? Do we have all the voices represented? Are we going to want to bring additional people into the working group? Are there questions or comments about the process or anything we have talked about so far?

DR. GUTHRIE BIRKHEAD: Could you just say a little bit about the anticipated timeframe of this process?

DR. PAVIA: Yeah. Thanks Gus. Clearly, we need time to put together a report that's going to take a series of conference calls and some drafting. We need time to digest and hear the public comments that are both made today and that are going to be posted and to put that together. I'm anticipating, based on past experience and Dr. McCormick has far more experience at this than I do, but we're looking at three to four months to draft a report and submit it to NVAC so it would probably - I think we might commit to having it ready for consideration at the fall meeting.

UNKNOWN FEMALE VOICE: Just one question. I was reading through this. There were two things that struck me in terms of variants where there are some important questions and I am not sure if we have the expertise on this subcommittee to just flag these. And one is the area of hereditary immunodeficiency syndromes and the other is the area of hereditary metabolic syndromes and ___ mitochondrial defects and I think that it might be good in the future. I know that today we're not even really poised to dig down that deeply but in the future it might be good to have one or two experts in this specific ___ areas as a member of this working group.

UNKNOWN MALE VOICE: Thanks.

DR. PAVIA: That reflects thought that I've had as well. Any comments along those lines? (INAUDIBLE)

UNKNOWN MALE VOICE: My suggestion - we've put (INAUDIBLE) who we'd have in the working group and we find to be fairly complete. My suggestion would be that we have some discussion among the working group regarding what additional areas might be useful. We give consideration to comments we have already received among - from the public and then as the ____ you know, we go from there.

MS. BUCK: I would like to just make a quick comment. I am basically the consumer voice on the panel and I would encourage perhaps additional consumer representation. I represent an injury from quite a time back and I believe that there is a lot of expertise out there for working on and identifying that public - improving public trust in this process is important. I believe one way to do that is to include more than one consumer voice on this. So I would like you to consider that.

DR. CHRISTOPHER CARLSON: Thanks and I think that's pretty much what we want to do in this discussion this afternoon - how to do that. I was going to ____ given that I don't think anybody here knew I had a child with Asperger's. I wasn't selected as to represent that community and given the current public - public debate/discussion, it would be helpful to have a _______.

DR. PAVIA: Part of what we wanted to do was to have the group itself refine its composition. We didn't know - I didn't quite how to lead consumer groups in a fair and balanced way and I felt we needed to work on that together and then as far as scientific expertise we though that would evolve as we spoke. You'll notice that we also put up ____. There are many ways we're sort of capturing the ideas here, but it would be helpful as key issues come up if we write them down and it's clear that - there will also be questions about - I anticipate that are not CDC ISO issues but that we want to keep very much in our mind for our later deliberations about the white paper and so that this may help us just take issues that we cannot really address today put in what facilitators like to call parking lot and then have them so we can come back to them. Are there comments from the ___ about composition or about the process? We're actually running just a little bit of ahead of time so _______ turn it over to you and your colleagues to introduce the main topic.

DR. JOHN ISKANDER: Thanks very much. The purpose of these introductory remarks is to provide a brief scientific and historical context to NVAC's review of the Immunization Safety Office or ISO scientific agenda.

UNKNOWN MALE VOICE: John, would you pull your microphone down just a bit, please?

DR. ISKANDER: First, I would like to thank the Deputy Secretary, Troy, for his attendance and support. I would like to express CDC's sincere appreciation to NVPO for organizing this meeting and thank the NVAC reviewers for agreeing to undertake this important review. I also want to thank the members of the public in attendance today for their interest and last but not least I want to acknowledge the contributions of the large number of scientists who have contributed to the development of the draft ISO agenda. The ISO mission is focused on assessing the risk of vaccines and we are strongly committed to fulfilling that mission. We recognize that no medical product is completely without risk but risks must ultimately be weighed against benefits and that vaccine safety research is a broad field that encompasses numerous areas other than risk assessment. Our office is engaged in broader science and policy initiatives related to vaccine safety, for example the revision of the national vaccine plan as well as activities at CDC and FDA around patient safety and medical product safety.

In 1986, Congress asked the Institute of Medicine to assess the causal relationship between vaccines and specific safety concerns referred to as adverse events. Either no or inadequate scientific evidence to accept a causal relationship was found for two-thirds of 76 adverse events reviewed by the committee. The Institute of Medicine attributed a poor understanding of adverse events to limitations in knowledge and research capacity. Deficiencies identified included insufficient or inconsistent information from case reports. In 1990, CDC and FDA created the Vaccine Adverse Event Reporting System or VAERS in response to the National Childhood Vaccine Injury Act. VAERS serves as a National Vaccine Safety Surveillance System and last year received more than 30,000 reports.

Another weakness cited was inadequate size and length of follow up of many population-based epidemiologic studies and limited ability to provide persuasive evidence for or against vaccine causation. The Vaccine Safety Datalink or VSD, a collaboration between CDC and eight managed care organizations, was established in 1990. VSD investigators have published more than 80 peer reviewed studies and have established themselves as leaders in both scientific methods and infrastructure development for medical product safety. The IOM also noted inadequate understanding of biologic mechanisms underlying adverse events. The Clinical Immunization Safety Assessment Network or CISA serves as ISO's clinical research platform for addressing such questions.

It is reasonable to ask why gaps still persist in vaccine safety knowledge. Reasons include the rarity of serious adverse events, the difficulty of high quality scientific study, the newness of vaccine safety science relative to the field of vaccinology, and the broad scope of the field which encompasses all licensed vaccines and numerous known or suspected adverse events. There is, therefore, a need to collect, organize, and prioritize vaccine safety studies using tools such as the development of this scientific agenda so that we can continue to address the most important safety issues of concern and the remaining gaps in our knowledge of vaccine safety. We are looking forward to working with NVAC and NVPO in this endeavor. This slide provides an overview of presentations you will hear from ISO this morning and this afternoon. Dr. Karen Broder will be our presenter for the background information and draft recommendation sections. Dr. Dixie Snider will present considerations for prioritization as part of this afternoon's session. I will turn it over to Dr. Karen Broder.

DR. KAREN BRODER: Thank you. Good morning and I appreciate the opportunity to present some background information about CDC's Immunization Safety Office Scientific Agenda Development for the NVAC Vaccine Safety Working Group on behalf of the Immunization Safety Office of CDC. More information is also provided in this first talk in a background document that the working group received in their passage. This document is also posted on the CDC website. Resources are provided at the end of this first talk.

As we heard earlier, Centers for Disease Control and Prevention is one of several programs and agencies involved in vaccine safety in the federal government. At CDC, the Immunization Safety Office or ISO leads most of the agency's vaccine safety research and surveillance activities for vaccines used in the civilian population. Since 2005, ISO has been a part of CDC's Office of the Chief Science Officer, Office of the Director, and its mission as well as its supervisory and funding chains are distinct from other immunization programs at CDC. As Dr. Iskander describes, the mission of the Immunization Safety Office is to assess the safety of vaccines administered to children, adolescents, and adults. And we seek to accomplish our mission by working closely with partners to support and develop high quality research and surveillance, to communicate this work in a clear and transparent manner, and to develop scientific methodology and standarized case definitions in the field of vaccine safety science.

Our office has four principal research and surveillance components that conduct vaccine safety activities. These are reviewed in detail in the materials that the working group received. Briefly, the Vaccine Adverse Event Reporting System or VAERS is a passive surveillance system that is jointly operated by CDC and the Food and Drug Administration. VAERS identifies vaccine safety areas of potential concern and generate hypotheses. The Vaccine Safety Datalink Project is a collaboration between CDC and eight managed care organizations. VSD provides comprehensive medical and immunization histories for more than 5.5 million people annually and VSD tests hypotheses suggested by signals from VAERS or other sources. In addition, VSD conducts vaccine safety surveillance in near realtime. The Clinical Immunization Safety Assessment Network or CISA is a collaboration between CDC and six epidemic centers with vaccine subject matter experts. CISA studies the pathophysiology and adverse events following immunization. In addition, CISA studies risk factors including genetic associations for the development of adverse events following immunization. Finally, the Brighton Collaboration is a global collaboration that develops standardized case definitions related to vaccine safety by improvising a common vocabulary for vaccine safety research and surveillance that is used throughout our office and in other venues as well. The fourth component is interrelated and the slide shows how we work very closely together in our office. In addition, the Immunization Safety Office collaborates with many immunization and other partners not shown here including other CDC programs and FDA on a daily basis.

In the rest of this presentation, we will focus on development of the first office ISO scientific agenda which is referred to throughout these talks as the agenda. As Dr. Gellin mentioned earlier, one of the driving forces behind this agenda was a recommendation out of the IOM report in 2005 titled Vaccine Safety Research Data Access and Public Trust. And I'll just note that this report was different from the reports that came out of the Immunization Safety Review Committee earlier. In this 2005 report, IOM recommend that a subcommittee of NVAC that includes representatives of a wide variety of stakeholders review and provide advice on the Vaccine Safety Datalink research plan. They went on to state that the group should meet publicly and allow interested persons to observe the process and provide input through established mechanisms. In addition to being responsive to this 2005 IOM recommendation we just discussed, carrying out effective vaccine safety science activities requires integration across the Immunization Safety Office research and surveillance activities. So focusing on the entire office agenda rather than just VSD makes sense. Also, an agenda will promote scientific excellence and public trust through transparency and it will contribute to vaccine safety science and other patient safety initiatives. The objective is to develop a comprehensive five year Immunization Safety Office scientific agenda with extensive expert input. The scope covers vaccine safety research, selective surveillance, and selective clinical guidance activities that are part of ISO's mission, are in ISO's realm to lead, and could be implemented during the next five years with infrastructure generally accessible to CDC. The ISO's scientific agenda focuses on scientific activities. It does not cover other very important activities of vaccine safety such as communication activities.

During 2006 through 2007, CDC, the National Vaccine Program Office or NVPO, and the NVAC Subcommittee on Vaccine Safety established and implemented a process for developing the scientific agenda. First, ISO and CDC developed a draft agenda which the working group has received and this is what we will discuss today. In developing this draft agenda, we solicited external and internal input from scientists with diverse expertise. ISO staff synthesized input to establish the draft recommendations which we will review this morning. Starting today, the NVAC through its working group will facilitate a scientific review of the draft ISO scientific agenda and after the NVAC scientific review is complete, ISO and CDC will respond to the feedback from the NVAC review process and finalize the scientific agenda. ISO and CDC will carefully consider the feedback from the NVAC review process, but it is important to notes that it is the responsibility of ISO and CDC to make final decisions about the content and priority on the ISO scientific agenda.

We recognize that obtaining external input before this and the scientific review would enhance the quality of the agenda and help inform the review which we are beginning today. During May 2007 through November 2007, CDC and NVPO convened three scientific meetings to obtain input on the agenda from the following groups and many of these people are represented in the room today. External expert scientists, vaccine safety representatives, federal government, HHF agencies in the Department of Defense, and U.S. vaccine manufacturer representatives. Reports from these meetings were included in the working group briefing package and these will be posted for everybody on the CDC website in the near future.

In addition to the planned meetings, ISO obtained input from its day to day partners including ISO Research and Surveillance Team and ISO Writing and Reviewing Group which was formed in January 2008 and CDC immunization experts and other stakeholders including persons involved with the advisory committee on immunization practices. We also obtained unsolicited input by reviewing selected ___ key statements, IOM reports, and the literature as well as other sources. Public input is important and approaches for obtaining public input for the scientific agenda as you heard earlier will be discussed during the meeting today.

This is just a reminder of the charge that Dr. Pavia discussed earlier. CDC has asked that the NVAC Vaccine Safety Working Group undertake and coordinate a scientific review of the draft agenda and specifically we are asking the working group to advise on the content of the agenda which we will review shortly, to help us learn about prioritization for the topics, and to identify and suggest ways to address possible scientific barriers for the agenda. Today, we will begin discussions about the agenda's content and priorities. We appreciate the working group's efforts and look forward to collaborating today and during the coming months. And the next recommendations could be about the draft recommendations.

In closing, on behalf of the office I would like to thank the more than a hundred people represented by the groups listed on this side who during the past year have contributed to the development of this draft agenda including Dr. Pavia, Dr. Gellin, and Dr. Salmon. And we also really want to thank Dr. Skillen from the Immunization Safety Office for her assistance in preparing the documents for this meeting. Resources are provided on this slide. Thank you.

DR. PAVIA: Thank you Dr. Broder. I think perhaps what would be most efficient is if we go on to the next section you talked - then we have some time to talk about the process that you want ___ develop these recommendations, as well as this first portion. Then I think rather than do the specific content areas in question and then break, we will take our break before that, have you present the content variants, then we can discuss those because that will, I think, take a good deal of our time.

DR. BRODER: Thank you. In this next very brief presentation, we'll provide an overview at the draft ISO scientific agenda recommendations. This is the document that we will be following. The working group should have this document titled Centers for Disease Control and Prevention Immunization Safety Office Scientific Agenda Draft Recommendations April 4. In addition, we provided one additional handout as a late breaker for this discussion. What we will be talking about now are the three recommendations which are sections one to three of the document.

The agenda makes three broad recommendations. The first is to respond to emerging issues and conduct core required scientific activities. These are all for the Immunization Safety Office at CDC. The second is to enhance vaccine safety, public health, and clinical guidance capacity in seven areas. And the third it to address five year research needs. To respond to emerging issues and conduct core required scientific activities, ISO ___ to do the following. We need to monitor the safety of all newly licensed and ___ recommended vaccines and previously licensed vaccines with new recommendations. The office needs to respond to new vaccine safety concerns and hypotheses which continuously emerge and are generally not predictable. We provide technical consultation to CDC, immunization experts, and multiple other stakeholders on a daily basis for collaborative and multidisciplinary scientific activities including activities that are not directly a part of our mission but involve subject matter expertise investing safety. And lastly, we need to be prepared to monitor vaccine safety in the event of a mass vaccination campaign or other vaccine safety emergency for example as part of pandemic influenza preparedness.

The second broad area of the recommendation section 2 is two enhance vaccine safety public health and clinical guidance capacity in seven areas - an infrastructure for vaccine safety surveillance in our Vaccine Adverse Event Reporting System which again is jointly operated with CDC and FDA, an infrastructure for Vaccine Safety Surveillance and Research using our Vaccine Safety Datalink Project. We need to enhance capacity in epidemiologic and statistical methods for vaccine safety science and laboratory methods for vaccine safety science in the newly emerging field of genomics and vaccine safety, for case definitions, data collection, and data presentation for adverse events following immunization. And in addition, we strive to enhance capacity in vaccine safety clinical practice guidance.

The third recommendation area is to address five year research needs. These needs are classified into specific vaccine safety questions and three scientific thematic areas. The thematic areas are vaccines and vaccination practices. We will discuss these more after the break. There are eight items. There were seven vaccine specific questions. In the thematic area of special population, there are seven items. And in the thematic area of clinical outcomes, there are eight items. This concludes the overview presentation and the last content presentation is a more detailed look at the five year research needs.

DR. PAVIA: Thanks. So Karen if you would not mind putting slide 22 back up. There is a lot of information on that slide and I think that was a very large portion of this first group of recommendations and what I would like to do now is to throw it open to questions and comments about the presentation so far and particularly about the areas that we have shown up here, the area of capacity improvement. I'm going to move over so that I'm in the front, not speaking from the side.

DR. GOODMAN: I just have a question. It was mentioned that the issues of communication are not part of the ring yet. Who handles that and how is that coordinated?

DR. ISKANDER: Vaccine safety communication which might include risk communication activities might include communication activities related to scientific publications. Our office does have a communication staff and we also would coordinate that with other relevant communication staff in relevant CDC centers including the National Center for Immunization and Respiratory Diseases, the Office of Director's Communication staff, as well as communication staff from other federal agencies. So communication is actually a very significant portion of the day to day work that we do and again we do have some staff dedicated to that, but there is also - one of the themes I think that is sort of emerging is there is a very heavy piece of ___ that is coordinating with partners with other parts of CDC and other federal agencies.

DR. GOODMAN: Is that an area that is thought to be an area where research can be done or is it just an issue of communicating conclusions?

DR. ISKANDER: To answer that question, let me provide a brief historical context to that. At one time, there was a group within our office that focused on vaccine risk communication research. Their expertise were in areas such as behavioral science and survey research. As part of a review of our office which was undertaken about four years ago, at that time it was determined that those activities while important were not consistent with a focus on risk assessment and so those activities were moved to another part of CDC. It is important to note that that group did produce I think some very important research and my understanding is there are now some sort of targeted communication materials that they helped develop that are being pilot tested. So while we recognize that as in fact a very important area of research, right now it is neither part of our office as a mission nor do we have the capacity in terms of specific subject matter expertise to be able to undertake or lead that type of research.

DR. PAVIA: ___ part of our second charge, if we find areas like this that don't fit into ISO that we think need to be addressed, that's for us to keep in mind and to work on.

DR. DIXIE SNIDER: This is Dixie Snider. I just wanted to elaborate a bit - reemphasize what John said that this is really a very important activity. One of the problems, and I'm speaking because as a science officer I was involved in making this decision, is that as people do work on communication, some aspect of that work is clearly or can be perceived as work to allay people's concerns or to help promote vaccines and one of the reasons that the Immunization Safety Office was moved out of the National Immunization Program and into what was my office at that time, now Dr. Boboik's office was to address issues that had come up that some of the people in the room are very familiar about the vaccine safety people being focused on vaccine safety and not being perceived as being part of a vaccine promotion enterprise.

DR. MARIE McCORMICK: In thinking about your office, who do you see as your primary audience? Who are you talking to and to whose concerns are you listening?

DR. BRODER: For the agenda recommendations?

DR. McCormick: Yes.

DR. BRODER: Our primary users of the agenda will actually be the scientists in the office that will be carrying out the agenda. The agenda also will help define scientific areas that will guide other vaccine initiatives, other patient safety initiative. We are writing our agenda to try to define the best science in a transparent manner and to try to involve and obtain input from a wide variety of stakeholders.

UNKNOWN MALE VOICE: Be specific Marie.

DR. McCORMICK: (Crosstalk) If you are designing the research, you better design the research for somebody and so my question is who are - and even if you're talking about the agenda, the agenda is to set a research priority for an office that is responding to someone and so my question is who do you see is your primary audience?

DR. SNIDER: John may have some additional comments, but I do want to point out that users of the information from the studies that have come out of the Immunization Safety Office include the Advisory Committee on immunization practices as they develop their recommendations, they include the Food and Drug Administration which uses this information to make regulatory decisions and obviously the public is of a particularly important target audience for the risk assessment information comes. There are others as well but I think those policy making groups are particularly important and on our minds as we complete these studies and communicate the findings. John?

DR. ISKANDER: Just to reinforce that, we do see an important part of our mission is to make sure that while we are not the policy making body for vaccines that we work very closely with the advisory committee and immunization practices and we want to make to sure that we have the very best vaccine safety data and information available, again recognizing - coming back to one of my initial points that ultimately while we do not- we have been separated from the policy making body, that those decisions of weighing known risks and known benefits must ultimately be made to have well informed vaccine decisions and we see are pieces of the puzzle as providing that best available safety data to inform those recommendations.

DR. LARRY PICKERING: Marie, one thing from - Larry Pickering, ACIP. At each ACIP meeting, there is a vaccine safety slot on the agenda during which safety issues for all new vaccines are discussed. So those discussions may resolve in changes, enhancements, alterations, or whatever to the recommendations of the ACIP has made and that is done at each meeting. In addition to that, the work groups, there are 14 ACIP workgroups and on each appropriate workgroup where immunizations recommendations may be considered, there is a member of the Immunization Safety Office and so vaccine safety issues are considered through the whole course of development of recommendations.

DR. PAVIA: I am going to try to keep track of the order in which people have their hands up and I think - Mark were you next? And then Dr. Goldman and then -

DR. MARK FEINBERG: These are not specifically scientific questions but I think they do relate to our ability to assess the agenda and the first one is - yeah with any activity it has to be right sized and funded appropriately and it's a little difficult to know how to define what the appropriate scope of the research agenda is for ISO without having a sense about what the funding available for that research is and how decisions are made of about funding. The second issue that I would like to raise for the chair or maybe Bruce's input is there is this associated process that this group will be responsible for working is looking at the federal government's response to the very important area of vaccine safety overall and I am wondering how assessment of the ISO as an appropriate piece of that pie as done in the context of what the broader federal response is and what is the appropriate part of federal government to address each specific vaccine safety component.

DR. PAVIA: Thanks. I think that's something that we ought to again keep on our board as something that's very much in our thought process.

DR. ISKANDER: And to provide just some at least minimal degree of specificity to answer Mark's question. You know, our office's budget is a matter of public record and so let me just give some broad outlines in that area. So our appropriation is approximately $21.6 million, approximately $12 million of that goes to the VSD, approximately $4.2 million of that goes to the CISA Network, approximately I believe $2.8 million goes to the VAERS system, and the rest is made up by the remaining activities. As far as the budget process, our appropriation goes to the same you know congressional appropriation process as all other federal appropriations. We have in the past year received some supplemental funding, approximately $1.85 million related to pandemic influenza preparedness. Karen gave some general outlines of the needs in the area, the need to be able to prepare for mass vaccination campaigns and monitoring their safety. So again, just so that in the interest of again full disclosure and so people know in a sense that if you will the general size of the pie that we're talking about you.

DR. LYNN GOLDMAN: ___ continuation of Mark's comments but it struck me when I heard the list of the people who are kind of on the receiving end of the office's work that I did not clearly hear NIH and whether there is any interest in an AID and of course NICHT and some of the areas that are identified by the office as being important in terms of research because some of that could be carried out in those contexts as well.

DR. PAVIA: Anyone - perhaps just leave that up on the board unless somebody wants to comment on that. I think that is a very important question.

DR. GOODMAN: Yeah, just briefly, and I may just be a little confused about all the boxes and circles and charts of the committee, but where - I understand better why issues of risk communication aren't specifically in the ISO Office, but do we - is it appropriate to have that expertise on this panel or is it already on the larger NVAC panel? Where is that input in this process?

DR. PAVIA: That's a very good question that I think I would dodge a little bit by saying we should chew that over as a group. I can see a couple of answers to that. One is we have some risk communication expertise on the NVAC itself. Trish Parnell who is a member of the public and on the phone with us and Sharon Humiston led a group for about two years that dealt with risk communication and public participation, but I think there's probably a lot more that could be done there. The other thing - I'm just - just to reflect back, I think I have heard a lot of times that risk communication is an area that has been separated out from the Immunization Safety Office but we are not sure where it resides and maybe that is something we want to explore in more detail, in particular research in terms of how people think about risk, but I turn that over to the group and their thoughts about it. Sharon, you -

DR. SHARON HUMISTON: I think that is an important point. I don't know that it fits in a logistic section, but I do think that it needs - the science behind risk communication around that seems - needs to be strengthened. We've seen that in the proposals we get for the NVPO grant raise.

DR. PAVIA: Just to reiterate. What we thought would happen is that as we have this discussion with ISO, that many things are going to come up that don't fall into their charge or ability and are going to loom very large and that is why we emphasize that we would be reminisce if we didn't have a second piece where we look for what else needed to be done and who else needed to be charged. And already risk communication has come up, development, and basic science has come up and I'm sure we're just beginning.

DR. CARLSON: So Karen - Dr. Broder had brought up unexpected avenues for research and a five year agenda versus unexpected avenues is always a little bit of a tension. And I am simply curious about within - this budget is going to be a little bit small if there is a lot of investigator initiated research coming from the outside of the office. Is there another avenue for investigator initiated research or is this the official avenue through which investigator initiated research would happen?

DR. ISKANDER: At this time, this is basically be the avenue within such research would happen. There is certainly great interest not only within our office, but I think broadly withIn CDC many of you may be aware of CDC's express desire to have more and broader opportunities for extramural research. There is a small extramural research activity which, although if you kind of trace the budget line item, it is linked to our office but we are actually not involved in the scientific conduct or oversight of that work but it is very small. So - Is that a sufficient answer?

DR. SNIDER: Yeah, if I could just elaborate John? I want to make it clear Julie Gerberding, the Director of CDC, and I have discussed this a number of times. We at CDC would very much be pleased if all those who are involved in the federal budgeting process were to see fit to make additional resources available and use not only to us but to NIH and other places, perhaps, you know, FDA to support the extramural research program would be very open to that.

DR. PAVIA: I ask the question myself because it follows on to the previous line of research. You identified one of capacity building areas as genomics in vaccine safety and I wonder if you could just give us a little bit of your thoughts about where that research might occur within ISO, what portion of it would go outside, what portion might be appropriate for investigator initiated research.

DR. ISKANDER: Okay, I may ask Karen or others to add some follow on thoughts. So NBPO did sponsor a workshop which our office led along with the CDC Office of Public Health Genomics. This occurred in late January of this past year and the objectives of that meeting were to, if you will, provide some introductions among the researchers with relevant expertise and to help set some reasonable research objectives. So to the extent that there is in fact some expertise within the CISA network in this area and in fact it is very congruent with CISA's mission of looking at individual level variation as a potential risk factor for adverse events. We see CISA as the primary platform, again using those criteria that can Karen outlined as sort of things reasonably accessible to us. We also understand that again one of the purposes of the meeting was to make introductions and create potential collaborations that these research platforms, you know, raise and other, you know, whole genome association studies and are more resource intensive and in fact some of the existing studies that are going on right now are collaborations with NIH or have been read by FDA and so we recognize that there is the need for collaboration in that area to undertake, you know, a research program.

DR. BRODER: If I could just add, there are - although it's a new area and certainly there is a need for collaboration and a need to almost define a subagenda in that area, in that session, we have described some activities that are going on in that area, for example a study evaluating genetic risk factors for Guillain-Barré syndrome after vaccination is going on. There is a study looking at development of rheumatoid arthritis in persons receiving hepatitis B vaccine, a study looking at wheezing, genetic influences on wheezing after live attenuated influenza vaccine, and in addition the CISA network has established a biological depository. So there are some beginnings of that platform in place and I certainly welcome Dr. Dekker or anybody else with more expertise in this area that could elaborate.

DR. SNIDER: So the bottom line is that we are doing what we have the capacity to do. I don't think that we want to present to you any notion that this is completely adequate response to the questions around genomics and vaccines and it's clearly an area where we would really appreciate recommendations not only for us but as you do a broader agenda how the nation especially - I hope Bruce it's not interrupting your authority, but how the whole department can move forward better in this whole area of genomics and vaccines.

DR. PAVIA: Thanks Dixie. I think if I'm, you know, just sort of putting words in your mouth you can stop me, but we have heard over the last couple of questions is a lot of interest in areas that in part CDC can work on through CISA projects but that also requires significant extramural funding programs which are not really in CDC's portfolio and work with a lot of other scientist both within government and outside. Is that fair to say?

DR. SNIDER: Correct.

UNKNOWN MALE VOICE: ___ In the past year, how much NIH funded vaccine safety research has there been? However you want to define that.

DR. PAVIA: Now, I am not sure we have anyone in the room who can answer that, but can - what I think I am going to suggest we do is that we - to some degree we are not an IOM Committee but we can act a little bit like the IOM and ask, if thinks come up like we can request from the department to get back to us and provide us these kinds of information for deliberation. So as we go forward maybe as a group, we out to think that way, the way we would if we were an IOM, when there are questions we want answered that are being asked if can get those through the staff. So one would I think ___ government portfolio on this.

UNKNOWN MALE VOICE: I mean, we have some parts, I mean how many institutes are there in NIH, 30, 23? So we have some representatives. I think part of the what the deputy secretary acknowledges is that there is a lot of this throughout the department and across NIH as well. So I can think that obviously you're welcome to speak here but I think your questions are important ones to see how this strand crosses the federal government particularly within the HHS family.

DR. MCCORMICK: Could you check - this is Marie McCormick. Could you tell me or describe a little bit more detail the organizational locus of the ISO and in particular, was I misunderstanding that this is part of a larger patient safety agenda or did mishear that completely?

DR. SNIDER: No, the Immunization Safety Office as John explained at one time was part of the National Immunization Program and with input from a panel which Dr. Lee Cooper who is here chaired and a large number of public comments subsequently the director, the executive leadership board of CDC decided to put it in the office of the Chief Science Officer. The Chief Science Officer reports directly to the Director of CDC. And so the number of options were laid out and it was decided to put it in the office of the Chief Science Officer at least for a while. And the point Karen sort of subtly made was that what we were responding to were perceptions of that vaccine safety group as being part of a larger immunization program whose interests are perceived as being promotion of vaccines would perhaps not have an unbiased approach to vaccine safety. And so they were moved to the office of the Chief Science Officer so that their supervisor would change and decisions about their funding and so forth would be made in a completely different part of CDC than decisions about immunization ____

UNKNOWN FEMALE VOICE: ____ now that you've had experience for a little while, is this optimal? Is your thinking about your pursuing scientific agenda would this be the place you'd like to stay or is there - are there other places or other organizational loci that might be useful?

DR. SNIDER: The Immunization Safety Office currently, being in the office of the Director, I think to be perfectly honest, I would have to say that anytime you put program activities in an office that deals lot with policy issues presents a challenge. I won't admit to doing a bad job of trying to separate the two and trying to support the ISO and I believe Dr. Popoik has done that. Our patient safety worker that I mentioned is a group that is recently formed while working on a number of things including working with Dr. Woodcock at FDA on the sentinel network which you may have heard about and so part of our charge is to look at where the various components of vaccine - of patient safety including medical product safety, how they might be best organized at CDC and we have not completed our work yet so I don't know the answer of what we think the optimal is.

DR. ISKANDER: Can I just make a brief follow on comment? I think that despite the separation if fact, our work, in my eight years of working with this office we have really never had a more - more collaborations with the immunization center and more issues that we have had to work very closely with ACIP on and you know that has continued and in many ways strengthened despite the organizational separation. The other observation I would make is that if you look at other models internationally. This sort of separation of risk assessment from risk management does really seem to be the model that is, you know, that does seem to be the way that things are going. And so it may suggest that there is for public policy and for transparency reasons that that may be an important consideration.

DR. PAVIA: I was reminded that we should all identify ourselves before we speak so the transcriptionist can recognize our voice and before Sean Hennessy speaks, I just wanted to remind the members on the phone that we are anxious to hear from them if they have questions.

DR. SEAN HENNESSY: Thank you, this is Sean Hennessy. When deciding on a research agenda, it may be helpful to know a little bit more about the infrastructure and the research trajectory that's going on so far and I do not know very much about the Vaccine Safety Data Link or the Clinical Immunization Safety Assessment at work. And I couldn't tell from today's agenda whether we are going to hear more about the details of that or not.

DR. BRODER: If I could just respond. In the - in the interest of time, we've kept goals, took the talk to a very brief overview. In the binder that you received, there is a section both for CISA and for VSDL as well as for VAERS and the Brighton Collaboration where we've describe some more background. We have included project lists and there is also some information about ____ and some web links and so we are certainly happy if - to address any specific questions later if there are specific questions that are not address. I just wanted to bring that to your attention.

UNKNOWN MALE VOICE: Excellent.

DR. GOLDMAN: I have a question, kind of a follow up question about the budget. And what I was curious about is how much do we have in the budget in terms of - I guess Congress has appropriated it, in terms of being able to shift resources between different activities or reserve a certain amount of lock-in in terms of the way you receive the money.

DR. ISKANDER: Well, I will give a, sort of a relatively high level answer, and Dixie we may wish to follow on. Because of congressional concerns dating back 15 years or perhaps even longer than that, there is - when Congress, you know, appropriates certain amounts of funds for certain activity, there is the expectation that those funds will be expended on those activities so not only just across CDC, you know, my understanding is that there is limited ability to undertake that.

DR. GOLDMAN: I guess I was specifically wondering in terms of the appropriation for the ISO. Within that, do you have flexibility or how much flexibility do you have within that?

DR. ISKANDER: My answer would really be the same.

DR. PAVIA: Any questions from members? Members on the phone? Ms. Parnell, Dr. Miller and Dr. Lambert, do you have questions on the first portion. Thank you. I have one last - one question ____. We started to talk about patient safety and we were specifically in constructing this panel wanted to get people involved in the drug safety side of things because the parallels are enormous and in the IOM review recently of the drug safety apparatus, a number of suggestions were made. To what degree are you looking for synergies in developing methods in developing capacities in using resources that can deal with patient safety issues in both drug and vaccine?

DR. ISKANDER: I'll respond briefly but I will ask Dixie also to respond. So many of the methods, you know, scientific methodologies as well as the kind of infrastructure establishment that the Vaccine Safety Data Link has led, you know, we had our annual VSD meeting last year and the constant theme I heard was “it's not just the data” meaning that what they have established is a network of expertise. They are constantly developing and refining new methods and so the extent that those methods may be applicable to broader fields, that is certainly one potential connection that, for example let me give you a specific example, the so called distributed data model - the idea that there is not a single VSD database but rather there are eight sites that maintain strict confidentiality and privacy of their data but that allow again through a distributed network allow studies to be conducted with pre-specified IRB approved protocols. That is a model that is really being look to in many not only FDA read but other product safety read initiatives. So that is my answer kind of from my prospective, but again Dixie may have more policy level issues to add.

UNKNOWN MALE VOICE: Well, let me first go back to Lynn's question because I don't think Lynn - I think there's miscommunication across the table. So let me try to back up. The Immunization Safety Office receives $22 million or $21.6. The way this system works, I think you know this from your prior experience, is that, as John said, you know, Congress has certain expectations that if the appropriate money for X they expect it to be worked - that work is done on X. Agency directors can ask to reprogram money. I was the recipient of that I was Director of the TB Division when we had the problems with multidrug resistant tuberculosis and we reprograms from HIV money to support TB efforts until Congress could convene and provide us more resources. So in terms of possibilities, the CDC Director could request through the department that additional resources be put in vaccine safety through those channels and you know, either Congress would approve or not disapprove and that could be done. So that's - all I can do at this point is just speak for complete openness that that could be done.

With regard to the $21.6 million, it is a determination then of the supervisory team at CDC how to allocate the $21.6 million to VSD versus CISA, versus VAERS, etc. At the same time, I am sure you can appreciate with 30,000 various reports coming in and being joint venture with FDA, that flexibility is sometimes more theoretical than it is realistic and that our contractor is under tremendous pressure already with reports - processing the reports they are trying to get right now. So try to take money out of there right now would have severe implications.

So I hope that that gives you a better kind of idea and then you know with regard to the VSD and CISA, money could be transferred at the same time ____ have been made to certain institutions and individuals and at least for a certain period of time. I'm not saying CDC could make a decision to allocate funds differently and would be interested in your, you know, advice and counsel about, again not specific funding, but where we should put focus on along some of these activities. That's one of the things I am going to ask at the end of the day about some of the relative priorities and how you would allocate resources across some of these activities. But adjustment could theoretically be made but putting them in to the practice on the other hand, you know, presents its challenges.

DR. ISKANDER: Just another brief - I alluded earlier to a small amount of supplemental funding we have received for pandemic influenza activities and undergo circumstances. We do have some ability to develop a “spend plan” for that money as long as it again meets the objectives of pandemic influenza preparedness.

DR. PAVIA: Thanks John. I think what we are going to do now unless there are any questions on this specific section that people would like ask is going ahead and take our break and when come back, we are going to hear about the specific topic areas that have been developed as part of the agenda and have a chance to take down our notes and then we'll again have a chance to come back after lunch and talk about those in addition. I have 10:15, we're going to start again promptly at 10:30.

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UNKNOWN FEMALE VOICE: _______ an MRB human papilloma virus vaccine ____ the licensed product. Two products for tetanus ___ pertussis vaccine for adolescents and adults as well as influenza vaccine. I just wanted to bring that to your attention.

UNKNOWN MALE VOICE: So my sense is that a large percentage of the VSD, particularly rapid cycle analysis studies are done without the need for additional funding, is that right?

UNKNOWN MALE VOICE: Yes, that's correct.

UNKNOWN MALE VOICE: Thank you.

MS. BUCK: This is Tawny Buck and I have a question, forgive me if it's not a real educated one, but I'm every interested in knowing about prevention of adverse events to begin with. Can you tell me how that's being addressed?

DR. ISKANDER: Yes, I can. Thank you for that question Tawny. In fact, this is an emerging area of vaccine safety science. It's actually - one of the categories on this slid, post-vaccination syncope or fainting. We think it may be preventable. There are existing recommendations for a post-vaccine waiting and so we are interested in pursuing and collaborating with studies to answer question like is the waiting period followed? Is the waiting period effective when it is followed? This is where - in fact, we have to recognize that this is now - we're talking about now patient safety issues that have a different scientific focus. We are very interested in this because, as you say, we want to be able to prevent things we can prevent. Another category is that vaccine administration errors which the reporting of those appears to have increased over the last several years, not surprisingly with many new vaccines, products with potentially similar names, and so we have collaborated with one paper on FDA that they actually led where we looked in both drug and vaccine safety databases. One of Dr. Ball's medical offices led that study which is going to be published soon.

So recognizing that these - that that science of analyzing systems is a little different from what we traditionally do. We are still you know very interested in preventable adverse effects and we would anticipate that as the science of vaccine safety builds incrementally, we would hope to add more events to that list of what is potentially preventable.

DR. SNIDER: And I am sure you are very aware of this, but you know examples in the past where we have taken action to prevent adverse events were what the first Rotavirus introduced and when we started getting signals through VAERS and subsequently began to do epidemiologic studies. Even the ____ studies were a complete - we consulted with the CDC Director and with the CIP and withdrew our recommendation and FDA and the manufacturer subsequently made decisions that led to withdrawal of that product from the market. Similarly, you know, despite the lower cost of oral polio vaccine and its value for global polio eradication, we were seeing, I believe the number was seven or eight vaccine associated polio cases in the United States and so the advisory committee on immunization practices recognized the efforts of people like John Salomone and _______. We made a decision to move to inactivated polio vaccine so that we would have _______ vaccines associated polio cases. So sometimes, you know, we can take action and sort of on a grand scale if you will to prevent these things from occurring. I think the other thing I wanted to point out is that we were talking about genomics earlier and this offers a potential opportunity to the future that may not be realized for a number of years. But I think there's enough literature to suggest that certain outcomes such as encephalopathy for example might be, once we have the tools in hand, we might be able to identify children at risk of post-vaccination encephalopathy, the so called post-vaccination encephalopathy by identifying genetic markers for that kind of health outcome.

DR. PAVIA: Thanks, Dixie. Let's - can we move on to a few other questions because _____ do you want to?

UNKNOWN FEMALE VOICE: No thank you.

UNKNOWN MALE VOICE: Okay, good.

DR CARLSON: Chris Carlson. Conveniently, I actually had a follow up on that one. I'm sorry. In the context of what I see here, the prediction of outcome is something that I think is very important and very interesting and I don't see a lot on the agenda. There's a tremendous _____ associated, but we know about things that are associated and I really want to see more research done on predicting those people and genomics, excuse me, I'm sorry, genomics is too expensive for your budget. We - there are some cheaper technologies we might be able to use. I don't see a lot here done about looking at ____ distribution in the population of response to vaccines because we might be able to do pre-administration screening to see who is at risk of an adverse event. I know it's perhaps a ____. I don't mean to put this out to there, but there may people who don't need a particular vaccine because they are at too a high risk of a particular adverse event if we can predict that.

DR. BRODER: If I could just comment on that. A couple of places where we've tried to articulate that. One of them is clinical guidance section where we do recognize the value of putting forward clinical guidance based - based on the evidence for trying to prevent these vaccine adverse events and managing them. Within the research needs topics, I think it may need to be stated, but I think a follow up question in addition to is there increased risk would be, if there is increased risk then we need to understand a little more about the nature of this increased risk and that was what we talked before in the general principle is that if there is an increased risk we're not just asking epidemiologic questions, then we want to know are there particular host factors involved? What is the pathophysiology? Are there sequelae? And in the ____ areas, obviously those kinds of discussions could happen. Certainly open to suggestions on how to improve the wording on the questions to articulate that point. Obviously, if there is no risk on an epidemiologic study then one might need to go back and ask do we need to keep looking at special subpopulations or can we just stop and so I think those are two different issues whether you have a risk and need to move forward ______.

DR. SNIDER: You know today, I mean, in this process what we're trying to - we've learned from you folks is what we should be doing, you know, to try help move this forward, recognizing that there are - there is the need for other players and other people to come in and help complete the portfolio if you will. So we want to do what is in your view and ultimately in our view as well seems to be the right way to help move areas forward even if we can't do the whole thing, but we realize we can't do it all so now - and we're not saying also that just tell us things we can do within the constraints of our budget. I mean, if you tell us what we need to do then, you know, we will do the best we can by allocating resources or obtain resources to do it, but we we're not really ____ have a budget, you know, discussion or a discussion about what other agencies should be - should be doing. We hope you will take that up later on. I feel that you probably will and make it part of your larger ____.

DR. PAVIA: We appreciate that. It sounds like you really want to see what needs to be done and then you and we will go out and figure out where that money is going to come from.

UNKNOWN FEMALE VOICE: I'm looking over the list. I'm hard pressed to think of other issues in terms of individual matters, ____, and some of the literature that I'm aware of when the hypothesis ____ as well. I think _______ which is the area of population base effects and there has been a lot of research for example on a ____ hypothesis, children being immunized has changed the rates _____ I think that may be slightly out of the scope of the safety office but I do think it's important and one reason I'm raising it is that I do think that that kind of research is being funded elsewhere and might provide an opportunity to look at some other issues.

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UNKNOWN FEMALE VOICE: We're still on the drawing board, and I've had an opportunity and the NIAD has an awful lot going, on and some of the areas that kind of connect with this ______(INAUDIBLE) what's going on in relation to this.

BARBARA MULACH: This is Barbara Mulach. So I haven't had a chance really to go through the exact specific medicines that you questioned and talked about, specifically what we're doing, but I will say in particular some of the things we're doing that's flu vaccine research. I'm sure there are areas of collaboration, and we were close to the CDC on specific issues. Some of the things that are listed here are post-licensure activities that are less of a focus of what NIAD is doing unless there's a specific hypothesis that we're trying to address, so some of those things generally do fall into the CEC category, but we are more than glad to work with them, you know, where there's good connections.

DR. PETER SCHEIDT: I should just declare a something of a conflict in interest in that University ______(INAUDIBLE) on the National Children's Study, so I have a - and my boss is a principal investigator. ______(INAUDIBLE) the National Children's Study could address a number of the questions that came up here to the extent that children enrolled in the study — there are enough children in the study that do not receive any particular vaccines, and we're going to have an opportunity to compare exposure and non-exposure outcomes, outcomes _____(INAUDIBLE) non-exposures. The ______(INAUDIBLE) hypothesis is one of the specific hypotheses of the National Children's Study as well. The hypotheses of the National Children's Study, other than the hygiene hypotheses, are not specifically targeted in vaccines. We do attempt to collect vaccine data by report from the caretaker or parent and there's ongoing, you know, personal health records being maintained and fed into a database. We do not currently plan to collect specific vaccine data, lot numbers, manufacturers, and that level of data without extra effort. We were asked to look at what would be involved in collecting those kinds of data, which would allow a much more fine-grain, in-depth detailed kinds of study, and we had those, the information ________(INAUDIBLE) several years ago and asked us to think through what it would take to get those kinds of data, and so we're prepared to entertain that if the interest in funds, you know, are available to do it, and to the extent that that electronic _______(INAUDIBLE) information becomes available over the next decade or decades, you know, we would welcome that opportunity to collect those data electronically.

That gives you a sense of where their position is.

UNKNOWN MALE VOICE: And to those who, not to spend too much time on the National Children's Study, but it intends to collect a great deal of toxicologic and environmental exposure data, genetic data and to have many, many years, perhaps generational follow-up.

UNKNOWN MALE VOICE: That's great, so that's a tremendous opportunity for looking at subgroups at risk's interactions with either genetic factors or other environmental exposures that might place it generally at risk when exposed to a vaccine.

UNKNOWN FEMALE VOICE: I can add something in regard -- specifically regarding autism research and ICHD is one of the members of inter-agency autism coordinating committee, and we are in the processing of setting research priorities and in a broader scope, not necessarily vaccination but gene, environmental interactions in, you know, effecting at a prevalence of the phenotypes of autism is definitely within the scope of strategic planning. So that's in the drawing board, and the committee is working on it.

UNKNOWN MALE VOICE: Just to remind everyone that's speaking now, say your name into the microphone for the purpose of the transcripts.

MARIE McCORMICK: Getting back to the VSD, this is Marie McCormick, what's sort of the life cycle of one of these studies, sort of from start to publication because the main part of this is actually getting communication of your results out, so what kind of timeframe and, I guess, more importantly, for some of the recommendation that we might make, what do you see as potential barriers that would -- might impede or slow down the release of important information on vaccine adverse events?

DR. ISKANDER: Okay, so let me again follow that sort of three type, three-tier model that I outlined earlier, so the planned protocol approved epidemiologic study is on the order of years from start to, if you define finish as publication; however, that's on the order of two years to greater than that if it's a particularly, you know, complex or challenging study. The Bill Thompson study on neurodevelopment and exposure to thimerasol took something more like six years to complete. That's really an outlier in that it was a very, you know, extraordinarily, you know, rigorous study with individual level standardized assessment, so the sort of standard, typically hypothesis testing is vaccine X associated with outcome Y on the order of, again, years.

Rapid cycle analysis can go from, you know, the start of the protocol to signal to detection to, you know, the follow-up planned studies within a shorter timeframe than that. The signal detection, of course, can happen within weeks to months after the start of the protocol. At that point, you shift more into an epidemiologic study model where you have to adjust for confounders, and so again it's, you know, more rapid than a planned study. The ability to look at, you know, a very specific, very targeted urgent public health question again, such as, you know, utilization of loss of recalled vaccine, we can do that within realistically one to two weeks. So, if you want to think of it as sort of, you know, weeks versus months versus years in a very over, you know, kind of deliberately oversimplified manner, that's probably a reasonable timeframe.

DR. McCORMICK: But I just, to follow up on that question, you say, you can look at it one to two weeks, but I am thinking about reassurance of the larger community for professional and public how that gets communicated in terms of, you know, what is your timeframe there?

DR. ISKANDER: Well obviously, you know, for planned studies, I mean, those typically the results of those planned studies are communicated at the time of publication. Certainly if it is information that is going to be important to the advisory committee on immunization practices or to safe vaccine recommendations, we will of course arrange advanced scientific presentations of that typically to the ACRP working groups at ACIP public meetings, and basically the standard for the rapid cycle, obviously there is a balance there between wanting to make sure that the signal is not related to, you know, just data issues, and but again wanting to make sure that findings such as the MMRV vaccine findings that in fact may lead to a policy change are communicated in a timely manner and in advance of any, you know, formal scientific publication, and that was done for Proquad, and again you know, if the urgent looks require urgent communication then we do that.

DR. BRODER: Just to follow up on the - and I'll defer to Dr. Pickering, as was mentioned earlier, we do serve on a number of ACIP working groups and we do make routine updates to the ACIP, and those presentations are public. Our slides are posted. In addition, we commonly with the communications efforts around - often around those ACIP presentations and so forth. The most recent ACIP presentation of the MMRV data not only from the immunization safety office, but also interim data from the company, both data were presented to the ACIP and then a communication -- several communication materials were prepared including an MMWR article, which came out about two weeks of the ACIP meeting.

Another example over the summer, there were some reports there to Kawasaki syndrome following RotaTeq vaccine, and that information led to a small change in the product label, and that we -- the Food and Drug Administration and CDC work together to coordinate communication material, so publication is certainly one important form of communicating work, but on a routine basis, we communicate findings and coordinate closely with other groups, particularly the FDA through web postings and through other venues.

DR. CARLSON: Chris Carlson. I have a specific question that may be a symptom of the larger question, and so we'll start at the large _______(INAUDIBLE). On the life scale, the specific accident safety questions in ________ (INAUDIBLE), how many of these would we have had last year? If we're developing a five-year program, how fast do we need to adapt the specific questions to specific questions that have come up, and you can answer that, and I'll get into the specific question.

DR. ISKANDER: I think what we've tried to do is balance, you know, new and emerging questions. New questions do emerge in vaccine safety all the time. They emerge from our reviews of the VAERS system, they emerge from our review sometimes of pre-licensure data. They do often emerge from media or from other reports that make us aware of concerns that we then feel that we need to pursue. So, I think the specific question list is an attempt to balance emerging issues. If something is on that specific emerging, it's been judged by our scientists we've been talking with to be important, to warrant specific attention. Again, many of the concerns about vaccines and Guillain-Barré syndrome date back literally more than 100 years, so that's sort of one far end of the spectrum. Clearly, you know, some of the other issues, particularly about, you know, aspects of neurological deterioration clearly are more contemporary and yet they, you know, we felt they warranted some focused scientific attention.

DR. BRODER: Just to try to put some numbers around your question, I think if you look at the seven specific questions, in looking at them and just marching through them, it looks like three or four we would have had enough information to have put on last year and about three or four would have either not been on there last year, for example, the MMRV febrile seizure issue because we didn't see it as a special need because the concerns hadn't yet emerged to the level where we needed a focused investigation or it would have fallen into a thematic area, however, with the thematic areas when we look at those, there are few exceptions that are related to new vaccines coming up that are in biologic license application phase or where there's been a new ACIP recommendation that stimulated adding the area, for example, annual influenza vaccine that is on as a thematic area mainly because now we have repeat vaccination in that population, but I think most of these I you look through the list, most of these thematic areas would have been reasonable to put on the list two or three years ago.

DR. CARLSON: I absolutely agree. I mean B through D, I can see most of those being longstanding issues. So now sort of going down to the specific question, we've got simultaneous vaccination in vaccine and vaccine practices, we've got vaccine-drug interactions, but I don't see anything on here about the schedule, and the schedule has change a lot for the pediatric vaccination schedule in the last couple of decades. My three kids have seen a lot of pincushions, and this is something where for public reassurance, I -- scientifically the evidence may be not be as strong, but if there is a very serious public concern with this and I am curious about why it's not.

DR. BRODER: If I could just clarify, I think, a couple of other --when you say the schedule, I think what you're meaning is the - let me make sure that the recommended multiple immunizations --

DR. CARLSON: The recommended series across the person's --

DR. BRODER: And there's a separate one for children, adolescents, and adults. We have a couple of other questions that are related, one is off-label use, or a couple other areas, one is off-label use of vaccines and other is interchangeable use of vaccines in different product categories, as well as the one you mentioned, as well as within each of the other themes, one could think about for example, the schedule as it relates to one of the special population. I guess what I might ask you is what -- beyond what is articulated in the list, is there a -- can you bring a little more clarity to the schedule?

DR. CARLSON: In more specific terms, it's my understanding through reading to the ACIP recommendations is that there's basically a series where across the first couple of years of life at day zero one gets Hep B and day 31 gets this series. A lot of concerns that have been raised in the community were really addressing this once one size fits all. Is there an alternate schedule, is an alternate schedule feasible, just so that people have the opportunity to opt for an alternate? We all have to have our kids vaccinated by the time they go into daycare or kindergarten, sure, but we don't have to have them in the first two years if our kids aren't going to daycare and should parents have some choices? This is a scientific/public perception question. I mean I'm not saying that it's - there's proof one way or the other, but the lack of options is a concern I think we should think about.

DR. PAVIA: Just to clarify. It sounds like you're making two points. One is what's the safety of the schedule as it now exists or the safety of alternative schedules, and the other is policy question of in the absence of data should alternate schedules be evaluated for efficacy and feasibility.

DR. ISKANDER: I think, you know, again, part of it, as Karen pointed out, is this was an area where we in a sense split the issue, but I think we're happy to, you know, consider other ways of looking at that question. We certainly are partly -- we will be involved in some of these broader looks at, you know, this is an issue that has arisen within immunization leadership discussions, and we certainly have been invited to be part of those, you know, discussions/scientific investigations and we will certainly pursue that. You know, we also do have in fact some newly added expertise in our office related to, you know, the creation of the vaccine schedule and so I think again we would definitely consider what you are proposing as I think very well within the spirit, if not the exact letter of what we are proposing.

DR. SNIDER: But I do think, you know, I do need to point out as Andy broke it out, what we are asking today is hopefully pretty clear to you by now, and the parts of that that would fall to ISO would be asking those safety questions that Andy articulated. So we could take out the piece that - where you're raising questions about the safety of the crunch schedule, and if people were using or there was, you know, some kind of pilot going where alternate schedules were being used and we could get involved, and we being ISO, could get involved to evaluate safety, but ISO cannot be the, you know, is not, the part of CDC. We work through the advisory committee on immunization practices on what the policies are. So the policy piece would have to be handled by another part of the organization and not ISO.

UNKNOWN MALE VOICE: Okay, thank you.

DR. LARRY PICKERING: Couple of things from the ACIP point of view, there are couple of constraints that ACIP works under. Number one is vaccines are given before exposure to disease, which optimizes their protection. So that's one major consideration, and secondly is that vaccines are studied under certain conditions; age groups and so on, and that's the - they're the data that are presented to the ACIP, and since all the recommendations are evidence based, generally we stick within those FDA licensures for various vaccines, but thirdly, there are ranges for almost all of the vaccines. There are ranges that they can be given in. They don't have to be all be given in one visit. They can be ranged out, and that's something that in under active discussion. I will take this back to ACIP, which is another major group that needs to consider it because there are several members that are -- seem interested in this also. So I think it's something that does need to be looked at.

DR. PAVIA: And I think just to add, there's obviously a large FDA component to these questions about whether or not you can go beyond the data that was presented at the time of licensure and off-label use, and perhaps some of the data that you're receiving the FDA would be helpful for answering these questions as well.

DR. GOLDMAN: Just to add to this that the kinds of questions that I hear have to do with if there are multiple immunizations, separate immunizations given at same visit at certain time points, are there possible safety impacts that would not have been predicted from the trials, which tend to look at the immunizations one at a time. That's just the question that I hear and, you know, some people have asked me, “Well, should I ask, you know, my doctor to use an alternative schedule?” There is a range around it.

The other thing that I think, and this gets more into a communications issue, I think that one of the issues is that the way that the schedule gets communicated is that it's often used very rigidly by school systems and so forth and so then I've also gotten calls about things such as, you know, the child gets the immunization one day short of birthday, and then the physician consultant for the school insists that the immunization must be given again because they've taken that very literally. It's one, and this is a true story, one day short, that it's not a good take and I think that's been, you know, just more created friction I think about the whole issue.

DR. PAVIA: Karen did point out very clearly I think in the background documents that licensure studies are usually done without multiple simultaneous immunizations and then in practice we are giving them in a very large set of combinations. It sounds like what you've raised in own agenda and what we're saying here is that that's something that that requires some thought about how to get around those difficulties in the future.

UNKNOWN FEMALE VOICE: I've heard perhaps one additional question about alternate schedule that might not fit. Most of what I heard I think if I am understanding correctly -

UNKNOWN FEMALE VOICE: _______(INAUDIBLE).

UNKNOWN MALE VOICE: And the light are right behind you, so I apologize.

DR. FLORENCE HOUN: Just that the Food and Drug Administration encourages for licensure that manufactures conduct of portion of their safety and efficacy data in the United States to try to address the issue of concomitant use according to our immunization schedule, which is different from Europe and Asia and the type of vaccines licensed. So you'll even see in this recent Rotarix approval that a component of the study was done in the US with concomitant administration under our schedule, our ages, so that we can get that kind of data.

DR. PAVIA: I should remind everyone to identify themselves again. Sorry.

DR. HOUN: Florence Houn, Food and Drug Administration.

DR. BIRKHEAD: Gus Birkhead. Just in reading through the information, and particularly the background to each of the questions, I note that you haven't at this point formulated specific research questions or scientific questions in each of these areas. You've sort of summarized what's going on right now. Is the plan for this particular document to have more fleshed out the specific types of questions or -- and I think that would have implications for the methodology then and the feasibility and the cost. That all seems to me to be part of the equation at some point. I just wonder when.

DR. SNIDER: Yeah. Through the process that Karen described, we were able to extract some specific hypotheses, but a lot of the discussion in retrospect and going back through, people gave us general thematic areas that they apparently had some concern about, but didn't really articulate, you know, a hypothesis associated with it, and that - so that fell into our purview to try to decide if that thematic area, you know, might be under ISO's capacity to lead d take responsibilities for.

The thematic areas, as Karen has said earlier, are areas that were flagged by this process that's been previously described as areas that needed to be put before NVAC, but each one of them will require some element of significant consultation with a variety of experts, and so it was impossible prior to this meeting and it would be impossible even over probably a course of a year to explore every one of these thematic areas and tease out what the specific hypothesis would be, and so I guess the reason to bring it to you in this forum is to try to get a sense in a narrative way or in a numerical priority way, we can discuss that later, which ones will be thematic areas should we really be concentrating on.

You've heard about the resources that we have, you've heard about the ongoing required activities, so you know, rather than just saying, you know, we should pursue all of these areas and start trying to simultaneously doing it would be impossible. So, what we're asking you to tell us, you know, is among these thematic areas which ones stand out to you, and we're open in terms of how you do that. Which ones of these thematic areas you think are really, really terribly important to pursue and whether you want to do, you know, as your top ten or in a narrative form or how ever you want to convey that information, we can talk about later. What we really need, we need some sense, otherwise we'll just have to - we have to make our own judgments, and we'd rather make it informed by this group and public input, and to even know that we should start those engagements with neurologists and neuro-developmental people around one set of questions or another group of people around another set of questions, adjuvants, for example, immunologists and so forth to understand how these new ______(INAUDIBLE) agonist adjuvants modulate the immune system. Those are all different conversations, and they are going to take a lot of time.

DR. BRODER: If I could just add if in the __________ (BLANK)

MS. BUCK: This is Tawny Buck. I'm curious to know was the public involved in the process of developing this document that I'm looking at right now or is the public input coming now?

DR. BRODER: The ________(BLANK) a starting place for us to have a good high-quality discussion that involves the public as well as scientific partners. In developing this, we did indirectly, although the meetings were not open to the general public, we did I think indirectly trying to obtain input from public perspective by, for example, inviting Geoff Evans from the ACCV and a member from ACCV to participate in our consultancy meeting, by having a broad range of federal experts provide input from their experience, and by reviewing a variety of sources that in the development of those sources might have captured some public input, but we did not in the first phase have a formal process for involving the public.

DR. SNIDER: The point was not to exclude the public, but to try to figure out from scientists what are the questions or indications we were just discussing, what are the thematic areas from in their view we ought to be thinking about. I must say that many of the pediatricians that we involved conveyed the concerns of parents and, you know, pediatricians were out there on the front lines, so I think we indirectly heard from the public around some of these things and that's why some of the things appear on the agenda, but so general idea was we'll hear what the scientists have to say about these areas, what can they come up with in terms of specific hypotheses questions or thematic areas, and the whole issue of the public input is a complicated issue of which we, and I don't really have expertise, and in fact we have limited expertise within CDC and so part of today's discussion is devoted to how we might move forward to get public input, you know, into this, and so we always had the intention of doing that, but the question has always been how, and we still haven't answered that question and we're hoping that you can help us answer that question.

UNKNOWN FEMALE VOICE: Okay.

UNKNOWN MALE VOICE: The short answer was I guess that it's coming.

MS. BUCK: It's just that clearly there's a lot of work done to this point, and I feel a little bit bad in some ways of having to, you know, revisit a lot of these topics because there is concern from the public that perhaps a lot of work has been done without their input, and so I appreciate being here and being given the opportunity to sit here and I just needed to clarify in my head at what point the expectation is for the public to be involved, and I appreciate that.

DR. PAVIA: Let me go ahead and ask a question if I could, or it's only partially a question. As I look at the agenda, the items under C, the special populations ring as very important for the specific populations, and as we talk about moving towards understanding individual risk more than the whole population, but a look through some of the special populations, I think your ability to look at them varies a great deal with the tools that you've told us about. We talk about our children what inborn errors of metabolism, for instance, and thank you for using that term instead of focusing on just one small category of inborn errors like mitochondrial disorders, but your current systems as I understand it with 5.5 million people of all ages under surveillance may be very limited in their ability to ask specific questions there, and I guess to make this more of a form of a question, have you thought through, or is that a process yet to come, how to expand the ability to look at that population? The same applies for people with primary immunodeficiency because I think secondary immunodeficiency you captured within 5.5 million to probably be able to answer those questions.

DR. ISKANDER: Okay. I think we'll sort of divide our answer into two parts. I will ask Karen and others to fill in. It somewhat falls into two categories, so C1 through C3, premature and low birth weight infants, pregnant women, adults age greater than 65 years, we either - you know, we've already produced some vaccine safety research in this area. I don't want to overstate the amount or the size of that research, but, you know, VAERS and VFD have produced some studies in those areas. I think and I believe something like 13% of the birth cohort needs some minimal criteria for prematurity. So, I think in fact looking at specific outcomes in those categories, I think our infrastructure is able to look at the certain -- its piece of the puzzle. I think we're able to do studies in those areas, and you know, we're also involved in some of these, again broader activities about, you know, interest in looking in other systems that might be able to study, for example, birth outcomes in pregnant women and it may be, as one of our potential collaborators said in a meeting last week, that CDC can support this with a little S. In other words, not monetarily support, but be, you know, engaged in the work and be, you know, be coordinating in a sense our studies with theirs.

C4 through C7, then you clearly do run into issues there of how common or rather how rare are these conditions, and I think our CISA network they are, again, meant to focus on the individual rather than at the population, and I would potentially ask either Karen or Corey or others to amplify.

DR. BRODER: Well, I think that that's exactly right. They do fall into two kinds of categories, those that could be assessed with a population-based system like Vaccine Safety Data Link and those where CISA would be more well suited to studying at, and so the CISA and Dr. Dekker is welcome to add, but CISA has six sites, and one of the strengths of CISA is these academic centers that have access to specialty clinics that, you know, people from around the state or country will come to these clinics, and so in the area, for example, of inborn errors of metabolism, one of the CISA sites already has determined that there are what looks like at least 150 children in a center that might be accessible, for example, in some further follow-up. So, I think that would be the part of the discussions in the thematic areas would be looking towards CISA and their six sites in the specialty centers for access to some of these specific populations.

UNKNOWN FEMALE VOICE: Just to add to that, I think the list of -- and by the way, for people who haven't found this yet, table 3 that starts on page 28 of the draft, that really does flesh out the list. It gives much more background information about what we know and what is currently ongoing, but in the area of primary immunodeficiency, we're doing study in children with DiGeorge syndrome and determining whether they have received live virus vaccinations, gathering that information, gathering information about the disease, and we'll be pulling all that together to hopefully be able to make a recommendation of that.

We've got probably 200 patients that we can access at Stanford for that. We've gotten consent from 46 parents, and we're continuing to work on that particular study. Similarly, we are doing studies with rotavirus transmission where there's a household with immunocompromised patients. We are about to put forward a concept sheet for the study of rotavirus starting in premature infants who are leaving the NICU and have that approved through our NICU investigators. So there are smaller studies that are better tailored for the CISA abilities, and we of course partner with our VSD colleagues on some of the larger medical information-based studies, but we actually I think can do a little bit better job in gathering data information, having to consent patient, and also samples.

DR. SNIDER: Andy, this is Dixie Snider. I'd like to just add that in my roll as a co-chair CDC patient safety work group, which by the way we now have a joint FDA-CDC patient safety work group formed, and part of the activities that are going on particularly around the single network that FDA has been charged to build, has resulted in right now all the different entities inside government and out submitting to FDA the systems they might have that could be looked at medical product safety, and I think this offers an opportunity, as John was talking about collaborations, it offers an opportunity to look through those list of systems that are in place and approach those who are running those systems to see if it would be possible to put a vaccine safety question into one of those systems, and so, you know, I don't want to be looking through this, you know, through rose-colored glasses, but nevertheless seeing all the things that are going on and the openness that many of the managed care organizations and many of the operating physicians have to having their systems used for other purposes, I think it presents ISO a unique opportunity to build new collaborations, and finally I just wanted to say to Tawny, since I have to take responsibility for the sequence in which we did this, ______ (INAUDIBLE) we started outside CDC. __________(INAUDIBLE) insists that we start outside CDC and get ideas from outside CDC, but it's always a problem inside an organization and outside an organization when you start trying to engage people about, you know, an agenda or a piece of work, and you know, some people respond by saying, “Yes I'd like to be part of the initial process and offer some of my ideas,” but a lot of people say, “Well, I'm really very busy and I don't have a lot of time. I'd really like to see a draft of what you come up with and comment on that,” and so there is always that, you know, that tension there and so, as I said, there's always been --our intention has always been to somehow get public input, but since we couldn't quite figure out what was the best format to use to get, you know, truly representative public views on this and get that in place, we've talked about it endlessly, but we're hoping NVAC can help us or point us in a direction that we should go. We'll do our best, and so that really is the only point I wanted to make about that.

DR. PAVIA: I think we got - let's see, I've got three more people; Sean, Steve, and Lynn. Anybody else, so I can keep my list intact and not miss anyone?

DR. GERALD MEDOFF: Can I ask a question by telephone?

DR. PAVIA: Okay. I'm going to let you jump in just because of the telephone, and then we'll go to Sean. Go ahead.

DR. MEDOFF: This is Gerald Medoff. I'm sorry I'm not at the meeting. My trip was delayed by American Airlines.

(Laughing)

DR. PAVIA: Go ahead.

DR. MEDOFF: I wanted to commend all the people involved in this work. It certainly involved an enormous amount of work. My question is pertains to the _______(INAUDIBLE) of this process. __________(INAUDIBLE), for example, who decides what is an acceptable level of toxicity from the vaccine? I know the FDA has a project for that, but shouldn't that be outlined in this __________ (INAUDIBLE)? In other words, I think one of the charges _______(INAUDIBLE) adverse events _________(INAUDIBLE), and I think that over ________(INAUDIBLE). So shouldn't the effective process of what happened _________(INAUDIBLE) reactions to vaccines, the level of toxicity, and then the decision making in terms of whether or not special populations are excluded or vaccine is removed from the market, or the toxicity is acceptable in terms of the value of the _________(BLANK).

DR. PICKERING: One of the things - Larry Pickering, sorry. One of the things that the ACIP does when it approves of that or when it gives recommendations for vaccine after license by the FDA, as I said, is that we have regular updates on vaccine safety. These updates sometimes change regarding changes in recommendations to -- from what were originally made. Those changes will be based on risk versus benefit. In other words, if there's a side effect or an adverse event that's very minor like local pain, that would not be considered as important as if it were Guillain-Barré or some other major adverse event, and when you look at the major adverse events if an adverse event occurs that one in a million and the disease itself is a hundred times that and it's a significant disease resulting in death or significant morbidity, those are all taken into account and discussed in a public forum at the ACIP meetings with regard to making changes in recommendations that have been established.

DR. MEDOFF: I understand all of that, but shouldn't that process be outlined in a book like this?

DR. ISKANDER: I can comment briefly. In fact, you know, many of our consultants did in fact make this point. We --

DR. ISKANDER: - and ISO still practice regularly and so we're very well aware of the very important need to balance, you know, risk and benefit. The basic judgment we made was that it was, you know, out of scope activities for us to lead. I think it is certainly, and I certainly included in my introductory remarks of the need to recognize this. So again I think there are probably other ways that that very important concept and process that you describe can be incorporated. We just again did not feel it was in our purview to be able to really lead such scientific activities.

DR. PAVIA: I think the fact that it was raised at all suggests that maybe there is an issue of risk communication here and that, although there is a very clear process, it isn't obvious necessarily how some of these things are weighed and maybe that's something we can take away from this. We've got two more questions before we break so if we can move along, then we can all go to lunch.

DR. HENNESSY: Sean Hennessy. I suspect that there is more variability in heterogeneity internationally in what vaccines children get than within the United States and I'm wondering if there is opportunity or infrastructure to use cross-national comparisons to look at some of these questions.

DR. ISKANDER: I think that's an excellent suggestion. We certainly, although we do not have necessarily formal scientific collaborations that cross borders, we certainly - the global vaccine safety science community is really not that large and so, you know, NVPO actually sponsored a post-licensure vaccine safety surveillance meeting last year where you had probably 80% of the world's top vaccine safety researchers all gathered, did not quite fill up a medium-sized NIH auditorium, so I think there is a lot of ability for certainly, you know, dialogue, understanding what studies are being undertaken in other countries that might be, you know, relevant or that we might want to have some perhaps informal input into. There are also some proposals to develop international vaccine safety networks that would essentially use the existing research capacity of the GPRD in the UK, that's their general practice research database which is a large link database which they use primarily for drug safety, but they do vaccine safety studies as well. Other important models such as Denmark, so I think there has been recognition that there is a lot of that the global community can learn from each other's studies and from more or less formal collaborations in that area and I think that's something that we can incorporate.

UNKNOWN MALE VOICE: Thanks ____.

DR. ELIZABETH MILLER: (INAUDIBLE) _______ at this point.

DR. PAVIA: Yeah, go ahead please.

DR. MILLER: (INAUDIBLE)

DR. PAVIA: Not only does it ____, but it raises the issue of whether or not there is a similar long term agenda from European investigators that could be looked at in your process going forward with the final agenda to see where - what synergies could be discovered.

UNKNOWN MALE VOICE: So that we can get our last -

DR. MILLER: (INAUDIBLE)

DR. PAVIA: There is very vigorous head nodding rather than giving you a formal answer towards the idea of developing methodology and that was I think in the document is given quite a bit of priority.

UNKNOWN MALE VOICE: (INAUDIBLE)

DR. SCHEIDT: Let me just very briefly add to Sean's answer - Sean's question. The National Children's Study jointly with the National Cancer Institute have forged a consortium of large cohorts around the world to attempt to be able to address outcomes that are less frequent than the National Children's Study alone could do. This consortium includes the National Children's Study as it comes along, the Danish cohort study, the Norwegians, the Chinese, the _____ study in England, and ____ cohort in Australia, and other emerging ones. Concept hypotheses are already underway and proposals to test, for instance, folic acid levels in relation to childhood cancer, you know, translocations in relation to childhood leukemia and so on, but it would lend itself for the very infrequent outcomes of encephalopathies in relation to ____ differences in vaccine practices to answer those kinds of questions.

DR. PAVIA: What captured that, I think, when we talk in six months to a year about new ways to go forward, new concepts for research, that's a terrific one. Lynn you've been waiting patiently and then Steve and then we'll have to break for lunch.

DR. GOLDMAN: Yeah, I just had a comment about the overall process, just you know, and in response to a couple of the earlier comments and one is that I think it's very positive as I am hearing this that this office is starting to craft a five year or longer term agenda because I am seeing that there is a tremendous need obviously for the office to be able to respond when there are immediate concerns and if there are changes in the schedule or new vaccines, but that there is a longer term agenda and I am starting to sense that that has not really taken shape yet because of kind of the course of things, you know, the immediate need is always to address immediate problems and I think it's very commendable that the office is coming forward with an effort to develop a five year agenda. I just wanted to say that because I don't think that any of us has yet. And the other thing that it seems to me is that I'm taking this as a list of ideas, as possible avenues to explore. I mean, I'm looking at this, none of these cakes have been baked yet, you know, this is kind of like a menu of things that could be done and so I'm thinking that this is a very excellent time for us to be reviewing this as well as the public because in the sense what you've done and it's a marvelous favor to us all you've created almost like as strong end. This is the list of the things that you're thinking on the basis of, you know, expert consultations that you've undertaken, the people you've worked with, your knowledge, your thinking these are directions that can be taken, and so it gives us enough to be able to grab hold off to be able to say "yes, we like that" or "no, we don't like that," rather than if you had come to us a year ago with, you know, an empty table and said “fill this in”, I think that would have been a lot more effort, it would have been a lot more difficult, and so I kind of think this is a good way to approach this with this and I think for the public as well. I just wanted people in the public who are here also to feel the same way. I mean, I really see this as a list of things that are up for, that you know, can either be accepted or rejected. None of this has gone so far that, you know, we can say this is set in stone. So I appreciate that.

(INAUDIBLE)

DR. BRODER: Karen Broder. I do want to highlight, I think it's obvious for people who are reading the background, that in some of these areas we actually have done a fair bit of work. We have studies underway. I just want to make the point that the level of work that has been done in these areas varies across the topics. In some topics, we have done very little work because they are new topics or new ideas. In other areas, for example in the Guillain-Barré syndrome area, there are a number of activities underway in our office, in other settings as well. And that will - those issues will come up, I think, later when prioritization is discussed and we left them on the list because there may be more work that needs to be done in a variety of areas, but I did want to make that point that there are various activities underway already in some of these areas. Thanks.

(INAUDIBLE)

UNKNOWN MALE VOICE: Sure.

UNKNOWN FEMALE VOICE: It seems to me, you know, managing a very large research program, although some of us might think it should be larger, but as we heard from the UK, this is, relatively speaking, pretty large and so you are going to have choices, I think, about three things and that is the things that you are working on, how far do you take those, how much do you continue to invest in these areas, what are new things that you're going to take on? And then I think the third thing is, and I don't know quite how to put this, but how much search capacity do you need to have? How much capacity do you need to have left over for dealing with contingencies? The questions that will come up next year that we don't know about this year. And so, you know, and that's a difficult management, you know, but -

DR. PAVIA: Yeah, I'm not sure if we can - we could talk about whether we can help with that in terms of talking about how much should be held in reserve as capacity or we may have to leave it up to them to salvage difficult issues. Last question.

DR. GOODMAN: You mentioned the difficulty of figuring out exactly how to engage the public. I just wanted to mention a model from the cancer world which I think - and I don't live in the vaccine safety world so if this has been done before or maybe Sharon's work has covered some of this, I apologize. But one example in the breast cancer world is as something called Project LEAD. LEAD stands for leadership, for education, advocacy, something, I'm not sure exactly. Anyway, the important thing is that it's hosted now by the National Breast Cancer Coalition and what it sponsors really year round are two to four to five day courses where interested, usually breast cancer survivors, but also other women and persons interested in breast cancer advocacy come together with scientists to learn the science, to learn also the politics, they come together with advocates, and all dimensions of the issues, but they spend a lot of time on the science. And this has a tremendous number of benefits.

First of all, a lot of mistrust, misunderstanding between the two, between the advocates and the scientists, and others gets diffused. They become full scientific partners in the discussions where they're being trained for and they're being trained to serve on IRB's, to serve on data monitoring committees, to serve on protocol review panels, and they serve in all of these capacities. And just two years ago, there was the 10^th anniversary of this which was a big celebratory dinner that was attended by leading scientists from the NCI, other breast cancer scientists, and hundreds of advocates, hard to image that occurring in the vaccine field these days, and it was directly a result of the time, not only that the attendees spent, but that the scientific community devoted to teaching them and partnering with them. And it wasn't just a one way interaction, all of these courses and the reason that they take so long is because they involve a lot of both workshop components as well as sort of didactic components, and both sides have to commit to a fair amount of time together. So it shows both goodwill, but also sharing of both concerns and information that the two sides find extraordinarily useful and ends up in much more constructive engagement in meetings like this. I think one of the problems is for public representatives like Tony or anybody is that the points of contact occur, you know, in very abbreviated formal settings like this and it doesn't make for the kind of exchanges that are really needed. So this is not something your office can do, but you could participate in these if the others took it upon themselves and it may be the advocacy committee itself to sponsor these kinds of forms which really focus on education. Of course, in the vaccine field it may be a little bit more difficult because the people who might come to these workshops themselves may not be "representative" of the community whatever that means. I think that's a very, very complicated topic and I won't go there, but to have these forms available and other domains where the "public" and the scientific community can interact in both formal and informal ways for mutual education, I really want to stress that, could have tremendous pay off for forums like this and many, many others where the two interact.

DR. PAVIA: I think you've said that beautifully for the effort we want to make between two and four where we want to think about better ways to do this. I think the breast cancer community and the HIV world where I've lived for many years have done a much better job than we have in vaccines and the whole idea of what we are doing this afternoon is to brainstorm about ideas that will work better. With that, I am going to call a break for lunch. We've run just a couple of minutes over so I'm going to have us still try and get back together by about 1:05 back in this room. And the members of the working group, we have a room set aside. We're just going to talk about conference calls and schedules, and the like so -

DR. PAVIA: There are a number of people on the committee and ex-officio's who have very tight flight connections and in light of it problems with American Airlines and lack of alternative flights. I think you'll understand if people have to leave on time to make their flights so they don't spent an extra night here. So they will read the transcript, they will be available, and I am one of those people who has to be out at exactly 4:30. So we are going to be very - unfortunately, be forced to be fairly rigid on closing the meeting, but I assure it's the beginning and not the end of that process. The next piece, and we're going to foreshorten this a bit so that we don't take any time out of the discussion of the role of the public here, but the next piece is going to be by Dixie Snider. Dixie is going to talk a little bit about ways in which we might think through the process of prioritization and ways in which it might be most useful to them at CDC. So Dixie-

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DR. BENJAMIN SCHWARTZ: This is scientific agenda. I wouldn't propose a specific approach to public engagement. If there is something that needs to be discussed further with stakeholders and experts, however what I would like to do is I would like to define what I consider the important principle that should underlie this process and the first principle is that of commitment. That is commitment that input from the public is important and that the continued success of our vaccination program depends on good decisions on where research if needed to address importance vaccine safety questions, to address public concerns, and to assure the public that their voice is being heard.

The second principle is that of inclusiveness and what this means if including and learning from those who are already knowledgeable and have a particular point of view on vaccine safety as well as from the general population. In our pandemic vaccine prioritization experience, we found that a group of dispassionate citizens were able to effectively contribute their values as well as their specific suggestions giving us the knowledge that the plan we developed reflected the views of population broadly.

A third principle is that of fairness to be achieved through mutual facilitation in planning and carrying out the meetings given that some mistrust exists between various groups and the government, and I don't think I am overstating that. We recognize the value of having the process planned and coordinated by those with expertise in public engagement but no stake in a specific outcome, and related to this is a fourth principle. That is dialogue before deliberation. Through a dialogue process one can create the conditions where common ground can be discovered. In this process, I suggest it might be useful to focus on our values before discussing specific research needs, as our experience suggests that these values are going to be broadly shared and will help bring people together.

A fifth principle is to acknowledge complexity and this has several components. It includes recognizing the complexity of people's genetic backgrounds and environmental conditions and illnesses, which might affect them, as well as the complexity and limitations of scientific investigations that might be done to explore vaccine safety hypotheses.

Sixth, I would emphasize the importance of focus; that is staying focused on the question at hand, and while there are many issues in the area of vaccine safety where community engagement may be a value, the process to be undertaken here would lead to engage specifically on the immunization safety offices, scientific agenda, and success in doing this may lead to further opportunities to address these other vaccine safety questions, and finally I would suggest a principle of accountability, and that is that the government has an obligation to provide feedback to the public on their input and how it contributed to the final outcome. The national vaccine program was established in 1986 by congressional legislation, and this legislation identified twin goals of improving disease prevention by vaccination and improving vaccine safety. These goals and the link between prevention and safety remain as important today as they did then. Public engagement on this research, scientific research agenda will help CDC, NVPO, and HHF address this congressional charge. Moreover, by building on successful public engagement activities that already have been undertaken, it will strengthen the commitment that our department has to a process which can best assure that public health addresses public means.

DR. PAVIA: I think we're going to move to _______(INAUDIBLE). So our next speaker on the agenda is Barbara Loe Fisher and do you have slides