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Interagency Vaccine Group

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Interagency Vaccine Group

NVPO Meeting with Manufacturers on ISO Agenda Final 3/21/08

    National Vaccine Program Office (NVPO)

    Individual Simultaneous Consultation:

    Input from Vaccine Manufacturers’ Representatives

    On the ISO Research Agenda

    November 16, 2007

    Meeting Summary

    In Attendance:

Centers for Disease Control and Prevention (CDC) GlaxoSmithKline

    Karen R. Broder Harry Seifert John K. Iskander MedImmune Dixie E. Snider (CDC moderator) by telephone: Aaron Mendelsohn Nelson Arboleda Jeff Roncal James M. Baggs Gabrielle L. Fowler Merck Paul M. Gargiullo

    Fabio Lievano Tanya Johnson

    Luwy Musey Barbara Slade

     Eric S. Weintraub Novartis Food and Drug Administration (FDA) Barbara Mahon Robert Ball sanofi pasteur Carmen M. Collazo-Custodio David R. Johnson National Vaccine Advisory Committee (NVAC) Alena Khromava Andrew T. Pavia Wyeth National Vaccine Program Office (NVPO) Ann Strauss

    Laura YorkKenneth J. Bart

    Bruce Gellin

    Daniel Salmon (Chair)

Disclaimer: This document does not represent Centers for Disease Control and Prevention (CDC) or

    National Vaccine Program Office (NVPO) policy, nor does it necessarily reflect which ideas will be

    incorporated into CDC’s final Immunization Safety Office Scientific Agenda. This document has been reviewed by meeting participants.

    1 Background and Administrative Summary:

    CDC’s Immunization Safety Office (ISO) is developing a comprehensive,

    scientifically robust Research Agenda with extensive input in a transparent manner; the horizon is 3-to-5 years. ISO is working with the National Vaccine Program Office (NVPO) and National Vaccine Advisory Committee (NVAC) to respond to a recommendation from the 2005 Institute of Medicine (IOM) report: “Vaccine Safety

    Research, Data Access, and Public Trust. IOM recommended that a subcommittee of

    NVAC advise CDC on the Vaccine Safety Datalink (VSD) Project research agenda. Because carrying out high-quality research requires integration across the ISO research and surveillance components, the scope of the research agenda being developed will include the full ISO research agenda, including the VSD Project.

    In this context, ISO collaborated with NVPO to obtain input from scientists representing vaccine manufacturers to inform development of the ISO draft research agenda before the NVAC scientific review. NVPO organized an individual simultaneous consultation with vaccine manufacturers and federal scientists. Two representatives from each manufacturer with vaccines that were licensed (as of August 24, 2007) in the United States and routinely used in the civilian population were invited. Scientists from other agencies and operating divisions of HHS who serve on the Interagency Vaccine Group (IAVG) were also invited to attend. Participants received briefing material before the meeting that included a charge and lists of current ISO scientific activities.

    The meeting convened in the Humphrey Building, Washington DC at

    approximately 9 am on November 16, 2007. It followed the agenda provided in the Appendix (A), with a few minor changes to accommodate the schedule. Dr. Salmon led the meeting and Dr. Snider moderated the group discussions. During the meeting Dr. Broder reminded manufacturers’ representatives of the goal to obtain individual input

    from the participants, rather than a consensus. Participants were encouraged to speak freely and were informed that documents would note the ideas that were discussed without using names. In addition they were asked to complete anonymous feedback worksheets at the end of each brainstorming session. These were summarized by Dr. Broder (Appendix B).

     1 Terms in the document reflect those that were in use at the time of the meeting on 11/16/2007. Disclaimer This document does not represent Centers for Disease Control and Prevention (CDC) or 2

    National Vaccine Program Office (NVPO) policy, nor does it necessarily reflect which ideas will be incorporated into CDC’s final Immunization Safety Office Scientific Agenda. This document has

    been reviewed by meeting participants.

Meeting Events and Discussion

Welcome From the NVPOBruce Gellin and Daniel Salmon

Dr. Gellin thanked the participants for coming. He stressed the importance of input from 2vaccine manufacturer representatives in the development of the ISO Research Agenda.

    The process of putting together that Agenda with input from federal agencies and stakeholders stems from a 2005 Institute of Medicine (IOM) recommendation for NVAC to review and provide advice on the Vaccine Safety Datalink (VSD) research plan. That charge has been expanded to include the ISO scientific activities as a whole.

    Dr. Salmon informed participants that they were encouraged to complete worksheets at the end of the brainstorming session. The participants would be asked to note research topics in each of the areas addressed during the meeting. He asked that any ideas for research topics that occurred to the participants after the meeting should be sent to him or to Drs. John Iskander or Karen Broder.

Welcome from the ISOJohn Iskander

    Dr. Iskander provided background information on the ISO Research Agenda as a context for the present meeting. Since 2005, the ISO’s mission has focused on vaccine risk assessment although it remains engaged in broader science and policy initiatives concerned with vaccine safety.

    Dr. Iskander noted a series of IOM reports on the assessment of the possible causal relationship between vaccines and adverse events in the 1980's and 1990's that found inadequate scientific evidence to determine whether or not a causal relationship existed in more than half of safety concerns investigated. IOM determined that this finding was due to limitations in knowledge and research capacity.

    Gaps in vaccine safety knowledge persist because of the rarity of serious adverse events, the difficulty of performing high-quality scientific studies, the relative newness of vaccine safety science, and the broad scope of the field. There is, therefore, a need to collect, organize, and prioritize vaccine safety studies.

     2 The ISO Research Agenda is also referred to as the “Agenda” in this document.

    Disclaimer This document does not represent Centers for Disease Control and Prevention (CDC) or 3

    National Vaccine Program Office (NVPO) policy, nor does it necessarily reflect which ideas will be incorporated into CDC’s final Immunization Safety Office Scientific Agenda. This document has

    been reviewed by meeting participants.

ISO Research Agenda Development: Process and Discussion Framework

    Karen Broder

Dr. Broder spoke about the ISO’s Research Agenda development process. First, CDC

    will develop a draft research agenda with input from scientists with diverse expertise. Today’s meeting is the last component of this first phase. Earlier input was received

    from other Department of Health and Human Services and Department of Defense agencies (8/2007) and programs and from an external scientific consultancy (5/2007).

    The input will be synthesized, and the key research themes prioritized to develop an ISO draft ISO Research Agenda. After this draft is complete, NVAC will facilitate a scientific review of the draft Research Agenda. CDC will have an opportunity to respond to the NVAC feedback and will finalize the Agenda.

    Dr. Broder also spoke about the mission of the ISO, the interrelationships of its main research and surveillance components, and the general research themes that had emerged from the earlier input from external consultants and federal scientists. These themes included research on specific vaccines, vaccination practices, host factors (e.g., genomics), clinical outcomes, vaccine adjuvants and nonantigen components, and risk perception.

The charge to the manufacturers’ representatives was similar to that given to the previous

    groups. They should identify vaccine safety research areas and gaps in knowledge that are or will be important for public health and could be studied by the ISO. They were also encouraged to indicate why these topics are important, suggest feasible approaches to their study them, and advise ISO as to their relative priority.

Objectives and Format for the DayDixie Snider

    The meeting was divided into five brainstorming sessions: One on vaccine adjuvants and other nonantigen vaccine components and new vaccine technologies and four sessions divided according to life stages of the vaccine recipients (Appendix A).

Discussion

    In response to a question, Dr. Snider said that a report will be generated from the series of discussions and will be in the public domain.

    One participant noted that the data could be useful in the creation of physician guidance. The example offered had to do with immunocompromised children inappropriately vaccinated.

Disclaimer This document does not represent Centers for Disease Control and Prevention (CDC) or 4

    National Vaccine Program Office (NVPO) policy, nor does it necessarily reflect which ideas will be incorporated into CDC’s final Immunization Safety Office Scientific Agenda. This document has

    been reviewed by meeting participants.

Another participant hoped that there would be FDA “buy-in” to the current solicitation of

    input from manufacturers. Dr. Snider replied that the ISO would be working with the FDA. He noted that there is some overlap of interest between the two bodies but that ISO’s primary concern is the safety of vaccines already being used in the national vaccine program rather than with the approval of new individual vaccines as they emerge from Phase III clinical trials.

    The question was raised whether vaccine failure is a safety issue. Dr. Iskander replied that although there is the potential for overlap, most studies are focused primarily on either safety or efficacy. For example, VSD conducts influenza vaccine efficacy studies that are separate from VSD influenza vaccine safety studies. We will also look to international standards (e.g. Council for International Organizations of Medical Sciences) for guidance.

    Brainstorming Session 1: Vaccine Adjuvants, Other Nonantigen Vaccine Components, and New Vaccine Technologies

    The following were suggested as areas for research or topics of concern:

    ; VSD and the Vaccine Adverse Event Reporting System (VAERS) are not

    designed to assess whether events are transient or long-lasting outcomes. It

    would seem important to assess the severity and duration of an event as well as its

    incidence in order to judge its importance.

    ; Although clinical trials may be considered by some to be the gold standard, they

    aren’t always easy to interpret. There are a lot of confounding variables in

    clinical trials; for example, the patient dropout rate may be due to anxiety related

    events rather than to anything intrinsic to a specific vaccine.

    ; In clinical studies, false signals can also appear. In addition, when studies are put

    on hold because of concern about an adverse event, other patients are lost to the

    study, making the final interpretation more difficult.

    ; New adjuvants are undergoing a degree of scrutiny not applied to alum, an

    existing adjuvant. This scrutiny may obscure the benefit of new adjuvants.

    ; A database of background adverse event rates might help in deciding which

    outcomes after vaccination warrant further study.

    ; Because of proprietary or confidentiality concerns, manufacturers are sometimes

    told by regulators to look at particular adverse events or groups of events without

    knowing any of the specifics (e.g., the reason for the concern, what factors to look

    for). More open communication from manufacturers should be provided about

    the frequency of the event and the biological relationship with the specific

    molecules or antigens.

    ; Particular receptors in laboratory animals may occur in different numbers than in

    humans. Bench work is great, but clinical studies are needed.

    ; Appropriate animal models are needed.

    Disclaimer This document does not represent Centers for Disease Control and Prevention (CDC) or 5

    National Vaccine Program Office (NVPO) policy, nor does it necessarily reflect which ideas will be incorporated into CDC’s final Immunization Safety Office Scientific Agenda. This document has

    been reviewed by meeting participants.

    Brainstorming Session 1: Vaccine Adjuvants, Other Nonantigen Vaccine Components, and New Vaccine Technologies (continued)

    ; Case definitions of serious outcomes should be standardized to define outcomes.

    ; When background rates of a putative adverse event are given, the characteristics

    of the population must be specified because the rates of an event will often vary

    depending upon a number of demographic and other variables.

    ; Attributable risk should be given as well as relative risk.

Brainstorming Session 2: Pregnant Women and Exposed Infants

    ; Research on vaccines in pregnant women and neonates has been minimal. This is

    considered a taboo subject in the research arena due to legal and cultural

    concerns.

    ; Given the current litigious environment and lack of robust data on pregnancy

    outcomes and variables, companies are unable to support studies evaluating

    vaccines in pregnant women. Also the point was made that there should be an

    overall approach to research in pregnant and lactating women and newborns.

    ; Studies involving pregnant women are not conducted, not only due to legal and

    cultural reasons, but also due to moral concerns (uncertainty about the effect of

    exposure to the offspring). However, in the post-marketing arena, spontaneous

    reports of vaccine exposure during pregnancy are collected and actively followed-

    up for outcome.

    ; Current vaccines and vaccine schedule are designed to provide immunity prior to

    the time of greatest risk to infants (e.g. differences in schedules used in developed

    countries versus the World Health Organization Expanded Program on

    Immunisation (EPI) schedule). There are important vaccines given to neonates

    like hepatitis B. Also, Influenza vaccination of pregnant women was

    recommended due to increased risk of influenza complications in the vaccinee,

    though there may be benefit to the newly born child (risks versus benefits).

    ; The data addressing benefits of vaccines to pregnant women are mostly anecdotal.

    ; There should be efforts to coordinate the existing data.

    ; There should be a national pregnancy registry with data on women who have been

    inadvertently vaccinated during pregnancy.

    o This would be problematic for vaccines that have not yet been licensed.

    o Data on smoking, drinking, etc., may be lacking in a clinical study or in

    databases like VSD. Follow-up interviews would be necessary to collect

    information on confounders such as these.

    o Several control groups might be needed to address all confounding variables.

Disclaimer This document does not represent Centers for Disease Control and Prevention (CDC) or 6

    National Vaccine Program Office (NVPO) policy, nor does it necessarily reflect which ideas will be incorporated into CDC’s final Immunization Safety Office Scientific Agenda. This document has been reviewed by meeting participants.

    Brainstorming Session 2: Pregnant Women and Exposed Infants (continued)

    o If there is an H5N1 epidemic, we will be seeing many inadvertently

    vaccinated pregnant women despite the lack of rigorous safety data on

    influenza vaccine or H5N1 vaccine in pregnant women. This situation is

    already seen with existing such as licensed trivalent inactivated influenza

    vaccine.

    o CDC is beginning an adolescent and young adult initiative. There will be

    inadvertently vaccinated pregnant women. We should begin accumulating

    data, even anecdotal, and get it into a registry. 3 (OTIS) collects o The Organization of Teratology Information Specialists

    information on pregnancy outcome and follows exposed infants for up to 1

    year. They should be contacted to see if they have, or could obtain, data on

    outcomes among women who were vaccinated. Ideally OTIS should be the

    basis for National Vaccine Pregnancy Registry. The infrastructure is already

    in place.

    ; Most concerns center on pregnancy loss. Data on background rates of pregnancy

    loss are limited and imprecise. The baseline rate of early pregnancy loss has been

    estimated to be as high as 50%, so that with any vaccine given in early pregnancy,

    this rate of loss would be expected, even with a perfectly safe vaccine.

    ; Vaccination programs in Third World countries are often eager to vaccinate

    people whenever they can catch them; this will necessarily include some pregnant

    women. Outcomes data could be collected from these countries. Although this

    might be perceived as exploitation, the information would otherwise be wasted.

Brainstorming Session 3: Adults Over 18 Years (Nonpregnant)

    ; Older adults are more likely to be taking other medications. This could confound

    the problem of detecting true vaccine associated adverse events in this age group.

    ; People with chronic illness or repeated episodes of acute illness are more likely to

    see doctors regularly. They may also be more likely to be vaccinated. Because

    these individuals are more likely to get sick again, their post-vaccination illness

    may be more likely to be attributed to the vaccine.

    o But since they are seeing doctors, they will also be likely to be diagnosed

    when there really is a vaccine adverse event.

     3 Information about OTIS is available at http://www.otispregnancy.org/, accessed on November 17, 2007.

Disclaimer This document does not represent Centers for Disease Control and Prevention (CDC) or 7

    National Vaccine Program Office (NVPO) policy, nor does it necessarily reflect which ideas will be incorporated into CDC’s final Immunization Safety Office Scientific Agenda. This document has

    been reviewed by meeting participants.

    Brainstorming Session 3: Adults Over 18 Years (Nonpregnant) (continued)

    ; Virus reactivation is a concern. Whether any instance should be viewed as a

    safety issue or not depends on whether the infection is more prevalent among

    vaccinated individuals than among a similar population without the vaccine.

    ; Why do some people overrespond and others underrespond?

    o Could be a safety issue. Could be an efficacy issue.

    ; Case definitions of expected serious events are important but they are not yet

    standardized. Brighton collaboration has done some but more work is still needed.

    ; The VSD is not robust enough to detect very rare events.

    ; Vaccine coverage is low for some vaccines.

    ; The size of a cohort for study depends on the background rate of a vaccine

    adverse event.

    o Time is also a factor. Even a small cohort will eventually yield results.

    ; The seriousness of a disease speaks to the importance of a study.

    ; Administration errors are a problem e.g., over-immunization.

    o Since safety is balanced against benefit, and as it is hard to imagine a benefit

    deriving from overimmunization, this is a safety issue.

    ; Are additional doses of vaccine needed in old age? Are they safe?

     Adverse events in this population would be especially subject to o

    misinterpretation.

    o Clinical trials would have to change to address these issues. They would have

    to include not only the elderly but also the frail elderly.

    ; Anxiety related events can be frequent (up to 2.9% in some studies) in adolescents

    and young adults. It is important to consider the possibility of such events when

    observing an increased diagnosis of hypersensitivity reactions.

    Brainstorming Sessions 4 and 5: Adolescents, Infants, and Children

    Sessions 4 and 5 were combined because of time constraints. The following issues were raised:

    ; With combination vaccines, there may sometimes be inadvertent administration of

    one of the components, i.e., an additional and unnecessary dose may be given.

    ; Reactogenicity is an issue with combination vaccines.

    ; The level of antigen may need to be boosted.

    ; In postmarketing surveillance, it is difficult to know which vaccine caused an

    adverse event.

    o For systemic events, in particular, this will often be unclear.

    o This is true especially in large postlicensure studies with subjects who have

    received multiple vaccines.

    To add a new adjuvant to a combination vaccine, a Phase I study will be done, but adverse events may not arise until a postmarketing study is undertaken. Disclaimer This document does not represent Centers for Disease Control and Prevention (CDC) or 8

    National Vaccine Program Office (NVPO) policy, nor does it necessarily reflect which ideas will be incorporated into CDC’s final Immunization Safety Office Scientific Agenda. This document has been reviewed by meeting participants.

    Brainstorming Sessions 4 and 5: Adolescents, Infants, and Children (continued)

    ; We hear from advocacy groups that every combination of vaccines that has not

    been studied in a Phase III trial is an experiment.

    ; Vaccine interference is a subsidiary safety issue. New studies are needed. ; After a vaccine is licensed, we have no control over how it is administered. The

    Advisory Committee on Immunization Practices (ACIP) has recommendations,

    but no one has data on interference, for instance.

    ; Manufacturers of new vaccines should conduct studies evaluating the concomitant

    use of their vaccine with existing vaccines and demonstrate lack of interference in

    immunogenicity/efficacy or impact on safety profile.

    ; An NVPO representative commented that manufacturers need to take more

    responsibility for postlicensing studies investigating off-label use. ; Companies do not want to appear to promote off-label use. The ability to conduct

    studies is becoming limited by the number of subjects available to participate in

    studies. It may not be practical to propose a large increase in studies, e.g. to

    evaluate every off-label indication that arises in practice. This situation is

    currently true for oncology trials, in which the number of subjects needed to run

    the current trials is more than the number of people with the diseases being

    studied.

    ; Voluntary recruitment may become a problem. We should examine some of the

    data collection methods used in Europe.

    ; We do not know the effects of repeated influenza vaccination in children. ; Demographic factors need to be better researched.

    ; Vaccines are tested on relatively small groups of high risk individuals. There is a

    need for research on special groups of infants; e.g., low birth weight or premature

    infants and those with apnea or bradycardia.

    o Sudden infant death syndrome and sudden unexpected death need more

    research.

    o Also, asthma in older children needs more research. But it is difficult to

    measure wheezing or exacerbation of cough.

    ; Risk-benefit for the company should be considered when doing this kind of

    research.

    ; Any institution or agent interested in off-label use must take more responsibility

    in designing and conducting studies to evaluate off-label use.

    ; More information is needed on the right schedule of administration and on

    modification of antigen levels in infants.

    ; What can be done to improve the environment/conditions in which vaccine is

    administered?

    Disclaimer This document does not represent Centers for Disease Control and Prevention (CDC) or 9

    National Vaccine Program Office (NVPO) policy, nor does it necessarily reflect which ideas will be

    incorporated into CDC’s final Immunization Safety Office Scientific Agenda. This document has

    been reviewed by meeting participants.

    Synthesis, Prioritization, and Potential Collaboration

    The following points were raised:

    ; Establishment of baseline rates of AEs that may have biological plausibility are

    helpful in design of both pre-licensure and post-licensure trials. The

    establishment of baseline rates is needed in order to determine how large a study

    must be or to determine the threshold. For example, which proportion of subjects

    seropositive to measles in a population is needed in order to determine the

    estimated proportion of seronegative subjects to be evaluated for vaccine response? ; Though there were questions regarding genomics, there was agreement that this is

    an interesting area of research. New discoveries to generate or improve immune

    responses are readily evaluated by vaccine manufacturers, the goal being new and

    improved vaccines that are generally applicable on a global basis (with benefit far

    outweighing risk). As science identifies individuals with a genetic background

    that may be associated with heightened responses (to infectious pathogens or

    possibly vaccines), it will be important to determine the benefit and risk of

    vaccination for that particular set of individuals. (A recent paper on the ability to

    identify infants at high risk of severe RSV bronchiolitis may be useful in thinking

    about this. Janssen et al. JID 2007; 196: 826. Genetic susceptibility to respiratory

    syncytial virus bronchiolitis is predominantly associated with innate immune

    genes.).

    ; The VSD should be expanded. Among other things, it should include background

    rates for various conditions of interest.

     Products come out in a staged way. Therefore, the ISO must stage its involvement ;

    with manufacturers.

    ; Priorities must depend on the highest safety concerns.

    ; Establish clear criteria of prioritization.

    o When there is a biological basis for vaccine involvement in an adverse event,

    the priority is clear.

     It is not clear how much weight to give to public concern in the absence of o

    compelling biological evidence.

    o Do we care more about adverse events in infants than we do about adverse

    events in the elderly?

    o Public input could help us sort through this kind of value-laden issue.

    ; What the public, in general, cares about is to be distinguished from the

    concerns of small, but vocal, advocacy groups. (But do such groups

    merely advocate, or do they activate?)

    ; Ambiguity around issues of value helps the claims of litigants.

    ; How do we find out from the public what their concerns are without

    raising their concerns?

    Disclaimer This document does not represent Centers for Disease Control and Prevention (CDC) or 10

    National Vaccine Program Office (NVPO) policy, nor does it necessarily reflect which ideas will be

    incorporated into CDC’s final Immunization Safety Office Scientific Agenda. This document has

    been reviewed by meeting participants.

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