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**[National Vaccine Advisory Committee (NVAC)]{.smallcaps}**

**[February 8-9, 2005 meeting]{.smallcaps}**

**[Minutes]{.smallcaps}**

[Meeting Overview]{.underline}

On the first day of the two-day meeting, the Committee received: 1) a
summary of the recent *2^nd^ NVAC Workshop on Strengthening the Supply
of Vaccines in the U.S.* (summary report attached);\
2) a progress report on establishing pediatric vaccine stockpiles; 3)
reports from the field regarding the influenza vaccine shortage this
season, documenting strengths and opportunities for improvement of
cooperation with great bearing on a potential pandemic event; 4) an
update on the current status of avian flu; and 5) a look forward to next
year's influenza season. As a result, the Committee obtained full
committee passage of the following two new resolutions:

-   The NVAC directs the NVPO to conduct a critical comprehensive
    after-action report of all aspects of each year\'s national
    influenza vaccination program. This report should include, but not
    be limited to, assessments by the CDC, ASTHO, CSTE, the ACIP,
    vaccine manufacturers, the National Influenza Vaccine Summit and
    representatives of providers and the public. Lessons learned as well
    as items for improvement should be featured. The results should be
    completed before the annual June meeting of the NVAC and should be
    subsequently delivered to the Assistant Secretary for Health and
    interested parties.

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-   The NVAC establish a working group to explore the legislative and
    regulatory changes that would be required to allow licensure of
    vaccines licensed for use in other industrialized countries in order
    to meet vaccine needs in the US. The working group should provide
    recommendations back to NVAC at its September 2005 meeting.

The Vaccine Safety & Communication Subcommittee received a presentation
by Dr. Gina Mootrey, Acting Director of the Epidemiology and
Surveillance Division of the NIP, evaluating the reports produced by the
Institute of Medicine's Immunization Safety Review Committee (ISRC).
Data were reviewed of a recent NIP conducted survey of stakeholders,
practitioners, pediatricians, and state immunization program managers
about how the reports are meeting the needs of both the CDC and NIH. The
surveys suggested that the reports were very useful to the CDC, NIH, and
stakeholders, but were less so for practitioners and immunization
program mangers. It was generally perceived that the usefulness and
impact for the public might be enhanced by stressing the ISRC's
independence, distributing the reports more widely, and adding plain
language summaries.

The Immunization Coverage & Future Vaccines Subcommittees held a joint
meeting to continue the planning of a National Stakeholder Meeting on
Strategies to Increase the Uptake of New Vaccines for Adolescents,
scheduled for June 2-3, 2005. The goals of this meeting will be to
identify approaches that will 1) most effectively and efficiently
increase the proportion of adolescents who receive newly recommended
vaccines, and 2) ways to integrate immunization approaches with
adolescent health, education, and development programs.

Day two also contained many important and informative reports including
a presentation by Dr. Matthew Davies, of the University of Michigan,
regarding insurance coverage of vaccines and a joint presentation by Dr.
Jim Alexander (CDC) and Dr. Stephen Cochi (CDC) on current efforts
towards global polio eradication and the status of U.S. and Global
Vaccine Stockpiles. Following this presentation, the Committee
unanimously voted to support a request made by Dr. Hamid Jafari (CDC) to
the National Academies for a meeting to discuss the feasibility and
technical and regulatory issues for an effective polio antiviral drug.
Dr. Charles Rupprecht (CDC) then provided a report on the current status
of rabies vaccine supplies in the U.S.

The Committee also received a very informative presentation by a team of
HHS, CDC, and FDA staff members, regarding the Office of the Assistant
Secretary for Public Health Emergency Preparedness' IND Influenza
Vaccine Shortage Program.

Agency and committee updates were presented by: NIP/ACIP (Dr. Melinda
Wharton), ACCV/DVIC (Dr. Geoff Evans), FDA/VRBPAC (Dr. Gary Overturf),
and NIH (Dr. Barbara Mulach)

[Committee Members in Attendance]{.underline}

-   Dr. Charles M. Helms - *Chair*

-   Dr. Gary L. Freed

-   Dr. Alan R. Hinman

-   Dr. David R. Johnson

-   Ms. Ruth Katz

-   Ms. Mary Beth Koslap-Petraco

-   Dr. Richard A. Raymond

-   Dr. William Schaffner

-   Dr. Patricia N. Whitley-Williams

-   Dr. Adele E. Young

## [Executive Secretary]{.underline}

-   Dr. Bruce G. Gellin, Director, National Vaccine Program Office
    (NVPO), HHS

## [Liaison Representatives]{.underline} 

-   Dr. Steven Black, Liaison, American Association of Health Plans and
    Director, Vaccine Study Center, Kaiser Permanente

-   Dr. Myron Levin, Advisory Committee on Immunization Practices
    (ACIP), CDC

-   Dr. Gary D. Overturf, VRBPAC, FDA

## [Ex Officio Members]{.underline}

-   Dr. Norman Baylor, Microbiologist, Center for Biologics Evaluation
    and Research (CBER), Food and Drug Administration (FDA)

-   Dr. Steve Cochi, Acting Director, National Immunization Program
    (NIP), Centers for Disease Control and Prevention (CDC)

-   Dr. George Curlin, Special Advisor, National Institutes of Health
    (NIH)

-   Col. Renata L. M. Engler, Chief, Allergy/Immunology Department,
    Walter Reed Medical Center, Department of Defense (DoD)

-   Dr. Geoffrey Evans, Medical Director, Division of Vaccine Injury
    Compensation Program, Health Resources and Services Administration
    (HRSA)

# [Office of General Counsel Representative]{.underline}

-   Elizabeth Saindon, Office of the General Counsel, HHS

# [Invited Speakers]{.underline}

-   Dr. Jim Alexander, CDC

-   Dr. Cristina Beato, Acting Assistant Secretary of Health

-   Anna DeBlois, Director, Immunization Policy, Association of State
    and Territorial Health Officials (ASTHO)

-   Dr. Matthew Davis, University of Michigan

-   Dr. Lawrence R. Deyton, Chief, Public Health, Department of Veterans
    Affairs

-   Dr. Christine M. Layton, RTI International

-   Dr. Alison Mawle, CDC

-   Andrew McKnight, Director New Product Planning, GlaxoSmithKline
    (GSK)

-   Dr. Stuart Nightingale, OASPHEP, HHS

-   Amy Nevel, OASPE

-   Dr. Glen Nowak, Acting Director of Media Relations, CDC

-   Dr. Peter Patriarca, MedImmune

-   Dr. Robin Robinson, OASPHEP, HHS

-   Dr. Lance Rodewald, CDC

-   Dr. Charles Rupprecht, CDC

-   Dr. Jeanne M. Santoli, NIP, CDC

-   Dr. Benjamin Schwartz, NVPO

-   John Trizzino, ID Biomedical

-   Dr. Melinda Wharton, CDC

-   Eddie Wilder, Public Health Advisor, Immunization Services Division,
    NIP, CDC

# [Committee Members Absent]{.underline}

-   Dr. Ann Margaret Arvin

-   Neal Brandes

-   Dr. James Randolph Farris

-   Dr. Fernando A. Guerra

-   Dr. Jerome O. Klein

    **[[Day 1 -- February 7, 2005]{.underline}]{.smallcaps}**

**Welcome from the National Vaccine Advisory Committee Chair -- Dr.
Charles Helms**

Dr. Helms recalled the October meeting and the announcement that Chiron
would be unable to deliver its influenza vaccine supply. Major problems
with influenza and a vaccine shortage were expected. The program made a
remarkable recovery despite what appeared to be a very large hurdle.
During a time when HHS and CDC were under close public scrutiny, they
managed to make their way out of a paucity of vaccine to what some are
calling, though inaccurately, an excess of vaccine. The events that took
place raised many vaccine supply issues and thus, much of the meeting
agenda would address these types of issues.

Dr. Helms noted that Dr. Beato would be there to hear the summary of the
*2^nd^ NVAC Workshop on Strengthening the Supply of Vaccine in the U.S.*
Additional presentations will cover: stockpiles, vaccine supply issues,
updates on the influenza season, and other interesting topics.

**NVPO Report -- Dr. Bruce Gellin**

Dr. Gellin commented that it was appropriate to spend more time on
influenza and vaccine supply given the past events. There has been
ongoing analysis of the President's budget and more specific impacts on
various programs could be addressed by different agencies. The recently
introduced Presidential budget for FY'06 includes more than a 10 percent
increase for HHS, but a 9 percent decrease for CDC. He noted that it was
his understanding that this decrease was largely for state and local
bio-preparedness efforts. There is \$120 million for pandemic influenza
preparedness, which was previously less than \$100 million, and a
specific line to encourage manufacturers to accelerate the development
of cell culture vaccines. This is separate from cross-departmental
investments in pandemic influenza preparedness. Although this gets some
special attention, it may also get misused.

Unmet Needs funding involves projects that come to agencies either out
of budgetary cycle or because they could not otherwise get funding. It
is an elaborate program with increasing activity by NVAC members, many
of whom had a chance to review the proposals.

Other pandemic preparedness activities are taking place. There has been
an early ratcheting up of activities given the increasingly worrisome
situation in Asia and more detail must be put into planning and
preparedness activities. The structure of a joint NVAC/ACIP working
group will be reported on by Dr. Schwartz. There is also an annual
meeting of the Global Health Security Action Group, including G7
countries and Mexico, with the EU and the WHO that focuses largely on
bio-security issues. Pandemic influenza was added to the agenda a few
years ago because of its similarities to many bio-preparedness issues.
More attention is being given to the issue in the form of a tabletop
exercise to be conducted by the United Kingdom later in the year.

**Welcome from the Acting Assistant Secretary for Health -- Dr. Cristina
Beato**

Dr. Beato welcomed the attendees and apologized that she was unable able
to join NVAC the previous week. She noted that she had been briefed on
the activities and thanked the committee for their hard work and
commended them for their continued work on strengthening vaccine supply.
Vaccine supply is an issue that has been dealt with live this last year,
and while the nation's attention has been justifiably focused on this
issue, ensuring an adequate supply of vaccines is an issue for many
years to come -- not just for influenza, but for other vaccines as well.
The recent vaccine shortage underscores the vulnerability of the vaccine
supply system and the limited redundancy of the entire industry. It is
important to reflect on the year's vaccine shortage and to learn from it
to see what can be improved. Dr. Beato asked the committee to look back
and see what can be learned from what happened this year.

Dr. Beato noted that they had asked for \$120 million in the President's
budget specifically for vaccine issues, which would help stabilize the
vaccine supply. She was hopeful that Congress would follow through and
noted that this was one of few HHS items for which there was an
increase. NVAC's expertise and creativity would be needed to use the
available resources to create new pathways and new incentives to start
building a foundation where both vaccine supply and safety are
considered, and the challenges would not be diminishing.

Dr. Beato emphasized that when they looked at the budget this year, they
knew the year would be tough and even tougher years would be ahead. It
was of great significance that the HHS leadership and the President have
requested an increase in this area. The items that have been increased
are very specific. The President set out priorities and vaccine issues
are considered high priority. Dr. Beato asked the committee to keep this
in mind.

**Discussion**

Dr. David Johnson asked for more specifics about how the \$120 million
would be used.

Dr. Beato responded that if they get the \$120 million, it would be used
to create incentives, as well as address litigation reform, vaccine
litigation, and FDA licensing while ensuring safety and effectiveness.
There would also be focus on domestic capacity and domestic capability.

Dr. Gellin noted that the \$120 million has two pieces. One is for "egg
security," which was a contract that went to sanofi pasteur to ensure
that eggs would be available to allow for the production of influenza
vaccine at full capacity every day of the year. There have been
discussions with Health Canada, which has had this program in place for
some time as part of its pandemic influenza preparedness program. A
large piece is to encourage the manufacturing of cell culture vaccine
produced in the United States and companies interested in this are at
very different stages in their development. An RFP that went out last
year is in the final stages of negotiation, and there will likely be
another RFP in the future to build on this.

Dr. Beato clarified that Dr. Gellin was referring to a short term goal
(i.e., ensuring an egg capacity for a short term need) and a long term
goal (i.e., investing in a more modern system where cell technology can
be sustained and diversify this to make it a domestic agenda issue).

**Summary of the *2^nd^ NVAC Workshop on Strengthening the Supply of
Vaccine in the U.S.***

**-- Dr. Charles Helms**

Beginning in late 2000 and through Spring 2003, the United States
experienced shortages with eight of 11 vaccines for children. In
response, HHS requested that NVAC make recommendations on strengthening
the vaccine supply of routinely recommended vaccines. A working group,
chaired by Jerry Klein, was appointed to identify causes of vaccine
supply shortages, develop strategies to alleviate or prevent shortages,
and enlist stakeholders to consider the applicability and feasibility of
these strategies. An NVAC report on this workshop was sent to the
Assistant Secretary of HHS in October 2002. A summary of the report was
published in the *Journal of the American Medical Association* the
following year and selected manuscripts of the workshop are expected to
be published in *Clinical Infectious Diseases* this year.

NVAC reported that supply disruptions were likely to continue and
recommended several broad strategies to strengthen the vaccine supply of
routinely recommended vaccines including:

-   Expanding vaccine stockpiles;

-   Increasing support for regulatory agencies;

-   Maintaining and strengthening liability protections;

-   Improving communication among stakeholders;

-   Increasing the availability of public information;

-   A campaign emphasizing benefits of vaccination;

-   Evaluating appropriate financial incentives for manufacturers; and

-   Streamlining the regulatory process without compromising safety or
    efficacy.

Dr. Helms noted that since the first workshop, recommendations derived
from these strategies have been considered through legislative
initiatives and executive approval. Periodic vaccine shortages have
continued to occur, highlighting intrinsic weaknesses in the U.S.
immunization system. A long-term, sustained effort by the United States
to shore up the national immunization system will be required to achieve
and maintain the goal of a safe, effective, reliable supply of approved
vaccines.

The events of November 2004 that led to a halt in production of the
influenza vaccine at the Chiron facilities in Liverpool, England have
recently underscored the continuing reality of the fragility of the U.S.
vaccine supply. This stimulated NVAC to sponsor a second workshop to
provide a forum for stakeholders to inject fresh energy, insight, and
discussion into the ongoing vaccine supply issues. The specific goal of
the second workshop was ambitious -- to identify concrete proposals that
might have a beneficial and durable effect on the U.S. vaccine supply.
The broad 2002 NVAC strategies were used as a framework to generate
fresh discussion and insights. The intent was to identify new or
emerging recommendations in vaccine supply that should be combined with
the 2002 NVAC strategies in a short list that made sense to the
participating stakeholders and policy makers.

To facilitate accomplishing the goal, the agenda was divided into four
major sessions:

-   Regulatory Processes, moderated by Dr. Walter Orenstein;

-   Utilizing Vaccine Stockpiles, moderated by Dr. Steve Cochi;

-   Liability Issues, moderated by Dr. Geoff Evans; and

-   Increasing Financial Incentives for Research, Development,
    Production and Administration, moderated by Dr. Marty Myers.

Pressing national interest in the vaccine supply issue underscored the
importance of informing Dr. Beato and NVAC of the proceedings sooner
rather than later. Due to limited time, the information would be
preliminary and abbreviated, and designed primarily to get the proposals
that surfaced from the stakeholders during the proceedings to Dr. Beato
and NVAC in a timely manner.

In the session focused on increasing financial incentives, the
stakeholders understood the complexity of altering the financing of
vaccines, but suggested that there were concrete steps that could be
considered now. First, "demand" could be increased by increasing public
awareness about the need for vaccines through education, focusing
especially on increasing awareness about and promoting the use of
vaccines for adolescents and adults. This should stabilize the size of
the market for old and new vaccines. Second, manufacturers could be
attracted by reducing regulatory and financial disincentives whenever
safe and reasonable (e.g. by limiting costs of clinical trials, allowing
investment tax credits for construction to meet FDA requirements,
removing price caps from CDC purchase of vaccines). The third proposal
was to attract healthcare provider "infrastructure" for vaccine delivery
through economic incentives (e.g. by reducing the risk of up-front
purchase costs to providers and by assuring administration fees that
accurately reflect provider work effort).

The session on regulatory processes was discussed. One of the goals of
the FDA is to ensure the availability of high quality, safe, and
effective vaccines in the United States. Although the vaccine approval
process has been complex, labor-intensive, expensive, and time
consuming, there was a consensus among stakeholders that progress had
been made in implementing the 2002 NVAC recommendations with respect to
regulation. The workshop identified additional proposals for NVAC
consideration. First, the FDA should consider a change from cGMP-focused
oversight of production facilities to final product-focused
characterization. This would maintain sufficient oversight to guarantee
vaccine safety, while decreasing the financial burden on vaccine
manufacturers. The second proposal was to re-institute the system of
informal consultations between manufacturers and FDA throughout the
processes of development, approval and manufacture. Although such
informal contacts may not constitute final FDA policy, it would expedite
the approval process and increase the efficiency of pre-licensure
trials. The FDA should evaluate which safety and efficacy issues need to
be considered in pre-licensure trials and which could be determined
post-licensure, lessening the burden imposed on the pre-licensure phase.
Third, there must be continued harmonization of regulatory processes to
encourage the availability of foreign vaccines in the U.S. market and
U.S. vaccines in foreign markets. Legislative mandates could inhibit
international harmonization. Specific mandates that affect FDA should be
identified and legislative remedies should be sought to remove the
impediments. Fourth, high priority should be given to increase funding
of CBER. Added resources might include additional funds and rampant
filling of organizational vacancies.

The session on utilizing vaccine stockpiles resulted in three proposals.
One proposal was to resolve the "revenue recognition issue" as soon as
possible through negotiations with SEC, HHS, and industry. The ideal
option would be for SEC to allow revenue recognition to the manufacturer
upon delivery of products into stockpiles as an acceptable method of
accounting. When no negotiated solution can be reached, a legislative
remedy should be pursued while alternative models (e.g., CDC-contracted
off-site stockpiles) are explored. The second proposal was to provide
external input to CDC on pediatric vaccine stockpile composition and
appropriate target quantities. To assist with this process, it was
suggested that NVAC consider establishing an advisory working group with
ACIP representation. Third, NVAC should consider endorsement of the
Vaccine Management Business Improvement Project as a mechanism for more
efficient and effective management of the U.S. vaccine supply, including
vaccine stockpiles.

Workshop discussions on liability issues largely revolved around the
Vaccine Injury Compensation Program (VICP), which was enacted in the
late 1980s to compensate individuals who suffered serious adverse
reactions to covered vaccines. VICP was established as a no-fault
program of compensation that covered vaccine administrators and
manufacturers, with the goal of simplifying the approach to litigation
(e.g., it included a table of compensable injuries and relaxed rules of
evidence), and was funded by a tax on covered vaccines. There is
currently over \$2 billion in the VICP trust fund, and all vaccines
recommended by CDC for routine administration to children are covered.
The program has been quite successful since its inception. It has
successfully stabilized the market by reducing litigation uncertainty
which prevailed in the 1980s over DTP vaccine. Over \$1.5 billion has
been awarded to families and individuals.

The 2002 workshop recommendations regarding litigation included
expansion of the VICP to include additional vaccines that were to be
recommended for routine administration to children. The report also
sought to clarify the original Act to ensure that the VICP remained a
viable alternative to the tort system. Specifically, "vaccine" was to be
defined to include the active ingredient, as well as preservatives,
additives, and other excipients in the product to be administered for
immunization. The filing of hundreds of suits in the civil system
alleging autism spectrum disorder from childhood vaccines resulted in
unprecedented costs of litigating which could jeopardize the program.
The second workshop proposals regarding litigation were as follows.
First, the National Childhood Injury Act 1986, as amended, should
require that petitioners first file with the VICP before pursuing legal
remedies in the tort system. Second, the legislative language defining a
"vaccine" should make clear that it includes the active ingredient, as
well as preservatives, additives, and other excipients. Third, other
VICP process improvements incorporated into a bill under consideration
in the previous Congressional session should be enacted.

Dr. Helms opened the floor for discussion and invited workshop attendees
to make corrections and add anything that may have been left out.

**Discussion**

Dr. Overturf asked for more detail on the regulatory process that would
change the focus from good manufacturing processes to other issues. He
noted that it seemed counterintuitive in that this is what happened in
October with Chiron, which resulted in a product that was not usable.

Dr. Baylor commented that he agreed with Dr. Overturf's comments and had
raised the issue at the workshop. Quality is built into the product from
the beginning and this is why cGMPs are in their regulations. He noted
that it was his recollection that most manufacturers who attended the
meeting recognize this. The primary focus was on the cost involved in
maintaining the cGMPs, and there was agreement from FDA and industry on
the importance of quality being built into the product and the need for
cGMPs.

Dr. Orenstein noted that the concern had to do with the characterization
of the final product. There has been a major change in focus over the
last several years since Team Biologics went into effect, and
manufacturing plants that had passed were no longer passing. The concern
was not over the elimination of the process (e.g., plant inspections),
but that the process had tilted too far away from focusing on where
industry representatives feel the major focus should be -- on the
characterization of the end product.

Dr. Helms noted that additional discussion on the summaries would need
to take place to understand what exactly was meant with some of the
proposals.

Dr. Overturf noted that, in order to comment, the workshop session
summaries should be available.

Dr. Helms agreed.

Dr. Gellin commented that Dr. Overturf's question raised a process issue
in terms of finding areas that should be further explored. He explained
that while the details presented were somewhat sketchy and the proposal
somewhat radical, it was inventive and the sort of thing that may
warrant further discussion and investigation. He noted that there had
been presentations from immunization managers from Canada and the United
Kingdom to contrast how they manage their vaccine supply, and that it
may be worth looking into differences in their regulatory approaches to
develop an understanding of what may or may not be more costly.

Dr. Baylor noted that FDA and other CDC equivalents attended the
meeting, but there were no national regulatory authorities.

Dr. Renata Engler noted that there has not been much focus or support
for research on modified dosing for existing vaccines. She noted that a
one size fits all dosing wastes vaccine and in an acute crisis
situation, such as the recent influenza vaccine situation, where people
were turned away or under-immunized, strategies for leveraging the
evolving the knowledge base about immunogenetic response variability
might have resulted in better delivery and preparedness at local levels.

Dr. William Schaffner noted that increasing vaccination among
adolescents and adults would increase the market, draw manufacturers in,
and promote redundancy. He added that the structure used for childhood
immunization should also be used for adult and adolescent immunization.
In considering modifying the VICP, changing the title of the legislation
to remove "Childhood" from the Act should also be considered to extend
all protections to all age groups.

Dr. Steven Black noted that in addition to strengthening supply,
strengthening the distribution system should also be considered.
Distribution problems were highlighted during the recent influenza
vaccine situation where, in some cases, vaccines were unavailable in
hospitals and healthcare facilities, but available at places that do not
do a very good job of screening risk criteria (e.g., Costco and
Wal-Mart). He commented that a well thought out means of synchronizing
communication is needed and suggested that the pandemic group could look
into this.

Dr. Gellin noted that Dr. Engler and Dr. Black had legitimate comments.
With respect to contingency plans when something is in short supply, an
analysis should be done of what is in place and what is being developed.

Dr. Alan Hinman noted that, in looking at expanding the number of
manufacturers, harmonization is one of the most critical strategies. The
U.S. regulatory process should be aligned in such a way that vaccines
manufactured abroad can be brought into the United States with
comparable, if not identical, standards.

Dr. Myron Levin asked for clarification on how redundancy would
encourage companies to enter a market where companies are already
well-established. The season normally starts off with what seems to be a
sufficient supply, but a surplus, which is needed if something goes
wrong, is not built in.

Dr. Helms commented that while redundancy might foster global
interactions and make things easier, in terms of what happens within the
United States, he agreed with Dr. Levin.

Dr. Schaffner noted that increasing demand would encourage manufacturers
to enter the market. Adults, adolescents, and post-adolescents are all
under-immunized and represent a much larger group than children. An
immunization program for these populations is necessary.

Dr. Levin agreed that demand would drive supply, but was unclear that it
would drive the number of suppliers. He noted that the result could be
that well-positioned manufacturers decide to produce more if demand
increases.

Mary Beth Koslap-Petraco noted that they are trying to get more adults
in their county immunized, but adult providers indicate that insurance
companies will not cover the vaccines and people do not want to pay for
them. She noted that this problem was experienced when trying to get
pregnant women vaccinated against tetanus. Vaccines were given to
mothers in order to protect their babies, but this is not done in the
private sector.

Dr. Gellin noted that the issue raised by Ms. Koslap-Petraco is a
systemic problem and systemic fixes need to be determined. There is a
need for two analyses. First, a better understanding of the numbers in
the IOM report is needed (e.g., why the number of manufacturers has
dropped dramatically over the past several years). Second, there must be
discussions with manufacturers who have products similar to those in the
United States to determine why they are not here. There are concerns
about products for which there is a single supplier when other potential
suppliers exist. Contingency plans need to be developed in case
something goes wrong and a determination must be made of why some
manufacturers stay away.

**Update of Pediatric Vaccine Stockpiles -- Dr. Eddie Wilder (CDC)**

The stockpile program began in January 1983 with pediatric vaccines.
There were very few vaccines in the stockpile and the funding for the
program was very limited. In January 1993, VFC legislation was enacted,
which established a requirement for 6-month stockpile of all routinely
recommended childhood vaccines. In September 2002, GAO issued a report
entitled "Childhood Vaccines, Ensuring an Adequate Supply Poses
Continuing Challenges," which discussed enhancing and expanding vaccine
stockpiles. In October, 2002, NVAC issued a report recommending
enhancement of the CDC pediatric vaccine stockpile program.

In May 2003, CDC contracted with the Logistics Management Institute
(LMI) to assist in the development of a broad strategic plan for the
stockpile program, which was done in November 2003. A contract was
established with Booz Allen Hamilton (BAH) whose ongoing work has
evolved into the Vaccine Management Business Improvement Project
(VMBIP). The VMBIP is a complete redesign of the national distribution,
ordering, inventory, and funds management system for publicly purchased
vaccine. One of the biggest accomplishments achieved is that vaccine
target quantities of MMR and Varicella, and partial target quantities of
Hepatitis A, Hepatitis B, Hib, and e-IPV have been reached.

CDC has been given adequate funding to purchase vaccine for the
stockpile to date (\$700 million over four years). While funds have been
allocated for some vaccines, not all have been delivered to the
stockpile. Manufacturers have been either unable or unwilling to deliver
the doses, primarily because of an inability to work out contractual
relationships with manufacturers. The biggest barrier to working out
contractual relationships is revenue recognition.

There are currently contracts with sanofi pasteur and Merck for the
storage and rotation of vaccine in the stockpile. There is no movement
forward with vaccine purchases from these manufacturers as their
contracts will expire this year. Furthermore, contracts with GSK and
Wyeth have not been established, despite efforts to do so. Again, due to
problems surrounding revenue recognition.

The Securities and Exchange Commission (SEC) has issued Staff Accounting
Bulletin (SAB) 101, which includes seven criteria for a sale to be
recognized as revenue. Neither the current contractual relationships
with manufacturers nor current situations with storage and replacement
meet all these criteria. All four manufacturers are affected by revenue
recognition and efforts are being made to work with these issues. The FY
2005 appropriations bill directs HHS to submit a report to Congress
within 90 days containing administrative actions being taken, proposed
solutions, and an identification of the legislative clarification
necessary to resolve this issue. The 90-day period ends in late March.

CDC developed two alternative models to address the revenue recognition
issue should it not be resolved through relief from SEC rules. The
"annual fee model" is a fee for service arrangement where CDC pays the
manufacturer for the right to purchase doses in the future. It is an
insurance policy in which a fee is paid to the manufacturer to maintain
a stockpile. The fee could be recognized as other income and possibly as
revenue. The advantages to this model are that it resolves the revenue
recognition issue with no major operational changes and simplifies the
management of risk of expiration. The manufacturer would have the burden
of maintaining the potency of the stockpile and have more of a market in
which to rotate the stockpile. The disadvantages are that it could
result in substantial and possibly unreasonable costs to CDC and
accounting constraints for the manufacturer. Furthermore, the model
would require significant negotiations to determine what the annual fee
should be. There are concerns that the vaccine would be paid for twice
if ever used in the case of a shortage or an outbreak. This would be a
short-term model.

The second model developed by CDC is the "off-site storage model" where
the vaccine would be at a third party distributor location. The
advantages to this model are that it would resolve the revenue
recognition issue and provide greater assurance to CDC of the stockpile
availability. The vaccine has actually been purchased and shipped to a
third party distributor. A disadvantage is that this model would require
a consolidated distribution approach, because the market shrinks when
the product is shipped to a third party distributor. The market would
not necessarily be the same as it would be for a vaccine manufacturer.
CDC's liability and risks of vaccine expiration could be dramatically
increased.

The major issue revolves around the ability of the vaccine manufacturer
to recognize revenue on the sale of vaccine to CDC for the stockpile
program. CDC is working with HHS and having ongoing discussions with
vaccine manufacturers in an attempt to resolve these issues. Otherwise
delivery to the stockpile will be stagnant. Existing contracts language
must be reviewed and revised with the two manufacturers who have
existing stockpile contracts, and new manufacturers must be brought into
the stockpile process. Finally, CDC will work with NVAC to determine
participation in the target quantity workgroup.

**[2004-2005 Influenza Vaccination Program]{.smallcaps}**

**CDC -- Influenza Vaccine Use, Distribution, and Communications --
*Jeanne Santoli (CDC)***

The events of the past four months with respect to vaccine supply and
distribution has involved hundreds of individuals. On October 5, 2004,
it was learned that Chiron would be unable to supply influenza vaccine
to the U.S. market this season. Beginning November 1, 2004, new
questions were being added to the Behavioral Risk Factors Surveillance
Systems (BRFSS) survey, which is a telephone survey to obtain influenza
vaccine status among all individuals aged six months and older and
reasons for non-vaccination. Data collected by the BRFSS between January
1, 2005 and January 22, 2005 indicate that targeting done over the past
several months has been effective in getting vaccine to adults in
priority groups, with coverage among priority adults at 43.1 percent and
coverage among non-priority adults at 8.3 percent. Coverage rates were
higher than what might have been anticipated on October 5, 2004.
Coverage among high risk adults 18 to 64 years of age was 28 percent
compared to 32 percent from the 2003 National Health Interview Survey
(NHIS). For adults 65 years of age and older, the BRFSS showed a
coverage rate of 58.9 percent compared to 65.5 percent from the 2003
NHIS. For healthcare workers, the coverage rate was 42.6 percent in the
BRFSS and 40.1 percent in the 2003 NHIS.

Pediatric data show that children in priority groups had a coverage rate
of 50.7 percent versus 12.4 percent among non-priority children,
indicating that targeting did have an impact. A key finding was that
during the first year of a full recommendation and during a shortage,
coverage among children 6 to 23 months of age was 57.3 percent.

With the Chiron announcement, the influenza vaccine supply decreased by
50 percent from an all-time anticipated high of 100 million doses. Over
50 percent of the remaining supply had been distributed, the bulk of
which was carried out by sanofi pasteur. Approximately 34,000 customers
had received vaccine, most of which was in partial shipments. Of those
who had already received vaccine, primary care physicians had received
the most, followed by hospitals and health department clinics.

In response to the October 5 announcement, Advisory Committee on
Immunization Practices (ACIP) provided interim recommendations
identifying priority groups. The number of persons recommended for
vaccination dropped from 188 million to 98 million. Sanofi Pasteur
voluntarily ceased shipment of vaccine and began discussions with CDC
regarding next steps. FDA authorized redistribution of influenza vaccine
among providers. State/local public health officials redistributed
vaccine, identified sites for vaccination of high risk persons, reduced
inappropriate use of vaccine, and sub-prioritized vaccine use as needed.

In addition, steps were taken to increase supply. Sanofi Pasteur freed
up additional doses by reaching out to large customers with outstanding
orders and produced 2.6 million additional late season doses. MedImmune
increased production from 1 million doses to 3 million doses. HHS
contacted several foreign manufacturers of influenza vaccine to inquire
about obtaining additional doses to supplement the U.S. vaccine supply
through Investigational New Drug (IND) protocol.

Detailed proprietary information about vaccine shipment from Sanofi
Pasteur and the vaccine distributors populated a system called the CDC
Secure Data Network (SDN) flu vaccine finder to make available to state
public health officials or their designees the location of vaccine that
had been shipped over the course of the season. This information was
updated throughout the season. The SDN was also used by states to place
vaccine orders for their jurisdictions.

Vaccine distribution was an iterative process and the plan evolved based
on supply and demand matching. The objective was to distribute a scarce
resource to the providers most likely to be able to reach priority
patients. Distribution dealt first with immediately identifiable orders,
followed by apportioned vaccine doses across the state, and then late
season strategies.

On October 5, 2005, approximately 33 million doses of inactivated
vaccine were distributed while 25 million doses remained.

The initial focus was on identifiable orders because it allowed vaccine
distribution to resume quickly. Halting vaccine distribution was
necessary, but created much concern. Identifiable orders included both
orders placed with Sanofi Pasteur and many public health orders placed
with Chiron. The public health orders known about were those placed on
Federal, state, and multi-state contracts. From these, orders were
selected for full or partial filling based on an attempt to target
providers serving substantial numbers of people at high risk, including:

-   State and local public health departments;

-   Long-term care facilities/hospitals;

-   VA/IHS/DoD;

-   Providers who care for children (VFC orders, p-free orders,
    office-based pediatricians);

-   Community immunization providers/VNAA; and

-   Office-based primary care providers.

Throughout this process, approximately 13 million doses were distributed
or committed to be distributed between October and early December. At
the close of this phase of vaccine distribution, approximately 46
million doses were distributed and 12 million remained.

State and public health officials have emergency powers that can be used
when necessary and have the best knowledge of the vaccine redistribution
activities that have taken place since October 5. Because of their
knowledge about local supply and demand for vaccine, state and local
public health officials are best suited to identify and address gaps in
vaccine distribution and to ensure community protection.

Approximately 3.5 million doses filled the remaining identifiable public
health orders, and working with state and public health officials, an
unmet need formula was developed to apportion the remaining 8.5 million
doses across states. Midway through this second stage, ACIP convened and
reviewed information about vaccine supply and coverage and recommended
broadening the recommendations to include individuals 50 to 64 years of
age and household contacts (at the discretion of state and local public
health officials). During the process, vaccine was reapportioned three
times since some states had more vaccine than needed while others did
not have enough.

By mid-January, the second stage of distribution was drawing to a close
and approximately 3.5 million doses of inactivated vaccine remained
undistributed. Because the demand for vaccine decreased significantly,
with increasing influenza activity and less than typical coverage
levels, options for enhancing the continued use of vaccine were
considered, and on January 27, 2005, CDC announced three strategies for
the final stage of vaccine distribution aimed at increasing demand for
late season vaccine and making vaccine more available:

1.  Continued CDC encouragement to target high risk individuals and to
    broaden vaccine administration to make the most effective use of the
    existing supply.

2.  Sanofi pasteur, was allowed to distribute doses from the CDC
    influenza vaccine stockpile and market them to public and private
    providers with a return policy to minimize the financial risk
    providers would face with late-season orders. The manufacturer would
    then repay or credit CDC for doses taken and sold from the stockpile
    at the end of the season.

3.  Limited amounts of VFC vaccine are transferred to state health
    departments for use in non-VFC situations in jurisdictions where the
    need for VFC vaccine among eligible children has been met.

Data over the past five years show that doses distributed as a percent
of doses produced ranged from 87 percent to 99 percent. In 2004, doses
distributed as a percent of doses produced was 93 percent.

Lessons learned:

-   Collaboration and communication between and among private and public
    sector partners was critical.

-   Alignment of roles during a crisis with routine responsibilities and
    authorities maximized accomplishments. - Real-time data supported
    management of the public health response and evaluation activities
    enhanced decision-making.

-   Optimal ways to ensure a reliable influenza vaccine supply require
    additional thinking and analysis. - Decisions about optimal
    approaches involve considerations of stockpile versus the ability to
    expand production capabilities on short notice versus other options;
    stabilizing or increasing demand for vaccination and extending the
    vaccination season; and the need to increase the number of licensed
    manufacturers to provide flexibility in the event of unexpected
    supply disruptions.

When it comes to influenza disease, supply and demand for vaccination
are highly unpredictable, which makes planning difficult. Despite a
difficult season, there were positive outcomes. There were relatively
high coverage rates among high risk groups and evidence of successful
targeting of vaccine. In addition, valuable alliances were forged and
strengthened. Timeliness of decision-making and implementation is
critical in an area where there is an opportunity for continued
improvement. Finally, the recent experience underscores the importance
of planning for future seasons (i.e., starting early, anticipating
multiple scenarios, and involving key stakeholders).

Dr. Santoli noted that any successes that can be claimed rest upon the
shoulders of more individuals and groups than can be named and thanked
the following:

-   Individuals who stepped aside to save vaccine for persons in
    priority groups;

-   Private providers for asking their patients to step aside and for
    supporting the state and local public health departments;

-   State and local public health officials for providing guidance and
    for taking on the task of vaccine distribution, as well as the
    frustrations of patients and providers;

-   Sanofi Pasteur for taking a public health approach to the crisis;

-   MedImmune for increasing their supply with very short notice and
    working to target their doses to priority groups;

-   Vaccine distributors for the information shared and their role in
    the distribution process;

-   FDA and other federal agencies for allowing vaccine redistribution
    and looking for additional sources of vaccine.

**Influenza Immunization Communication -- *Glen Nowak, CDC***

There are typically three primary communication goals going into the
influenza season:

-   Use provider materials, consumer education, and media outreach to 1)
    increase awareness of the benefits of influenza vaccination among
    people in ACIP recommended groups; and 2) motivate people in those
    groups to receive timely influenza immunization (and thereby
    increase the immunization rates and decrease death and illness from
    influenza).

-   Through additional targeting, increase awareness of influenza
    immunization recommendations and benefits among African and Hispanic
    Americans in ACIP recommended groups (and thereby increase
    immunization rates and reduce racial disparities).

-   Provide healthcare providers with resources that facilitate their
    efforts and encourage their vaccination.

After October 5, additional communication goals were developed. Public
and provider education materials, partnerships, and media outreach were
expanded to increase awareness of priority groups for available vaccine;
motivate people in priority groups to receive timely influenza
immunization; provide updates immunization recommendations and influenza
vaccine distribution; and promote later season vaccination, particularly
among those at highest risk for complications from influenza.

The effort has involved extensive collaboration across and within both
HHS and the CDC; other federal and state agencies; immunization program
managers; National Influenza Summit; healthcare providers and
professional organizations/societies; and state and local health
departments.

The 2004-2005 season had the strongest coverage around October 5 with
reports on the shortage, who should be vaccinated, and availability of
vaccine. The shortage of vaccine was the topic of media interest through
December, after which the focus was on the fact that there was vaccine
available.

Typically, influenza vaccine uptake is dependent on influenza actually
being spread. This poses a challenge because if influenza is not present
during the months of vaccination some people are not motivated to seek
immunization. This year, influenza was not widely present in October
through December and unlike the previous year, initial cases were not
reported to be unusually severe or occurring in groups not associated
with a severe illness. The media stories, unlike in the previous season
that were driven by reports of severe cases, focused on the supply of
vaccine and who should get vaccinated.

"Competing" messages and advice posed another challenge. For example:

-   Messages of urgency and the importance of getting the flu shot
    versus patience and asking people to wait.

-   Characterization of influenza as a serious illness versus being a
    manageable illness.

-   Other measures that could help prevent transmission, such as hand
    washing, respiratory etiquette, and staying at home when sick.

In terms of planning future communications strategies, the experiences
of the last two seasons suggest three general population segments exist:

1.  Those who strongly believe in annual vaccination, which appear to be
    primarily individuals 65 years of age and older (55 to 65 million
    people). Communication strategies for this group are relatively
    straightforward in that people would just need to be informed about
    where to get vaccinated.

2.  Those who do not believe in vaccination, which includes
    approximately 25 percent of individuals 65 years of age and older.
    People in this group tend to have fairly firm convictions about
    their belief, and unfortunately, much of this is focused on the
    belief that the vaccine causes influenza.

3.  Those who assess the likely severity of the season through the early
    months before deciding whether to get vaccinated. - This group is
    the largest and has the biggest impact on what the demand for
    vaccine will be and this must be considered in developing
    communications strategies.

Other considerations are the need to assess the "unintended"
consequences of the past year's messages and policies (e.g., flu shots
are primarily needed by people who are elderly and/or have chronic
health problems) and the need to address concerns that the "flu shot can
give you the flu" or make you more susceptible to illness. Furthermore,
it is unrealistic that the demand and supply will match perfectly. It is
likely that there may be too many or too few doses, but more doses would
be better. In order to get support for stockpiles or other strategies,
people need to be comfortable with the fact that it is acceptable to
have doses left over as long as coverage is maximized.

**Veterans Affairs Experiences -- *Lawrence Deyton (VA)***

The Veterans Health Administration cares for 5.1 million patients. There
were 7.5 million enrollees out of 25 to 26 million veterans in the
United States. The VA health system encompasses approximately 1,300
Sites-of-Care, including 158 medical centers or hospitals and
approximately 850 clinics, long-term care facilities, domiciles, and
home-care programs. The VA budget was \$27.4 billion last year, and is
the largest employer of healthcare providers in the United States. It
employs approximately 193,000 people, including 15,000 physicians,
56,000 nurses, and 33,000 allied health professionals.

The VA has a fully-deployed electronic medical records system to which
every VA facility has access. This system enables the VA to have a
clinical reminder system for health promotion and other screenings. The
VA can put in place contemporary expression of clinical practice
guidelines where a physician can turn on his computer and pull up a
patient's record, which will highlight various reminders that the
physician should respond to. Everything is recorded in the patient's
medical record for quality assurance and performance monitoring.

The typical VA flu program cycle begins in January, when a contract is
written for the next year's purchases. This is essentially a
solicitation for bids from vaccine manufacturers and is done through the
VA's national acquisition center. In the summer, the VA drafts its
annual Influenza Program Directive, which sets priorities and provides
clinical information. Also in the summer, the VA prepares its Influenza
Tool Kits, which include posters, publicity, and programs to remind
providers, pharmacists, frontline workers, etc., as well as patients,
that they should get vaccinated. In early fall, the Influenza Program
Directive is released, Influenza Tool Kits are distributed to all
sites-of-care, and vaccine shipments begin to arrive. Throughout the
year, the program is monitored by the infectious diseases, public
health, pharmacy, and prevention groups.

The VA's influenza vaccine purchases have increased steadily since 1998,
with an exception in 2000 when one of the manufacturers was unable to
provide the exact number they supplied and was therefore not included.
The projected estimate for 2005 is approximately 2.5 million doses.
While the number of vaccine purchases has been increasing, so has the
number of veterans.

Regional managers are evaluated based on a series of performance
measures, one of which is influenza vaccination rates, as judged by its
External Peer Review Program (EPRP). The EPRP is a contract to look at
the quality of VA healthcare that annually surveys about 100,000
randomly pulled charts across the VA system for a host of performance
measures. The rate of immunization among all veterans (49 years of age
or older or with chronic illness) was 70 percent in FY 2003 and 75
percent in FY 2004. The goal in FY 2004 was to achieve 79 to 82 percent.

Veterans' self-reported vaccination rates are estimated based on data
collected through the Survey of Healthcare Experiences of Veterans
(SHEP), which is mailed to approximately 160,000 veterans receiving
healthcare in the VA. Approximately 82 percent reported receiving
influenza vaccine, with 88 percent of veterans over the age of 64 years
receiving influenza vaccine. Of the individuals who reported having
received influenza vaccine, 38 percent got their vaccine from a non-VA
source.

The VA campaign for flu was released October 1, 2004. With the news
about Chiron released on October 5, the VA looked at the worst case
scenario. The VA estimated that 80 percent of the 7.5 million enrollees
were either over 65 or had a qualifying chronic illness, and that 60
percent of VA employees, trainees, and volunteers fulfilled criteria for
being hands-on providers that may need vaccine. Therefore, in the worst
case scenario, the VA estimated that it could potentially need 6 million
doses of vaccine following revised CDC criteria, and the VA had ordered
2.2 million doses.

In response to the shortage, the VA assessed its vaccine purchase and
100 percent was purchased from sanofi pasteur. Since the SHEP survey
showed that 38 percent of those vaccinated during the 2003-2004 season
received their vaccine from a non-VA source, the VA expected that many
of these individuals would come back to the VA for vaccination and there
would be a shortage. The VA entered discussions with CDC and sanofi
pasteur to assure that the VA vaccine supply would be filled.

Realizing that it had an obligation to make sure frontline providers and
veterans were aware of what was happening, the VA issued six VA
Under-Secretary for Health "Flu Vaccine Advisories" throughout October
and January to keep communication open. Through these advisories the VA:
established priority groups to receive vaccine; defined "hands-on"
health care providers; provided contacts for questions; provided status
updates of vaccine supplies; clarified VA relationship to state and
local health departments; recommended appropriate use of antivirals; and
redefined priority groups.

The VA distributed the advisories broadly via email and other channels;
arranged for the purchase of a small amount of live attenuated influenza
vaccine (LAIV); re-assessed regional supplies of vaccine in
mid-December; re-distributed vaccine within VA regions in December and
January; and removed restrictions on January 21, 2005 realizing there
was vaccine remaining in all VA regions.

The 21 VHA regions were surveyed in mid-December 2004 at which point 73
percent of vaccine had been used (ranging from 58 percent to 91
percent). There was considerable within-region re-distribution and no
region needed more supply.

There were many people who would have been vaccinated last year who
would not be able to be vaccinated this year and the VA developed a
campaign about non-vaccine preventive measures. The campaign included
approximately 60 posters distributed through VA medical centers
highlighting many public health measures that can be taken to help
prevent the spread of influenza.

Lessons learned included:

-   Multiple sources for VA vaccine are needed. - It was by luck that
    the VA had purchased all of its vaccine from sanofi pasteur and not
    Chiron.

-   Clear and timely communication is vital within the VA, with CDC,
    with state and local health departments and other agencies, as well
    as with pharmaceutical companies.

-   A better understanding of patient decision-making surrounding
    immunization; data on vaccine uptake and outcomes within VA and
    externally; and ongoing education of patients and staff about
    importance of flu vaccine, differences in formulations, non-vaccine
    preventive measures, and getting vaccinated are needed.

**The State Perspective -- *Anna DeBlois (Association of State and
Territorial Health Officers)***

On October 5, 2004, when Chiron's license to produce flu vaccine was
suspended and the U.S. supply of vaccine was cut by nearly 50 percent,
states immediately began working to determine how much vaccine had
already been shipped and where those doses were located. Fifteen states
and the District of Columbia acted to enforce interim vaccination
guidelines issued by ACIP. ASTHO surveyed the states via e-mail on
October 7 to get a "first look" at state vaccine surveillance capacity
and received 36 respondents. 34 states responded claiming they had
already initiated surveys, and of these, 24 were surveying both public
and private providers, five were surveying only public providers and
five were surveying only private providers. Detailed results of the
survey are available on the ASTHO website. States reported working with
hospital associations, medical societies, health plans, nursing homes,
corporations, and other entities to assess and survey private sector
supply. The Health Alert Network was also used. It became clear that
determining the location of vaccine would be difficult for many states
largely because of the ambiguities around the private sector.

The initial challenges included identifying private sector providers,
locating vaccine shipped before October 5, and producing effective and
timely communications. Price gouging was initially a big concern
however, it was quickly resolved because of prompt action by the
attorneys general and public cooperation/reporting. Another challenge
that persisted was the availability of VFC vaccine and its use in other
at-risk populations.

Phase 1 distribution began in October and included partial filling of
state and local public health orders. After this, state and local public
health orders were "made whole" and the remaining vaccine was allocated
to states based on need using a formula developed by CDC in coordination
with state and local public health departments. Not all jurisdictions
would receive equal amounts of vaccine, but this method was perceived as
fair. State health officials assumed the responsibility of distributing
the state's allotment of vaccine to providers in their jurisdictions.

When the shortage was announced, many states essentially stopped all
other immunization activities, and in some cases, additional workers
from outside the immunization system were brought in to help address the
issue. These types of staff diversions are not uncommon and employees
are often moved around to address urgent situations. There was a
tremendous programmatic and financial impact on the states, which will
continue until the season is over. Some states reported receiving
thousands of phone calls to their hotlines per day and many activities
had to be postponed or cancelled to accommodate vaccination clinic
needs.

States efforts included working with the media to communicate messages
in a timely manner. There were numerous, and in some states daily (e.g.,
Georgia), press releases. Websites and hotlines were established and
used in nearly every state. States used various tactics to assess
supply, including web-based and telephone surveys, as well as the Health
Alert Network, which was originally developed as a preparedness
initiative. Partnering with local health departments was critical in
targeting vaccine to the appropriate high risk groups. Another tactic
employed by states included vaccination clinics, such as in Arkansas,
where preparedness dollars were used to administer 53,000 doses of
vaccine across 79 clinics in one day. Montgomery County, Maryland was
one of the counties that used a vaccine lottery as a means to target
high risk groups and avoid long lines. To implement the interim ACIP
recommendations, many states issued emergency orders and in some states,
where the vaccine supply was extremely low, sub-prioritization was
necessary.

ASTHO's activities included surveying members an additional five times
to collect information on, for example, vaccine distribution status and
the use of IND vaccine. ASTHO also has a flu resources website and
participated in bi-weekly/weekly calls with CDC, NACCHO, AIM, CSTE, and
APHL. ASTHO served as a main line of communication for the states by
sending them e-mails with updated information as it became available and
communicating the states' needs back to CDC. ASTHO also developed a
position statement called *Vaccine Supply, Immunization Infrastructure,
and Emergency Shortages* (available on the ASTHO website).

In terms of challenges, while the interim ACIP immunization
recommendations were vital, additional guidance was needed for
sub-prioritizing in cases of severe shortage and expanding access as
more vaccine became available. Real-time vaccine surveillance was a
challenge without vaccine ordering and shipping information. In
addition, keeping up with the rapid evolution of events was a challenge
that involved quick decision-making. Also, as noted earlier,
communications is a challenge that persists.

One lesson learned thus far is to remember the good things and the good
decisions that have been made, including disseminating vaccine through
state and local health departments, which are best suited to address
gaps in distribution and allocate vaccine during shortages. An adequate
vaccine supply must be ensured, an essential part of which is increasing
demand. Ways should be sought to draw manufacturers to the U.S. market
and improve manufacturing procedures. Strengthening the immunization
infrastructure is critical. Dedicated Federal funding is needed to
support the delivery of vaccine and enable states to quickly and
effectively respond to shortages and disease outbreak situations without
impairing their ability to respond to other public health issues. The
development of a national vaccine shortage response plan may help
provide advance guidance on efforts to confront similar events in the
future.

**Discussion**

Dr. Hinman commented that the response to the October 5 announcement was
remarkable. News was delivered early in the morning and an emergency
conference call with ACIP was held at noon to prioritize. There was a
press conference and conference call with state health officers that
afternoon. As discussed, there were some unintended consequences that
can be learned from. In the effort to vaccinate those at high risk,
others received the message not to get vaccinated rather than to
postpone getting vaccinated. He noted that it was his recollection that
CDC ended up buying vaccine under IND and that the money was taken from
317 funds, which would normally be used for other activities that are
already in short supply. He asked for clarification on this and noted
that one of the most important ways to assure a continuing demand and
supply is to have a good adult immunization program in place to expand
317 appropriations to provide the kind of infrastructure that exists for
children.

Dr. Cochi responded that the funding to purchase IND vaccine
(approximately 1.5 million doses from two manufacturers for
approximately \$10 million) was taken from 317 funding with the idea
that it would be replenished. Discussions are underway with the
Congressional appropriations committee on where the funds will come
from. CDC had made a proposal that was not well-received, so more work
is being done.

Dr. Schaffner noted that this year provides an opportunity to learn from
experiences, which will translate to routine years, as well years when
there are shortages. There are also lessons for pandemic planning. He
commented that there were many things done supremely well and some
things that were done less well and that a formal serious after-action
report covering the entire array of activities, including NVPO reaching
out to manufacturers and providers to get their frank comments, should
be considered. NVAC should consider passing a resolution charging NVPO
to do this. He added that based on his conversations with Dr. Gellin, he
believed that Dr. Gellin would welcome doing this on an annual basis.
Dr. Schaffner noted that this was in the nature of a motion.

Dr. Helms responded that this would be a significant undertaking and
asked if a vote could be taken later in the meeting.

Dr. Whitley-Williams noted that while those in the immunization program
are aware of the efforts undertaken this year, providers and the public
may not be, and that a report on the response should be made available
and understandable to them. She noted that despite the excellent work
and access to information from public health departments, providers were
frustrated because they could not get vaccine. She also asked whether
Dr. Santoli knew how many doses of intranasal vaccine were dispensed or
used.

Dr. Santoli responded that approximately 2 million of the 3 million
doses produced were distributed.

**Report on the HHS/OASPE Influenza Vaccine Project**

***Amy Nevel (OASPE) & Dr. Christine Layton (RTI)***

The Office of the Assistant Secretary for Planning and Evaluation
(OASPE) has the broad responsibility of advising the Secretary on a
variety of HHS issues. Ms. Nevel's office focuses on science and data
policy issues, as well as policy research and evaluation. They
collaborated with NVPO to develop the Influenza Vaccine Project (IVP).
IVP was intended to outline some basic components of the whole system
for policy analysts and decision-makers, and was conducted by Research
Triangle Institute International (RTI).

The Influenza Vaccine Project is entitled, "Understanding the Dynamics
of Influenza Vaccine Supply and Demand." The project is a follow-up on a
previous project entitled, "Annual Influenza Vaccine Distribution
Process," which concluded in 2001. The purpose is to review the current
status of influenza vaccine demand, supply, and distribution, and
develop five issue briefs by the end of 2005. The issue briefs, to be
completed between April and September 2005, will cover an overview of
influenza vaccine, influenza vaccine purchasing and distribution,
influenza vaccine manufacturing, and influenza vaccine economics. The
topic for a fifth issue brief is yet to be determined.

The annotated bibliography will include various sources of information,
including: peer-reviewed journals; expert reports (e.g., IOM);
"fugitive" literature; websites; conference abstracts; print media
(i.e., newspapers).

The interviewees for the key informant interviews will include: vaccine
manufactures; vaccine distributors; Federal experts; other experts.

The influenza vaccine overview briefing report would summarize influenza
vaccine supply issues, update information presented in the previous
project, summarize other issue briefs, and provide case studies for
previous influenza seasons between 2003 and 2005. The influenza vaccine
purchasing and distribution report would focus on the role of
purchasers, distributors, and other participants. The influenza vaccine
manufacturing report would provide an overview of the structure of
industry, the nature of the influenza vaccine market, global market
factors, and decision making regarding the quantity of vaccines to
produce and investments in new technologies. The influenza vaccine
economics briefing would include factors relating to the costs of
production, pricing strategies, and factors that influence consumer
decisions to purchase vaccine.

**Discussion and Public Comment**

Dr. Hinman noted that none of the issue briefs deals with demand issues,
such as how to increase consumer and provider demand.

Dr. Johnson added organizational demand, such as managed care
organizations or employers.

Dr. Layton responded that they would try to incorporate these topics.

Dr. Johnson suggested the key informant interviews should include past
and potential manufacturers, and state and local health departments. A
possible source for interviewees from the practice community might be
the National Influenza Summit.

Dr. Layton responded that they do intend to interview both past and
potential manufactures. She noted that in the past, they have had some
difficulty in gauging the cooperation of the manufacturers. She asked
for advice on how to gain better cooperation.

Dr. Johnson commented that he and his colleagues would be sharing this
information to their respective companies.

**Avian Influenza -- Update -- *Dr. Alison Mawle (CDC)***

The H5N1 outbreak in poultry has been ongoing since December 2003 in
seven different countries: Vietnam, Thailand, Laos, Cambodia, Indonesia,
Malaysia, and China. As of February 5, 2005, there have been 58
confirmed human H5N1 cases and 44 deaths. Most of the cases have been in
Vietnam, with 40 confirmed cases and 31 deaths. Thailand has 17
confirmed cases and 12 deaths, and Cambodia has one confirmed case and
one death. The overall case fatality rate is currently 76 percent. Most
of these cases had contact with either sick or dead poultry, and the
majority of cases are in children and young adults. At the moment, there
is no evidence of genetic reassortment with human flu viruses and no
evidence of sustained human-to-human transmission.

These cases have occurred in three waves. From December 2003 to March
2004, there were 35 cases and 24 deaths. From July to October 2004,
there were nine cases and eight deaths, and from December 2004 to the
present, there were 10 cases and nine deaths in Vietnam and one case and
one death in Cambodia. The data indicate that activity increases during
cooler months and overlaps with the human flu season, increasing the
chance of reassortment.

The current human H5N1 outbreak in Asia is the largest in history. It is
associated with widespread H5N1 poultry outbreaks and consists of
sporadic cases distributed over a wide geographic area. The confirmed
H5N1 cases underestimate all human H5N1 cases, and the outbreak has a
very high case fatality and severe disease rate. The transmission
appears to be via direct contact with poultry, and there is no evidence
for efficient or sustained human-to-human transmission. However, limited
human-to-human transmission has occurred.

Of the probable human-to-human transmission cases, two healthcare
workers (Hong Kong, 1997) exposed to H5N1 patients (no poultry exposure)
had serological evidence of H5N1. In the current outbreak, there are
several clusters of confirmed and unconfirmed cases in Vietnam and
Thailand.

The 2004 H5N1 viruses isolated from poultry and humans are genetically
and antigenically closely related, and of avian origin. They are
resistant to amantadine and rimantadine, and sensitive to oseltamivir.
They are also antigenically distinct from the 1997 and 2003 H5N1
viruses; the H5N1 viruses continue to evolve.

From the public health perspective, there is no human H5N1 vaccine
available. The antivirals are in limited supply, and the surveillance
for avian influenza viruses in poultry and humans is inadequate in many
Asian countries, which requires laboratory epidemiological capacity.
There are inadequate resources for protective equipment, surveillance,
poultry culling, disposal, disinfection, antivirals, and compensation
for farmers. There is a lack of sufficient infection control measures
and protective equipment in many countries, and the public health
organizations need to work closely with animal health authorities to
control avian influenza.

**Discussion**

Dr. Johnson asked how H5N1 is transmitted from poultry to humans.

Dr. Mawle said they think it might be fecal, oral, and airborne. She
added that the virus has been demonstrated in fecal matter.

Dr. Johnson asked if serological surveys have been conducted in
communities where there are large avian outbreaks.

Dr. Mawle replied that she assumes that they are being done.

Dr. Black asked if there were any information on China.

Dr. Mawle responded that she has no information on China.

**2005-2006 Influenza Vaccine Program -- *Dr. Lance Rodewald (CDC)***

The key lessons from the previous seasons include:

-   Maximize availability and amount of information;

-   Plan for multiple contingencies (flexible plans);

-   Plan around limitations;

-   Plan with stakeholders.

CDC formed the 2005--2006 Influenza Season Planning Group as the primary
planning group for CDC focusing on next season's non-pandemic influenza.
It is charged with identifying priority activities for CDC, determining
who will lead and produce the activities, developing a timeline, and
monitoring the completion of those activities. The group has
comprehensive and strategic representation from CDC and state
policymaking bodies.

The plans are based on vaccine supply scenarios, which included the
following variables: number of manufacturers, vaccine type, production
projections, and licensure status. The scenario output will deal with
the timing, number, and type of doses available, and the rough
probability of occurrence. The scenarios range from a 50 million to 115
million-dose supply.

A critically important activity is to monitor the projection of the
supply productions. NVPO is taking the lead on this activity. The
monitoring will involve discussions with licensed and unlicensed
manufacturers (under IND), FDA, and CDC. The timing of the discussions
will be around sequential milestones that will drive the projections and
allow for more efficient planning. A key point is that the information
from these discussions must be actionable.

The prioritization of the recommendations for influenza vaccine was done
on an emergency basis last season. These priorities were important and
effective, but needed more flexibility, based on the availability of
local supplies. There is widespread desire to create prioritizations
ahead of time.

The ACIP Influenza Working Group met last month and is considering a
number of ways to make the sub-prioritizations. To do this, they are
looking at evidence for each groups on hospitalization rates, mortality
rates, group size, the usual coverage that is achieved, and vaccine
effectiveness. ACIP will be studying a multi-tiered approach,
emphasizing the role for a live attenuated influenza vaccine (LAIV), and
will be voting on some of the sub-prioritizations this week.

Every year, the manufacturers pre-book vaccine through a non-binding
order for vaccine. Pre-booking helps manufacturers determine their
market size and influences vaccine contracts. However, there have been
problems with double booking in the past.

Since the 2000 season, the predominant vaccine distribution strategy has
been partial orders to all customers, which allows for earlier
vaccinations. In developing the strategy, timing, prioritization, and
distribution tracking are important. Contracting for vaccine involves
estimations of need, balancing public/private purchase, and a
stockpiling strategy.

For next season, there is a good chance that IND vaccines might be used
in a routine program. There are a number of challenges with IND vaccines
in a routine program. First, the IND is not optimized for routine use.
Second, the IND must go through an institutional review board (IRB). If
something changes in the vaccine, the IND must go back through IRB.
Third, the IND has to have co-principle investigators. Fourth, insurance
carriers (including government insurance carriers) have limited
experience covering IND vaccines. Finally, the public and provider
acceptance of IND vaccines is unknown---a number of studies have shown
the rate to be low.

There are also a couple of strengths with IND. First, there exist INDs
for influenza vaccine that can be modified and improved. Second, many of
the problems with IND vaccines for routine use have been identified and
some solutions have been found.

Another activity for next year is to monitor the antigen-sparing
studies. There are several of these studies under review, and a couple
of them could affect the coming season. These studies will help to
develop new knowledge needed for future years, including pandemic
planning. The planning group is also working on activities on
communications, proper use of antiviral medication, infection control,
evaluation, and monitoring legislative endeavors.

Better planning could improve contracting, pre-booking and distribution,
IND vaccine use, recommendations, and communication. However, the
following questions need to be considered:

-   What influenza vaccine environmental changes would more effectively
    promote vaccine use?

-   What strategies should be used to ensure a safety net for influenza
    vaccine supply?

-   How can IND vaccine be used most effectively?

-   What are the optimal roles for local, state, and Federal public
    health, and how can they be seamlessly integrated?

-   How can we enhance public health's responsiveness to crises?

**Discussion**

Dr. Black commented that the IRB issues, in terms of getting IND
approval, are relatively easy because they only have to be dealt with
once. However, the reporting requirements are more difficult. He
encouraged NVAC to develop a recommendation for a different category for
vaccines that have been delivered to millions of people in Canada and
Europe.

Dr. Hinman offered another approach. Vaccines that are licensed in other
countries have been shown to be safe, effective, and meet requirements
that are similar to those in the United States. To bring these vaccines
to the United States, the way temporary or provisional licensures are
given could be adjusted.

Dr. Baylor noted that these adjustments could only be done through
legislative changes. The only current way is through an IND and the
difficulties of obtaining an IND are not insurmountable.

Dr. Black added that if legislative changes are required, it is the role
of NVAC to consider making such a recommendation.

Dr. Hinman agreed and noted that NVAC has been trying to promote
legislative change for a while. However, these changes will never happen
unless such recommendations are proposed. NVAC and VRBPAC should
consider what legislative and regulatory changes would be appropriate to
help assure the United States an adequate supply of products that are
licensed and used in other countries under certain circumstances.

Dr. Freed noted that another issue is that IND vaccines are described in
the press as experimental. This has a negative effect on the public's
willingness to take them. Therefore, a legislative mandate for drugs
licensed in other countries would positively influence the public's
perception.

Dr. Young asked how much of the IND vaccine was used this season.

Dr. Rodewald said none.

Dr. Young asked why there is an assumption that IND vaccines would be
used in the next season.

Dr. Rodewald explained that the projected supply for next season would
not meet the projected demand.

Ms. Koslap-Petraco commented that when the public learned that IND
vaccines were going to be added to the supply last year, many people
asked if these vaccines were experimental and indicated that they were
not willing to take experimental vaccines. They were even asking if this
was the thimerosal-free vaccine. The only way to prevent this is to
enact legislative change that would ease the use of vaccines licensed in
other countries.

Dr. Rodewald noted that CDC conducted focus groups on the informed
consent form as part of the IRB proposal. The results of the focus
groups indicated a strong aversion to these forms.

Dr. Raymond noted that one of the reasons IND vaccines were rejected was
because there was not enough time to fully communicate the full
information on these vaccines to the public, since they were introduced
so late in the season.

**[Supply Updates from Influenza Vaccine Manufacturers]{.smallcaps}**

**GlaxoSmithKline -- *Andrew MacKnight (Director, New Product Planning
and Policy)***

Fluarix is an egg-derived, inactivated trivalent flu vaccine. It was
introduced in 1992 and more than 125 million doses have been distributed
in 78 countries in Europe, Latin America, and Asia. GlaxoSmithKline
(GSK) has a dedicated flu vaccine manufacturing facility in Dresden,
Germany, which operates year round.

On December 7, Secretary Thompson announced that FDA had authorized the
use of Fluarix in the United States under an IND and agreed to purchase
1.2 million doses to help address the flu vaccine shortage. This event
represented the culmination of an extraordinary collaboration between
industry and the government. GSK was contacted by HHS and within a week,
management decided to purchase 1.3 million eggs.

Within an eight-week period, GSK, HHS, and CDC collaborated to bring
Fluarix to the United States. They prepared and submitted a drug master
file, which represents all of the clinical and safety experience with
the vaccine outside of the United States over 10 years. They prepared
and submitted an IND to FDA. FDA accepted the IND protocol and completed
an onsite inspection of the manufacturing facility. They documented and
validated the supply chain of product from a manufacturing site to the
United States. Additionally, they developed a detailed logistical plan
for the distribution of vaccine.

In parallel with these activities, on December 9, 2004, GSK announced
the launch of a clinical trial, in partnership with the National
Institute of Allergy and Infectious Disease. The objective of this trial
was to evaluate the immunogencity and safety of Fluarix and to support
its licensure in the U.S. market.

As a relative newcomer to the U.S. vaccine market, GSK has obtained
first-hand experience of the complexity and the unique challenges
involved in obtaining an IND. They also learned that a disproportionate
risk is borne by manufacturers in this market. Specifically, they
learned of the risks of making a vaccine for delivery before October of
each year in the face of unknown demand. They learned that even in the
most acute supply crisis, demand controls the manufacturer.

In the case of the IND vaccine, of the four million doses that were made
available, GSK received commitments to purchase 1.24 million doses,
leaving 2.76 million doses unpurchased. In addition, because of the fall
of demand this year, the Fluarix IND program has yet to be initiated.

Concerning the future, GSK's goal is to be a long-term supplier to the
U.S. flu market. They are in discussions with FDA to seek licensure for
Fluarix under a biological license application. Their interest and
investments extend beyond egg-derived technology to include the
development of cell-derived vaccines.

On the demand side, GSK urges the continuation of efforts to communicate
to the public the health value of annual flu vaccination. On the supply
side, GSK suggests that investment by industry in future innovation will
depend on a reexamination of the current business model and addressing
some of the unique risks inherent in this vaccine market.

**ID Biomedical -- *John Trizzino (Senior VP, Business Development)***

ID Biomedical is committed to supplying the U.S. market with flu
vaccine. This is supported by their facility expansion to a 50
million-dose capacity by 2007 and the current 10-year distribution
agreement with three distributors.

IDB has the capacity to bring 10 to 15 million doses to the United
States in 2005, while satisfying all of its Canadian commitments. The
2004 season shortage has left the U.S. healthcare community wondering
about the flu vaccine supply for the future and the concerns about the
consequences of a widespread outbreak or a failure to supply by one or
two manufacturers. Each flu season has a unique set of challenges and
risks. The 2005 season already has a known supply risk that needs to be
addressed.

ID Biomedical has fully cooperated with all HHS agencies, including FDA,
CDC, and NIAID. There are many short-term issues that need to be
addressed that will aid with the long-term goal to annually vaccinate
150 million Americans and the completion of a pandemic plan. In that
regard, it should be noted that ID Biomedical is the only company in the
world with a long-term pandemic supply contract with any country.
Furthermore, ID Biomedical has received a three-year grant from NIAID to
develop a cell-derived vaccine.

The demand for flu vaccine is a very practical issue for all
manufacturers. The problems of the past season have made clear that the
nation's confidence in the consistent supply of product must be rebuilt.
This will require cooperation between government and industry.
Therefore, it is critical that two things happen. First, there must be a
sufficient supply in 2005 to rebuild the nation's confidence. Second,
the need for vaccination must be once again reinforced across all
priority groups and healthy adults.

The effective balance between supply and demand is unique to flu
vaccine. Solutions to this past season's problems will require better
management and cooperation between all vaccine constituents, including
policymaking authorities.

In closing, IDB can have 10 to 15 million doses available in the U.S.
market in 2005. ID Biomedical has committed a long-term supply of flu
vaccine to the U.S. for routine vaccinations and pandemic preparedness.
Finally, ID Biomedical's modern, North American operations are valuable
and critical to the U.S. flu vaccine supply.

**sanofi pasteur -- *David Johnson (Director, Scientific & Medical
Affairs)***

Sanofi pasteur is the only company with U.S.-based manufacturing of
inactivated influenza vaccine and is contemplating an expansion of that
capacity. An expansion of capacity will require a large investment in
new manufacturing and filling and packaging facilities, and will take
multiple years. In the meantime, if sanofi pasteur is to increase its
production, it will have to extend the manufacturing season. Starting
the manufacturing season earlier would result in "at-risk"
manufacturing, since agreement on the strains would not have been
reached.

It is important that demand continues for a longer period of time. It
has been noted that demand falls off towards the holidays, and in
January, there is almost no demand. It would be an advantage for the
nation if ACIP recommends that certain groups be vaccinated starting in
September. In closing, sanofi pasteur is committed to communicating
frequently and openly with CDC and FDA.

**MedImmune -- *Dr. Peter Patriarca***

MedImmune manufactures the FluMist vaccine, which is different from the
other products. When the shortage was announced, MedImmune did have bulk
vaccine and was able to increase production to three million doses,
versus the planned 1.1 million doses. MedImmune was also able to work
closely with FDA to eliminate the freeze box to simplify the cold chain.

This process raised some concerns for MedImmune. First, the problem for
FluMist was that it was not differentiated from trivalent influenza
vaccine (TIV). It should be noted that most of the recommendations
pertaining to flu vaccines in general did not apply to FluMist. This
created confusion among practitioners. As a result, MedImmune has only
sold 1.7 million of the three million doses. This means that 1.3
additional persons could have been immunized.

MedImmune is an innovator in the industry. TIV is a generic drug and is
easier to produce and test than FluMist. As a result, the licensure of
FluMist is relatively more difficult and cost intensive. Therefore, if
NVAC wants innovation and more effective products than the current TIV,
it should be careful about how it recommends the acceleration of the IND
process for TIVs. If TIVs from other countries easily enter the U.S.
market, MedImmune will be driven out of the market.

In closing, demand will drive supply, and not the opposite. MedImmune
currently plans to make three million doses for the next season, even
though it could make 40 million doses per year.

**Discussion and Public Comment**

Dr. Overturf noted that one of the issues surrounding FluMist is the
uncertainty for healthcare workers. He asked what has been done to
clarify issues for that population.

Dr. Patriarca commented that a lot is being done and that it will take
time to see the effects. MedImmune has a study, as part of its
post-licensing commitment, to look at shedding in the indicated
population. MedImmune believes that the study will show that the risk of
transmission from healthcare providers will be small. They are also
conducting a study with immunocompromised individuals, such as those
with HIV and children undergoing chemotherapy. The purpose of the study
is to generate data that would reassure people that studies on the
monovalent and bivalent forms of FluMist were done well, to show that
there is a low frequency of transmission, and to show that the
consequences of a transmission are nil. It will take years to assemble
this information.

Dr. Levin asked the manufacturers what their incentives were for
submitting an application for licensure, considering all of the
challenges.

Mr. McKnight noted that the challenges are not insurmountable. He added
that an incentive for entering the U.S. market is the growing
recommendations for flu vaccine. Another is the increasing price of flu
vaccines.

Mr. Trizzino added that IDB had been planning to come to the U.S. market
for several years because the vaccination rates have been increasing.
IDB is confident that the United States is a 150 million-dose
marketplace.

Dr. Baylor commented that FDA has had a number of investigators and
manufacturers approach them about developing flu vaccines before this
crisis, so an interest has been there before.

Dr. Helms noted that he is hearing two themes about the need for an IRB
and the need for legislative change. Next year's problem will not be
solved by legislation, which will take considerable time, and the IRB
situation will continue to be present. As a result, the IRB process will
need to be smoothed out. In the end, the IRB process is inconvenient and
affects the public's perception.

Dr. Hinman noted that he had proposed a motion for NVAC to form a
workgroup to consider the legislative and regulatory changes that would
be required to permit temporary or special licensure of vaccines
licensed for use in industrialized countries. The workgroup would report
recommendations back to NVAC at the September meeting.

Dr. Helms asked if there was a second.

Ms. Koslap-Petraco seconded the motion.

Dr. Helms noted that the motion would be discussed tomorrow.

Dr. Deyton noted that there is legislation in place that permits
temporary or special licensure. For example, Project Bioshield has an
emergency use authorization process that allows the Secretary of HHS and
the Secretary of Homeland Security to declare a public health emergency
and to use agents that are not currently licensed.

Dr. Baylor commented that the emergency use authorization requires a
threat to national security. This is why that was not used for this
year's shortage. Therefore, the emergency use authorization must be
amended to include other emergencies beside bioterrorism.

Dr. Hinman noted that although influenza and pandemic influenza can be
described as a national security issue, there are other vaccines, such
as the polio vaccine, that could fall under the emergency use
authorization.

Dr. Overturf commented that he would take the information discussed at
this meeting to the VRBPAC meeting next week.

Dr. Whitley-Williams asked if an IND vaccine would be covered in the
Vaccine Injury Compensation Program (VICP).

Geoff Evans replied that IND vaccines would be covered.

Elizabeth Saindon added that the VICP process was included in the
informed consent.

Dr. Helms adjourned the meeting.

**[[Day 2 -- February 9, 2005]{.underline}]{.smallcaps}**

Dr. Helms called the meeting to order.

**[Subcommittee Updates and Reports]{.smallcaps}**

**Immunization Coverage and Future Vaccines Subcommittees -- *Dan
Fishbein (CDC)***

The two subcommittees met to plan the meeting focused on strengthening
the delivery of vaccines to adolescents on June 2--3 in Washington, DC.
This meeting will aim to convene the key stakeholders with an interest
in adolescent immunization to: 1) identify approaches that will most
effectively and efficiently increase the proportion of adolescents who
receive vaccinations and 2) identify ways to integrate these approaches
with other adolescent health issues and education and development
programs.

A decade ago, NVAC conducted an adolescent workshop, which resulted in a
publication with specific recommendations on how to increase the
proportion of adolescents receiving immunization. At that time, there
were other competing issues, and a number of these recommendations were
not implemented.

The goal of the joint subcommittee meeting was to develop overarching
questions that would be considered by seven different theme groups
including: adolescent medical homes; alternative health care settings;
schools, where there is experience with Hepatitis B vaccinations;
legislation related to school mandates, which have had success in
increasing immunization coverage rates, and to consent; prevention
priorities for adolescent health; cost of improving adolescent health
(financing); and communication with adolescents, parents, and providers.

The subcommittees successfully came to closure on following five
overarching questions, which will be addressed by stakeholder meeting
participants:

1.  What would be the goals of an adolescent immunization program?

2.  Which approaches would most likely be effective and efficient in
    increasing the proportion of adolescents who would receive newly
    recommended vaccinations. What are the best ways to reach
    adolescents for vaccination? What are the most effective
    implementation strategies?

3.  How will vaccination be paid for under each approach?

4.  How can we enhance the demand/acceptance for vaccines among
    adolescents, parents, and providers?

5.  How will we evaluate these immunization programs?

**Vaccine Safety and Communication Subcommittee -- *Dr. Geoff Evans***

The subcommittee discussed an evaluation study on the IOM Immunization
Safety Review Committee, which was presented by Dr. Gina Mootrey from
CDC.

A contractor was asked to evaluate the extent to which the IOM Safety
Committee Reports met CDC and NIH needs, to assess immunization partner
and stakeholder knowledge of the reports, and to assess the impact of
the reports on information clinicians provide their patients and on
patient immunization decisions.

Among agency personnel, the viewpoints were that the contract met all of
the major requirements. The reports were timely. The safety concerns
they thought would materialize during the course of the contract did not
seem to. A few people suggested that an ad hoc group could continue to
review safety issues as needed, but eight out of 10 people felt there
was a continuing need to have standing body ready to conduct these kinds
of assessments. There were also widely varied views about which agency
should coordinate and oversee the follow-up reports. The most common
response was NVPO and NVAC should have this responsibility. Sometimes
the reports did not review alternative hypotheses or explain biological
mechanisms as much as CDC and NIH staff thought they should have. The
primary audience for the reports was the scientific community. Later
reports seemed to be more useful than the earlier reports. For example,
discussing biological mechanisms was more useful than just addressing
plausibility.

Of 11 partners and stakeholders surveyed, only five of these
organizations had read all five IOM Committee Reports, while two read
none. Most agreed that the IOM is an objective and credible source on
issues concerning vaccine safety and that there is a continuing need for
the committee. Six partner and stakeholder representatives thought that
the general public should be the main audience, while five believed the
reports should be directed toward government representatives or health
care workers. However, there was an agreement that the language in the
executive summary should be accessible to the general public. Individual
recommendations included the need to: make more definitive conclusions;
address conflict of interest; include vaccine safety experts; examine
global implications; and task the committee to address individual cases
and causality. There was some concern that the committee members might
not be familiar with vaccine research and not able to render as
insightful of an opinion.

The last surveyed group was medical and public health professionals.
Respondents were pediatricians, family practitioners, and state
immunization program managers. The objectives were to evaluate how
easily and to what extent the IOM reports were used in responding to
patient and constituent concerns, assess the impact of the reports on
patient vaccination decisions, and collect input to inform decisions
about the future of the IOM committee. Fewer than half were aware of the
committee and less than one-third had read any section of an IOM report.
None of the clinicians or program managers shared the report with their
patients or constituents, and none of their patients brought the reports
to their attention. They thought the language and content of the report
was too dense for patients. The recommendations provided were to include
a short abstract or summary; to make the independent nature of committee
explicit, which may make the report better accepted; to better
disseminate the report; and to make the reports unequivocal in their
conclusions.

In summary, it was thought that the reports were useful to CDC, NIH,
partners, and stakeholders but not directly useful to physicians or
immunization program managers. They would be more useful to physicians
if the reports were more concrete in their recommendations and less
equivocal in their conclusions. Additionally, the IOM committee's work
was recognized by government staff, partners, and stakeholders, but few
physicians had heard of the IOM Safety Committee or felt that the
reports would have an impact on their patients' decisions. They also
thought communication and distribution should be enhanced. Most thought
the IOM Safety Committee was credible, and in terms of future
directions, some sort of entity should be kept either as a stand-alone
committee or an ad hoc group. There is also a need to define the
audience(s), develop a communication and dissemination plan, and employ
appropriate language and a format for each audience.

The NVAC Safety Subcommittee discussed these findings, and there was
general agreement on what was heard. They began by discussing the
intended audience and the recognition that the reports are largely for
the public health community and those dealing with immunization science.
For the most part, the results are in "IOM speak" language and there is
little available that puts the results into more understandable terms.
This is important if they are to try to communicate to a broader
audience.

Since there had been some leftover monies before the final report was
completed, there was discussion with Dr. Stratton about possibly hiring
a medical writer to develop a summary of all of the reports for the
general public. This never happened but could be done in the future.
They were not surprised that few physicians had read the reports, but
there is little question that the IOM committee filled a critical need
at a time when there was little certainty about how to manage the
increasing vaccine safety concerns.

The subcommittee believes there should be another contract/freestanding
committee that could quickly respond to issues as they arise. This
subcommittee has begun creating a list of communication recommendations
and are interested in completing the recommendations. Next steps should
be to inventory these recommendations, see what has or is being done,
and report back to NVAC.

**Discussion**

Dr. Johnson asked Dr. Evans for clarification about the 4- to 6-month
ramp up time to deal with another issue. If there were an HHS commitment
to a standing committee, would there be a shorter time period to get to
a safety review if a safety issue were to come up?

Dr. Evans believed this to be the case and asked Dr. Mootrey to join the
discussion as the project officer.

Dr. Mootrey explained that Dr. Stratton was not specific about this.
According to Dr. Stratton, although it is not their typical procedure,
they could arrange to have something like a contingency fee where a
committee would be ready and waiting for an annual fee, whether or not
the committee is called upon. Designated individuals would be in place,
so they would not have to go through the member identification and
selection process. These individuals would be briefed, but once the
topic is identified, some preparation time would be necessary since they
do a literature review and often some kind of analysis beforehand. It
would, however, substantially decrease the amount of lead-time needed.

Dr. Freed asked if they are looking at two separate needs or desires.
One is the rapid need for information, and the other is the more
thoughtful approach to what and how they should do it and what is known
on a particular issue in a broad sense. He wondered if two different
groups could fulfill these functions. The IOM group took a deliberate
and relatively long-term approach to an extensive review of an issue,
which is not very conducive to pulling something together quickly to
make it useful. This could perhaps be another group that could provide
immediate information to guide immediate response or policy, whether it
is internal to CDC or a different contractual group with a different
mission.

Dr. Mootrey noted that this point was made during yesterday's
discussion. If something was needed immediately, a group would probably
be formed using parts of different advisory groups that already exist.
Then, a group like the IOM committee would have more time to look at the
larger issue in more depth.

Dr. Overturf agreed that they have to be very clear about the
differences. With the IOM reports, the independence of that group was
maintained because the group was overlooking data that had been
generated over months and years prior to those reports, often by
independent researchers or investigators. That is completely different
from an acute event, which by its nature, can only be investigated and
handled by the suspected group. He did not think they could be separated
out in an acute event; it is a necessary part of the functions of NVAC,
CDC, FDA, and other groups.

Dr. Gellin asked if they had these people standing by when rotavirus
hit, what role would they have played relative to other groups? He was
not clear what the acute emergency would be to require this to happen so
quickly.

Dr. Mootrey was not sure they would have played a role in the rotavirus
example. Their use would have been after several studies had been done,
at which time they would look at the compilation of studies and then
release their determination of these studies.

Dr. Gellin thought they should explore how expedient IOM could be, but
he is not convinced that a couple of months are that critical.

Dr. Hinman noted that the IOM committee produced eight reports in a
short time, showing they can operate in a compressed period. It is
unlikely that they would need something shorter than that. The question
is how to set up an arrangement so that they could be convened through a
contingency or some kind of contractual agreement that would, for
example, call on them twice year and no more than six times a year. This
could be a reasonable approach to take. In terms of communication to the
public, there has been improvement. The most recent report on MMR and
autism was remarkably clearer in the message that went to public than
the first report. Spending more time on how to communicate results will
be very useful.

Dr. Johnson added that the report Dr. Hinman mentioned was supported by
a press conference and other media outreach; that got the message out
effectively. He was unsure whether this happened with the preceding
reports.

Dr. Evans felt that the effort was so good because they had a definitive
report and conclusion. An example of the IOM limitations would be the
thimerosal episode. In July 1999, their existence would have been little
help at that time because the first thimerosal report had inadequate
evidence. There were no controlled studies; there was very little to
examine. It was not until a few years had passed when they were able to
issue a more definitive report in 2004. This shows that the utility is a
moving target.

Dr. Curlin noted that he did not participate on the IOM committee but
thought they produced eight good reports, especially the last one, which
was definitive and on the mark. This list, however, was already in
existence. The committee slowed down at the end until autism came along
as a big issue to address. This raises the question that Dr. Gellin
asked about whether they should have a committee just standing by until
a major issue emerges. They picked up all of the big issues already.

Dr. Overturf shared that a rationale for reconvening the committee in a
given period of time was to reevaluate data and see if any changes could
make current reports more conclusive. That may happen in 3 to 5 years.
He is not sure who should determine if this is the case and suggested
that it could be the initial contractor. Short of a new topic or issue
coming up, there would be some value. As was already mentioned, if they
tried to evaluate thimerosal in 1999, no conclusion could have been
reached. Five years from now, however, they will be able to reach even
more definitive conclusions than they did with the first report. There
is some rationale for reconvening the committee and using and learning
from this process, but there are questions about the issues that cannot
be answered by a committee like this.

Dr. Gellin noted that they would discuss this with IOM. He then noted
that there are separate issues with vaccinations, particularly for the
military. He asked what the relationship with IOM was for these types of
independent analyses.

Col. Engler explained that DoD, through their data vetting process at
the Military Vaccine Agency, provides input to the IOM reports. Through
the Vaccine Healthcare Center Initiative, they have tried to translate
information into their community but have struggled, as this survey
demonstrated. She noted the comment in the individual recommendations
about the committee needing to address individual cases and causalities
and the relevance to clinicians. The feedback they get from clinicians
is that IOM is very nice, but misses some of the key issues that they
struggle with in terms of frontline concerns about adverse events, new
case definitions, and a process whereby clinical information work
through of in-depth case evaluations can be vetted.

Clinicians also say that IOM's membership does not include the right
people to formulate some of the right questions for vaccine safety.
Referencing the report dealing with multiple antigens and immunologic
questions, Col. Engler shared that she showed the membership list to the
president of the Clinical Immunology Society, which has helped DoD with
case assessments. The president commented that there were big holes in
clinical immunology competencies and the adult medicine perspectives
with which they struggle and would like help. IOM is part of vast body
of information, and they use pieces of it. Concerns on the clinical
frontline are that it is incomplete in working with them through vaccine
safety issues that then go to Congressional staffers or hearings. It
does not help them much without a credible response, such as the
Clinical Immunization Safety Centers and VHC partnering with these kinds
of expert groups and asking questions about defining vaccine safety.

Col. Engler shared that she understands the need for and usefulness of
IOM; they spend a lot of time trying to teach people about IOM, NVAC,
and other groups because service members are distrustful of the
processes. As a clinician, she is impressed with the integrity and
commitment. Some committees are not grappling with the hard questions;
they have an epidemiological approach and review existing literature.
She understands the reasons behind these approaches, but several
questions remain. They have this increasingly branching process in the
official vaccine safety positions and in what the public and clinicians
are struggling with. They need bridges. Frequently, their perception on
the frontline is that the focus is on pediatrics and not adults.
Translating an IOM report to deal with those critical vaccine safety
challenges does not help much.

Col. Engler suggested that it would be nice to have an IOM equivalent
where clinical problems and concerns could be vetted and worked through,
which could build into guidelines and practical aspects for clinicians.
Building bridges between the vaccine "no" groups and understanding their
concerns and what draws them, is crucial for the future success of all
of their programs, whether they are adult or pediatric.

Dr. Cochi announced a footnote on the work of IOM. CDC will receive an
IOM report on data sharing criteria for the vaccine safety databases
that CDC has or has used, as well as guidance on how to provide
preliminary information about studies in progress. These reports will be
available in the near future.

**NVAC Pandemic Influenza Working Group -- *Dr. Ben Schwartz (NVPO)***

Dr. Schwartz explained that they are in the process of formulating a
Pandemic Influenza Working Group as a continuation and extension of the
working group that was formed when the pandemic plan was presented and
made publicly available.

The draft HHS plan was released in August for public comment. It
contained several key issues that require decisions and was upfront in
stating the need to resolve these issues to achieve real preparedness.
Many of the comments received from the 60-day public comment period were
requests for more specifics and guidance for state and local public
health agencies and other groups in the healthcare sector. In addition
to the planning process, there are several ongoing preparedness
activities. Manufacturers have been produced candidate H5N1 vaccine, and
NIH will be testing these vaccines in clinical trials over the next
several months.

HHS has completed a contract with one manufacturer to assure the
necessary egg supply should pandemic vaccine need to be produced at any
time of year. Discussions are ongoing to finalize contracts to diversify
U.S. influenza vaccine production, particularly emphasizing vaccine
production in cell culture. Finally, CDC has also developed a number of
working groups that are providing guidance to state and local health
departments that is more specific than what is currently in the HHS
plan.

Given these baseline planning and preparedness activities, Dr. Schwartz
presented four next steps and critical needs that must be addressed at
this time:

-   Provide options to HHS to guide decision-making on unresolved
    issues. Key issues are to define vaccine and antiviral priority
    groups and to make recommendations on vaccine purchase and
    distribution in a pandemic.

-   Revise the plan and provide more specific guidance and reflect
    revisions made by the WHO regarding phases and levels. Since the
    plan was written, the World Health Organization (WHO) has revised
    the phases and levels that would lead up to a pandemic, the
    different stages of disease, and the activities to be undertaken at
    these stages.

-   Move from a focus on planning to preparedness; develop guidelines,
    algorithms, software programs, and other materials that can be used
    in a pandemic.

-   Obtain input from and increase engagement with stakeholder
    organizations to both gain their perspectives and input and better
    engage and encourage them to take the necessary steps to improve
    pandemic preparedness.

To accomplish these needs, the working group is proposing an ongoing,
expanded, and energized NVAC Pandemic Influenza Working Group. This
group was developed initially to coordinate NVAC comments on the draft
plan. Chaired by Dr. Hinman, the group was composed of many NVAC
members. They propose a new and expanded role that would be to:

-   analyze options for key decisions;

-   provide input to NVPO on revisions to the plan;

-   obtain stakeholder perspectives on pandemic planning and
    preparedness; and

-   increase engagement of stakeholders and communication between HHS
    and participating stakeholder organizations.

Dr. Schwartz shared the proposed working group membership and asked for
comments and suggestions from NVAC members. They want to include the
relevant stakeholder organizations, while keeping it to a reasonable
size. Dr. Hinman has also agreed to continue chairing the group.
Proposed membership includes representatives from:

-   NVAC

-   Federal agencies (FDA, NIH, CDC, HRSA, VA)

-   Federal advisory committees (ACIP, HICPAC, VRBPAC)

-   Medical societies (AAP, AAFP, ACP, IDSA, AMA)

-   Healthcare organizations (AHA, AHIP)

-   Public health organizations (ASTHO, CSTE, NACCHO)

-   Public Health Agency of Canada - Canada has done an excellent job
    with their pandemic planning process and has included U.S.
    representation on their committees. Continued cross-fertilization in
    pandemic planning would be useful.

-   Ethicists - Many of the decisions to be made and the issues to be
    evaluated relate to values, such as who should be in priority
    groups. Having ethical input into these issues is important.

For the working group process, they would first establish subgroups to
analyze issues and develop options to present to NVAC. One obvious
subgroup would examine vaccine priority groups for a pandemic, which
would be a joint group with ACIP. They have already had conversations
with Dr. Levin, ACIP Chair, and with the CDC staff who support the ACIP
Influenza Working Group. They have agreed to work on this topic
together. A second proposed subgroup would examine antiviral priority
groups and strategies. Other subgroups may be formed based on needs
identified by HHS, working group members, or stakeholders and on the
committee's capacity to staff the various subgroups.

The working group as a whole will consider the subgroup analyses,
provide input on issues that affect stakeholders broadly, and hopefully,
comment on guidelines and materials that are developed. If, for example,
HHS develops a communications plan with CDC and other agencies, this
group could read and comment on the plan.

They anticipate holding two working group meetings per year. Subgroups
would likely have an additional meeting, but most of the communication
will be done via conference call and email. NVPO would provide staff and
administrative support.

They have set an aggressive timeline and propose an initial presentation
on priority groups for vaccine and antiviral drugs at the June NVAC and
ACIP meetings. This is a specific request from the Assistant Secretary
for Public Health Emergency Preparedness.

They hope to form the Working Group before the end of February for an
initial meeting in mid-March.

**Discussion**

Dr. Whitley-Williams requested that the list of stakeholder groups
include Hispanic, American Indian, and other minority physician
organizations. These groups may not have the same resources as AMA and
will not always be able to send a representative, but there should be
some outreach to those groups. She also noted the absence of national
nursing organizations and of the Society for Adolescent Medicine. Though
adolescents may not be a priority group, this would be consistent with
other NVAC initiatives. In response to the influenza issue, she asked if
the state health departments were required to submit at least an initial
plan for pandemic influenza preparedness?

Dr. Schwartz explained that the CDC bioterrorism grant program guidance
to the state health departments has completion of a plan as one of its
critical benchmarks for this fiscal year. All states will be expected to
have a plan by the end of September. Today, there is a regional meeting
that CDC had organized with Western states to help communicate the
issues that surround the plan's development. Regional meetings that
include all of the states will be held over the next few months.

Dr. Whitley-Williams noted that they are discussing revisions to the
plan. If states are already in the process of developing their own
plans, she is concerned about the timing and the resources at the state
level to adjust to the changes. It sounds like some of these changes may
be incorporated into these regional meetings.

Dr. Schwartz commented that pandemic preparedness will inevitably
continue to change. As they learn more, they are likely to make new and
changed recommendations.

Dr. Johnson noted that several public health organizations are on the
stakeholder list, and APHL should also be included since they will play
an important role.

Ms. Koslap-Petraco suggested adding pharmacists to the list as well. In
some states, pharmacists can vaccinate.

Dr. Schwartz thanked the members for their suggestions, and they will
consider all of these organizations. They need to balance the size with
comprehensiveness and recognize that there are many relevant groups.

Dr. Black suggested that logistically it might make sense to have a
small core group and to do outreach to other groups once they have an
initial plan and test it with stakeholders.

Dr. Raymond noted that the biggest group they do not have on the list is
the American Public Health Association (APHA). They represent a lot of
organizations that are not otherwise represented. He agrees with the
other suggestions but this one is critical. Representing the state
health officers, Dr Raymond then shared that many states already have
basic guidelines that were developed several years ago. The plans,
however, do not have enough in them. One concern with working with Dr.
Hinman's subcommittee is that they will move forward, put down their
priority list for vaccines and antivirals, go through the political heat
of getting it approved, and then, get the priority list 3 months later
from CDC. It is very important for the states, not so much to have the
specifics, but to have more in the national plan. He is happy to
continue working with Dr. Hinman on the subcommittee, noting that it
prevents problems with the states.

Dr. Young seconded the suggestion to include the nursing profession. If
they are defining priority groups, there are groups within the nursing
profession that will be different priorities.

Dr. Schwartz shared that he wants to include a nursing group and
suggested discussing which group to include with Dr. Young and Ms.
Koslap-Petraco.

Dr. Gellin asked how the pandemic influenza working group was organized
in Canada.

Dr. Schwartz explained that they have a Pandemic Influenza Committee
composed of representatives from the Public Health Agency of Canada and
each province and territory. The Canadian system is much more
decentralized than in the U.S. system. Canada also has working groups
that deal with specific issues such as vaccine and antiviral drugs, and
those groups are more broadly constituted, including representatives of
stakeholder organizations. Dr. Schwartz is a member of the Antiviral
Working Group and after participating in a number of meetings, thinks
they have done an excellent job of defining priorities, antiviral use
strategies, and specific priorities groups, such as essential service
providers and healthcare providers. They get into the specifics of who
would be in those groups. The Canadians have set up this model, and they
will be replicating it to some extent in the United States.

Dr. Johnson noted that they seem to have received many comments on the
plan. He asked what the process is now for posting and responding to
comments and what the timeline is.

Dr. Schwartz explained that the key issue is to review the comments with
a broader group and to see how the comments contribute to plan revisions
or subgroup discussions. They have reviewed the comments internally, and
many are relatively non-specific. They say things like they need more
guidance, rather than suggesting a particular action or set of
priorities. In part, forming this group and addressing those issues are
a response to the comments. Some comments suggest a particular approach
to an issue, and those comments will be considered in this process as
further decisions and revisions to the plan are made.

Dr. Johnson asked if they had an obligation to post the comments
publicly.

Sarah Landry replied yes, since they were part of a public comment
period. It has taken a while to finish pulling the comments together.
They will be posted on the website in the next month.

**Discussion of Proposed Resolutions**

Dr. Helms brought up business from the previous day. Two resolutions
were seconded and on the table for discussion and a vote. The committee
had waited for the final vote to make sure NVPO resources were available
and Dr. Gellin could provide input; Dr. Gellin was in and out of the
meeting at the time they were prepared. Both Dr. Schaffner and Dr.
Hinman wrote the resolutions up in more detail.

Dr. Whitley-Williams asked Dr. Schaffner, regarding his resolution for
an annual NVAC review of the previous influenza season, for
clarification of the timing; would it be presented at the June NVAC
meeting and then delivered, or will it be delivered to the Assistant
Secretary before the full NVAC meets in June?

Dr. Schaffner explained that he intended to say that the report would be
ready for the June NVAC meeting, and perhaps the resolution should read:
it will be delivered "subsequently" to the Assistant Secretary and other
interested parties.

Dr. Gellin noted that it would be a sprint to the finish line for
delivery of the first report. The goal would be to have it discussed and
presented to the Assistant Secretary at the NVAC meeting and then to
have subsequent discussion and revisions. As the flu season winds down,
they can take advantage sooner than later of the lessons learned to
package them for that kind of a timeframe.

Dr. Schaffner confirmed that this was the spirit of his intention.

Dr. Hinman proposed slightly amended wording to last sentence to say,
"The results should be presented at the annual June meeting of NVAC and
should subsequently be delivered to the Assistant Secretary for Health."

Dr. Helms called for a vote on amendment to the first resolution, and
all voted in favor. Dr. Helms asked if there were any other amendments,
and no one responded.

ACTION: Dr. Helms called a vote for the first resolution, and all voted
in favor.

RESOLUTION: The NVAC directs the NVPO to conduct a critical
comprehensive after-action report of all aspects of each year's national
influenza vaccination program. This report should include, but not be
limited to, assessments by the CDC, ASTHO, CSTE, the ACIP, vaccine
manufacturers, the National Influenza Vaccine Summit and representatives
of providers and the public. Lessons learned as well as items for
improvement should be featured. The results should be completed before
the annual June meeting of the NVAC and should be subsequently delivered
to the Assistant Secretary for Health and interested parties

Dr. Helms then moved the discussion to the second resolution, regarding
vaccine supply and global harmonization.

Dr. Gellin noted that Dr. Baylor is not at the meeting, and he wanted to
make sure they discuss this with him.

Dr. Hinman explained that the motion was intended to address the
specific regulatory and legislative barriers to introducing vaccines
licensed for use in other industrialized countries into the United
States. There could be other barriers as to why the vaccines are not
here, such as market reasons. He offered to delay consideration of the
resolution until Dr. Baylor is in the meeting this afternoon.

Dr. Black explained that the proposed resolution addresses specific
situations where vaccines have widespread use, such as with the flu
vaccine, where a manufacturer has given millions of doses and a safety
profile is available. There are specific contingencies in this country
where it might be desirable to introduce such a vaccine. He noted that
Dr. Rodewald discussed the current IND mechanism, which Dr. Black thinks
is awkward, if not impossible, to do. It might be necessary to come up
with another means of provisional licensure or other situation, which he
recalls Dr. Baylor saying would require legislative change. The
resolution was not developed in the context of generically introducing
vaccine, but if there were a designation by the Secretary or someone
else about a specific need, there might be a mechanism available through
legislative means that would allow a third pathway that did not have all
of the IND requirements or blanket introduction. The resolution suggests
that the committee could explore what the requirements might be for
doing this and possible mechanisms for surveillance and other activities
that might take place.

Dr. Helms noted the importance of this resolution and suggested they
wait for Dr. Baylor's arrival.

**NVAC Working Group on Public Participation -- *Ruth Katz***

Ms. Katz noted that there was a long discussion in October about the
working group's activities, and they were charged to move forward. The
working group has been collaborating with Deliberative Democracy
Consortium (DDC) to develop a strategy to engage the public in vaccine
policy discussions and decision-making. DDC is a collaboration of
practitioners and scholars from the United States and around the world
whose goal is to promote the citizen voice in government
decision-making.

Since the last NVAC meeting, the working group has convened a conference
call with a distinguished group of vaccine experts, both inside and
outside of government, and representatives of DDC to discuss criteria
for selecting appropriate topics for discussion and debate through a
public engagement process. Some criteria they discussed to determine
appropriate topics included: clarity about what is expected from
whomever participates from the public; how individual comments from the
public will be used; and plain messages. From their conversations with
DDC, they also learned the importance of choosing a topic that will 1)
appeal to people they want to engage---topics those individuals would
feel invested in and 2) be presented understandably and impartially.

Based on these and related guidelines, conference call participants
discussed two potential areas for public engagement review. One was the
broad area of adolescent vaccines. With a number of recommendations for
vaccines for adolescents under consideration, many people thought this
might be an appropriate topic to try to engage the parents of
adolescents on their views on which vaccines and what the risks may be.
Although, Ms. Katz noted the upcoming meeting on strengthening the
delivery of vaccines for adolescents; even if they decide this is the
right topic, she is not sure if the timing would work.

A second issue discussed was vaccines and risk communication in general.
The specific issues were: finding out what the public regards as
acceptable risk; how that might be communicated to those taking the
vaccine and their families, and the possibility of asking relevant
questions in the context of three different vaccines (polio, pertussis,
and chicken pox) based on the varied perceptions of the risk involved in
contracting these diseases. People may be willing to risk more if the
risk is getting polio versus chicken pox. Chicken pox is not
traditionally seen being as serious as polio. Focusing on one vaccine
tends to result lightening rod responses from people. If questions they
raise relate to risk and risk communication across a broad spectrum,
they might learn more.

Today, Ms. Katz hoped to get NVAC's thoughts on these two and other
topics they would like the working group to consider. The working group
will continue their discussions, and once they identify a potential
study question, they will then work with DDC to identify the best public
discussion strategy to examine the question. They will bring both parts
of the recommendation back to the full committee for final review,
recommendation, and consideration of how to proceed.

**Discussion**

Dr. Hinman suggested considering prioritization issues around which
groups should receive influenza vaccine during a pandemic, an issue that
the Pandemic Influenza Working Group is trying to address.

Ms. Katz explained that they discussed this question. In light of what
was happening with the current flu vaccine, there was some concern that
because CDC had come out with a list of priorities and people might be
too influenced by what was happening.

Dr. Hinman agreed this could be the case. However, the prioritization
that was done this year was among high-risk groups---people who are
individually at risk. During a pandemic, prioritizing people who keep
society moving rather than those who are at greatest risk of dying of
influenza is likely. Substantial public discussion on a topic would be
useful.

Dr. Evans explained that his general understanding with the VPACE
project is that some money was made available. A small subgroup is
trying to determine what would be the three best possible approaches for
funding, timing, and other similar issues. The decisions are pending,
and he has not heard anything for the past couple of weeks.

Dr. Levin asked if pandemic flu was their target topic, and Dr. Evans
replied affirmatively. Ms. Katz asked if they have definitely settled on
this topic.

Dr. Evans replied, yes, clarifying that the topic will be how to
determine priority groups for a pandemic situation.

Dr. Levin commented that both topics are good. For the first topic, he
suggested including both the adolescents and their parents. With respect
to the second topic, they may want to consider a vaccine that is given
in childhood but where the major benefit is later on in life, such as
Hepatitis B or the HPV that is coming. They do not have a good handle on
this special question. They have been successful with Hepatitis B, but
it is a different animal.

**Insurance Coverage of Vaccines -- *Dr. Matthew Davis (University of
Michigan)***

Dr. Davis stated that this is an era of multiple vaccines. Currently, of
great opportunity to reduce children and adult risk to multiple
infectious agents. At the same time, employer-sponsored plans are the
dominant health insurance for children. There is also robust national
public health insurance for children, such as Medicaid and the State
Child Health Insurance Programs (SCHIP). Both childhood vaccination
efforts and health insurance have come of age, and while they share some
aims, their incentives are not aligned in some ways, which has caused
some tension.

According to 2003 Current Population Survey data 61 percent of children
under the age of 19 have some kind of private insurance, 27 percent have
public insurance, and 12 percent are uninsured. The uninsured number is
lower than usual due to the SCHIP program instituted in the late 1990s.
Considering the child vaccination schedule, the timing of a lot of
doses, and forthcoming adolescent recommendations, rates by age group
give some idea of where emphasis is need in insurance coverage work. For
infants less than 1 year old, over one-third have public insurance
coverage. Early pre-school children also have a higher ratio of public
insurance coverage than children overall. For school-aged children and
adolescents, emphasis will need to be on private health insurance
coverage to do a good job.

Within the Federal framework, both the Vaccines for Children Program
(VFC) and Section 317 grants make funds available for vaccine purchase.
VFC covers vaccine purchase for children who are uninsured, under
Medicaid, of Native American and Alaska Native backgrounds, and
underinsured (e.g., those in private plans). VFC vaccine must be
provided in federally qualified or rural health centers. A dwindling
number of states also contribute their own funds for vaccine purchase
and system infrastructure. Section 317 Federal funds can also be used
for system infrastructure.

The vision and generosity of these public programs are threatened by a
couple of challenges. First, in the current economic climate where
states are struggling to balance their budgets in a period of lower than
average revenues, it is highly likely that patient access to
Medicaid/VFC providers who stock public vaccine has been decreasing. All
states at one time or another over the last 2 to 3 years have either
frozen and/or decreased reimbursement to providers.

In addition, funding for public-sector vaccine purchase is threatened by
rising vaccine costs caused by increasing numbers of recommended
vaccines and comparatively higher costs of newer vaccines. As was
discussed earlier in the NVAC meeting, it is not so much that today's
new vaccines are expensive; yesterday's vaccines were remarkably
inexpensive. State immunization program managers have also found
difficulties in the timing of new recommendations vis-à-vis their state
government budget cycles. States cannot budget in anticipation of a new
ACIP recommendation. Underinsurance in private health plans. According
to the most recent IOM Vaccine Financing Report (2004), this problem
affects upward of 10 percent of all child enrollees in private plans or
approximately 5 million children. This is about half as many as the
uninsured.

They have found that underinsurance promotes fragmentation of care
because private doctors are referring underinsured children to local
health departments to get their VFC-provided vaccine. Parents are
puzzled that underinsurance exists and do not understand why insurance
plans are not supporting what is perceived as a standard of care, since
there is a set of recommendations on what vaccines children should and
should not get.

Traditionally, private insurance plans emphasize coverage of therapeutic
benefits, especially benefits related to unexpected and catastrophic
events. The advent and growth of managed care in the 1980s and into the
early 1990s initially increased the likelihood of preventive services
coverage in average plans available to employees. However, there was a
managed care backlash from consumers and employers, to some extent,
which led to a return to plans with fewer restrictions to access and
more emphasis on catastrophic versus preventive coverage. At the same
time, there has been a failure to control dramatic rises in health care
costs, which has led to other innovations designed to constrain growth
in healthcare costs such as the implementation of preventive care caps.
In looking at a national sample of health plans, about one-fourth of
enrollees in private health plans are facing these caps, which typically
limit coverage for vaccines.

There is another new trend with consumer-driven health plans (CDHPs). In
general, CDHPs are high-deductible health plans in which an individual
employee is at risk for the first \$1,000 or more of their healthcare
expenditures in a given year. The employer and employee pay a lower
premium. The idea is that employees will act more "wisely" once they
experience the actual cost of medical care. An offset to the risk with
the first \$1,000 is health savings accounts (HSAs). These are
opportunities for employees to set aside money in an account dedicated
to healthcare costs. The employee can draw form the account when paying
their annual deductible. About 20 percent of U.S. employees are enrolled
in these plans today. There are unclear implications for vaccinations
and uptake among families enrolled in these plans.

Regulatory factors include legislative mandates for children's vaccines
and VFC provision for underinsured children. Over half of all U.S.
states have some form of legislative mandate that compels insurance
plans operating in those states to cover recommended vaccines for
children. Those state mandates are limited, however, because of a
Federal statute that essentially exempts "self-insured" health plans.
The Federal statute Employee Retirement Income Security Act (ERISA,
1974) exempts all self-insured plans from state insurance mandates. Even
though 30 state legislatures have implemented a mandate for children's
vaccines, about 50 percent of employees in these states will be in
exempt plans. More than 50 percent of U.S. employees are enrolled in
such plans today. The number of child dependents enrolled is not known.
Self-insured plans typically have more of a traditional indemnity focus
and, consequently, a greater focus on catastrophic versus preventive
coverage.

There is concern that parents who might face a partial charge for a
vaccine might opt to go to a rural or federally qualified health center
to get a free public sector vaccine. This shifts the cost burden from
the private sector to the public sector program.

1.  There were three findings about the benefit decisions of
    self-insuring employers. First, employers commonly noted that they
    have inadequate information about short-term return on investment
    for newly recommended vaccines.

2.  New vaccine recommendations contrast with other benefit
    considerations, typically in the form of therapeutic benefits that
    are more expensive.

3.  Employers say that employee preferences are essential to benefits
    design. The question is, what *are* employees' demands about
    children's vaccines?

There are three promising opportunities to addressing these challenges
on which NVAC could comment: parents' demand for childhood vaccine
coverage, employers' "buy-in" for newly recommended vaccines, and the
unknown effects of current trends in health plan benefit design.

-   To induce greater parent demand for childhood vaccines, their
    options fall into the categories of "carrots" and "sticks." For
    carrots, it is possible to design more intensive information
    campaigns targeting parents about benefits of new vaccines. Daycare
    and school entry requirements, which have been associated with
    higher vaccination rates across multiple vaccines, is in the sticks
    category.

-   With employers' "buy-in" for childhood vaccines, there is an
    opportunity to acknowledge and target their economic interests and
    change the dynamic around underinsurance for children. More broadly,
    what are employers' incentives to design benefit plans that
    prioritize prevention for children?

-   Finally, related to underinsurance, current health plan design
    trends have uncertain effects on children's immunization rates. Is
    the financing structure---the risk families are seeing in terms of
    dollars spent upfront---influencing the family's decision-making on
    immunization for their children.

In conclusion, insurance coverage is likely an influential factor in
under vaccination for U.S. children. For the uninsured and publicly
insured, recent economic trends have limited access to care and VFC
providers in the context of constrained public funds. For the privately
underinsured where the benefit coverage not in step with latest
recommendations, there are several challenges related to benefit design
and regulatory mechanisms that may not be working as optimally as they
would hope.

In trying to address underinsurance, there are several opportunities
that fall into three categories: parents/employees, employers'
decision-making with good data that speaks their language and takes
their incentives into account, and effects of new plan benefits and
payment designs.

**Discussion**

Dr. Black commented that the presentation was both wonderful and scary.
He shared that the group he represents, America's Health Insurance
Plans, does not have a policy or position vis-à-vis first dollar
coverage or insurance coverage for vaccines. Within Kaiser Permanente,
his employer, which has had first dollar coverage for 58 years for all
ACIP-recommended vaccines, there are discussion for the first time about
copays and caps for vaccines because of competition and other available
plans. The other trend is that things that used to have either first
dollar coverage or very low copays---such as hospitalization, emergency
room visits, or CT scans---have copays that run up to \$1,000 or more.
If the trend in that area branches out, which seems to be the case based
on Dr. Davis' presentation, the whole nature of private insurance
coverage for vaccines could change. Within their own program, it would
dramatically change their ability to manage immunizations. If
immunizations start to be given both inside and outside the system, they
would not be aware of several of them. A lot of the progress made using
automated systems to raise immunization rates would go by the wayside.

Dr. Schaffner commented that this was the best exposition on the issue
he has heard and asked if universal purchase states influence private
insurance coverage of vaccines.

In their work with immunization program managers, it seems that not all
states were already up to speed in covering Prevnar one year after ACIP
recommendations. Optimally, in a universal purchase state, once the
public program has had a chance to incorporate the cost of a new vaccine
in its budget, it is possible that the universal purchase approach would
offset these private plan problems with underinsurance.

Dr. Freed added that the number of universal purchase states is
shrinking because of the increased cost associated with new vaccines.
Whereas, there may have been 14 to 16, they are down to 8 or 9 states.

Dr. Hinman noted that there are two-tier universal purchase
states---states that are universal purchase for everything but Prevnar.

Dr. Johnson commented that the extent of self-insurance is impressive.
If they take the 50 percent of employees and applied that to the number
of children who have private insurance, they would be looking at 25 to
30 percent who have private insurance through a self-insurance mechanism
(their parents' employers). He asked if they were seeing a nexus of
self-insurance with caps with high deductibles in these kinds of plans.

Dr. Davis explained that the same national trends with implementing cost
containment mechanisms (preventive care caps and consumer-driven health
plans with high deductibles) are appearing in the fully insured
company-provided plans and in the self-insured plans.

Dr. Black commented that as the disparity grows with self-insured plans
referring people to VFC, it incites more medium and large companies to
move in that direction. This is troubling to health plans because large
clients subsidize the smaller clients with an intrinsically large cost,
so the exit of large companies increases the disparity.

Dr. Hinman noted three slides at the end in the handout. He suggested
Dr. Davis speak to these slides and discuss possible solutions.

Dr. Davis noted that he is interested in the idea of inducing parental
demand and asking the question, are parents really going to prioritize
coverage of their child with the newer vaccines? How do they perceive
it, and what is their inclination to pay more to get these vaccines? He
is troubled by the usual approach in the literature that uses the
question of willingness to pay the full cost of vaccine, rather than the
more typical route---even in this age of consumer-driven health
plans---where someone would pay a slightly higher premium for an
expanded benefit package. They asked a national sample of adults through
an internet-based survey, would you pay a higher premium in order to get
access to any newly recommended vaccine as soon as it was recommended?
They used the actuarial value of \$3 more per month to assure coverage
of any newly recommended vaccine in the next year.

Dr. Davis explained that an internet-based mechanism called Knowledge
Network, which was set up by Harris Polling and used a national
representative sample of adults in the United States. A hypothetical
scenario was offered in which people were employed and had a choice of
health plans that were identical except for the vaccine coverage. These
individuals were asked if they would pay \$3 more per month knowing that
there might not be any newly recommended vaccines. The sample was
stratified in half by those in households with children under 18 years
old and those without children. Seventy-nine percent of parents with
children in their household were willing to bear higher premiums in
advance to assure coverage of new vaccines. The reviewers for this
project were surprised that the amount of money was so low. However, the
cost of vaccine would be spread over a year, and vaccines do not cost
very much compared to the other things covered. Twenty percent would not
take the chance, and of those people, half said they would pay at least
\$50 for a vaccine series if it were recommended by their doctor, even
though it was not covered in their plan. This raises some questions. Is
this "betting on the future" plan feasible? It is in era of
consumer-driven health plans. More importantly, will employees indicate
they want coverage like this? Again, where do vaccines fall on parents'
priority lists? This is an issue of prioritizing adolescent vaccines
among other adolescent services, as well as for adults. It is a
challenge to get adults to prioritize vaccines among other preventive
services.

Dr. Hinman noted that these findings suggest that benefits negotiators
are an important target audience. The possibility of new vaccines in the
coming year is not something parents would necessarily think about
themselves. There are a finite number of benefits negotiators who could
be approached about what the prospects for vaccines look like. They
could then make a presentation to the negotiators and union or employee
representatives as to whether this would be a good thing for them to
try.

Ms. Katz asked if they looked at the delivery cost of vaccine if only 75
percent bought into this. If the numbers vary greatly, the cost of
delivering the vaccine might exceed what is expected when the whole
group participated. If the number were 30 or 25 percent, the cost of
delivering the vaccine would be higher than if you had 80 percent
participation.

Dr. Davis explained that they set this up so that they would expect
parents to seek that vaccine in private doctor offices where the doctor
would handle the procurement.

Ms. Katz asked what would happen if only two families in a private
physician's office chose to participate. The cost of delivering the
vaccine for that physician would go up as opposed to a situation where
every child in the practice participated.

Dr. Davis agreed. The dynamic exists today and would exist in this plan
as well. Whatever the interest is going to be in adopting a new vaccine
in the public and by providers will affect providers' behavior overall.

Dr. Johnson asked for clarification. If the plan were to assess members'
willingness to pay this extra premium, this would go across all of its
members, not just across those who thought it would be a good idea.

Dr. Davis explained that they should imagine this as the menu of plans
available in open enrollment. If employers see that only 2 percent of
employees select a particular plan, they will not offer it in future
because it does not make sense administratively. They designed the study
to examine what the level of parental demand is for new vaccines, and it
appears to be robust.

Dr. Black asked about the stratified sample. He asked for the percentage
of employees across the country with children at risk of vaccination.
Currently, most immunizations are given in the first year of life, which
is a very narrow age band demographically. Only 15 or 20 percent of
total employees might require this. Eighty percent of this group is a
small number.

Dr. Davis acknowledged that this is a fair critique and part of a larger
discussion. They also looked at demand for adult vaccines and had
similar findings. They would expect this to be applied at the employer
level across child and adult vaccinations.

**Polio Eradication and U.S. and Global Vaccine Stockpiles -- *Dr.
Stephen Cochi (CDC)***

The purpose of the presentation was to keep NVAC informed of key
decisions and progress toward polio eradication and to get NVAC's
support for:

-   U.S. participation in the global stockpile and for response and
    access to the monovalent OPV (mOPV) stockpiles, which WHO plans to
    create as part of the global stockpile;

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-   WHO efforts to stop proliferation of wild polioviruses for IPV
    production. Developing country manufacturers are interested in the
    possibility of entering the IPV production market, whether or not
    for safety reasons it is desirable in a post-polio eradication
    environment. There is also a program to assess safety and efficacy
    of Sabin-IPV, which uses Sabin polio virus strains to create IPV;
    and

-   an Institute of Medicine (IOM) meeting to examine development of
    antiviral agents effective against polioviruses in a
    post-eradication environment.

Cases of polio were reduced from 350,000 cases in 1988 to just over
1,000 by 2004. There are six endemic countries. Nigeria's decision to
stop using OPV in the summer of 2003 for a 12-month period resulted in
polio spreading to 11 countries in West and Central Africa and
importations as far away as Saudi Arabia.

The endemic countries in South Asia are Pakistan, Afghanistan, and
India. Good progress has been made with localization of continuing
poliovirus transmission in relatively small geographic areas. In
Pakistan, most of the remaining cases can be found in two of four
provinces, Sindh and southern Punjab Provinces. Only four wild virus
cases were reported from all of Afghanistan, which is a very focal
transmission. In India, the continuing poliovirus transmission is
limited almost entirely to two areas of Northern India, Western Uttar
Pradesh and the Bihar state.

The last vestiges of poliovirus are in settings with high population
density and poor sanitation, resulting in very high force of infection
and basic reproductive rate and tenacious viral transmission. This
creates the biggest challenges for the program. Public health workers
and staff are also fatigued from doing multiple rounds of supplementary
immunization year after year. In response to these last vestiges, one
new measure will be implemented as early as May or June 2005.

In India and Egypt, where only Type 1 has been circulating, the plan is
to intensify activities and add Type 1 monovalent OPV (mOPV1) to stop
polio during the 2005 low season. The pursuit of mOPV1 is the first step
that WHO is taking to establish a global stockpile of mOPV. In Africa,
the situation may likely take substantially longer than in India and
Egypt. Rapid progress is possible, if the quality of the National
Immunization Day improves and it is sustained and if they continue these
large-scale, synchronized activities that began last fall and continue
this spring.

In terms of the post-OPV cessation policies and products, it is has
become a well-established WHO priority to not only eradicate the wild
poliovirus but also cease the use of oral polio vaccine. A number of
policies and strategies have been put in place to manage the risk of
paralytic disease caused by any poliovirus, including the
vaccine-derived viruses.

There have been recent polio outbreaks due to circulating
vaccine-derived polioviruses (cVDPVs), which is the basis for the
revised WHO strategies and plans. Egypt was a historical documentation
of cVDPV outbreak. In addition, there are very rare instances of immune
deficient vaccine-derived poliovirus (iVDPVs) chronic excretors. In just
over 40 years of OPV use, 24 such individuals have been documented,
including 22 long-term excretors or people who excreted for a period of
more than 6 months. There are only two long-term excretors currently
alive and still excreting the virus. This is a rare phenomena but one
that speaks to the issue of whether they should be developing antiviral
agents that might be able to clear these infections. The countries of
origin for these individuals are almost all industrialized countries.

The risks of paralytic polio after eradication include the ongoing risk
of vaccine-associated polio, which they estimate with current OPV use to
be an annual global burden of 250 to 500 cases per year. This is a
compelling reason to cease OPV use in a post-eradication environment.
The rare instances of iVDPV cases are less than one per year, and over
time, this incidence will likely decrease as OPV use continues to
decrease. The cVDPV risk frequency is approximately one outbreak per
year and an annual burden of about 10 cases. It is uncertain whether
this will be stable or increase over time, particularly in an
environment where there is no polio and maintaining high coverage with
polio vaccine becomes increasingly difficult.

After interruption of wild poliovirus, continued use of OPV will
compromise the goal of a polio-free world. This is the consensus view
first articulated at an expert consultation in Geneva on vaccine-derived
polioviruses in September 2003 and then reaffirmed the following year by
the Advisory Committee on Polio Eradication that advises WHO. The
decision was also a result of the original expectation of countries and
stakeholders when the global initiative was launched in 1988. There are
also high opportunity and financial costs of continued OPV use.

It is also important to put in place a series of prerequisites for OPV
cessation:

-   Appropriate containment of *[all]{.underline}* polioviruses
    (laboratory containment).

-   Global surveillance and notification capacity, which is currently
    very strong.

-   Establishment of a mOPV stockpile and a response mechanism in the
    unlikely event of the circulation of the poliovirus.

-   Coordinated cessation of OPV so that one country does not stop using
    it while an adjoining country continues to use it, creating
    transmission of the vaccine-derived viruses across borders.

-   \"Post OPV\" immunization policy in place before cessation occurs.

Most countries in the world continue to use OPV, which has implications
in terms of recommendations for possible shifting from OPV to IPV in a
setting where there is still wild poliovirus transmission in parts of
the world. In 2003, WHO released a position statement with IPV
guidelines. A major factor influencing WHO's guidance on whether or not
to change to IPV, was countries' assessed risk of importation due to
circulation of wild polioviruses in their geographic area or based on
migration patterns. Vaccination coverage was another factor. WHO
recommends not moving to IPV if a country is not able to achieve and
sustain very high coverage.

The WHO is examining the possibility of pursuing antiviral agents
because of rare instances of chronic excretion. It would be available
for post-exposure prophylaxis in a post-eradication environment and as
an option for outbreak control, vis-à-vis what is being pursued for
pandemic influenza preparedness.

There is also work to assess the possible use of Sabin-IPV to facilitate
poliovirus containment, since manufacturers currently use wild
poliovirus strains to produce IPV. If Sabin-IPV became feasible, then it
would serve as a \"warm-base\" for the restart of OPV production in the
event of reintroduction.

In conclusion, OPV cessation is a prerequisite for maintaining
eradication. Required elements are good poliovirus detection and
notification, development of a stockpile and an emergency response plan,
long-term containment of polioviruses, and national immunization
policies that are clear about whether a country has agreed to stop using
all poliovirus vaccines or has a preference of changing to IPV.

***Dr. Jim Alexander (CDC)***

This presentation provided updates on the U.S. OPV cessation period and
on the year that has elapsed since the recommendations were made to
develop a vaccine stockpile.

With the decline of OPV doses through the transition to an all IPV
schedule, the United States has successfully eliminated the third form
of paralytic polio, vaccine-associated. One of the transition issues was
whether coverage would be maintained with the switch. Data from the 2002
NIS shows that high vaccination coverage for IPV is being maintained. In
a recent study by Rebecca Prevots and colleagues at NIP, children were
vaccinated with either IPV-OPV or all-OPV schedules, and there was still
high seroimmunity to all three serotypes.

In the current post-OPV cessation era in the United States, the risk of
paralytic polio probably remains from imported wild virus. Affected
groups would likely be under-vaccinated children in urban areas and
vaccine refusers in religious communities. The magnitude would be very
low but not zero.

Last year, the NVAC/ACIP report stated that the projected and
recommended 8 million dose IPV stockpile should be sufficient, either
used alone or with OPV, for outbreak control. The report also noted
ongoing need for licensed, uncombined IPV for this specific purpose.
This is distinct from the other purpose of the pediatric vaccine
stockpile - the bulge in the supply chain for routine immunization
purposes.

The United States has set aside funding for 8 million doses, but less
than 4 million doses are in storage should a polio outbreak occur.
Economic issues in the contractual arrangements impede the stockpile
from achieving 8-million dose capacity. Work can continue at NIP through
the pediatric vaccine stockpile mechanism to deal with these issues.
Maintaining target supply is going to be an issue that they need to
think about.

WHO is also moving forward to raise the biosafety level for wild type
vaccines used in IPV production. The United States will need to get
involved with global IPV production and stockpile issues as they relate
to biocontainment.

There is currently no licensed OPV product in the United States. Last
year, the Committee recommended access to and effective use of OPV in an
outbreak. Eight million doses (tOPV or each of the three mOPV serotypes)
were considered sufficient. The preferred type for the stockpile is
mOPV. The committee also addressed the need to develop a mechanism for
use either through an IND or emergency authorization. A collaboration
with WHO has happened in the last year. The issue for the United States
is whether there is a vaccine manufacturer willing to make OPV available
in this country. This requires an investment in time, effort, and money
to develop an IND. CDC can consider developing an IND, but they have
held off to see what happens with WHO and to take part in that effort.
As Dr. Cochi mentioned, sanofi pasteur has responded to the WHO request
to move rapidly toward mOPV1.

One of the issues that has been discussed extensively is the
harmonization of regulatory options. Now that WHO has made it clear that
sanofi pasteur is at least one of the interested manufacturers, the
United States has a manufacturer it can begin to work with and can work
with others that take a role in the global response.

A question for NVAC is whether they should proceed to a mOPV stockpile
without making an effort to create a tOPV stockpile. They are in the
process of exploring what sort of emergency response mechanisms to use,
whether it is an IND or other at this point.

One of the highlights from the last year has been global collaboration.
The NVAC/ACIP report recommended that CDC, FDA, WHO, and other
international partners finance, create, and maintain global polio
vaccine stockpile with guaranteed and immediate U.S. access. CDC and WHO
staff have collaborated over the last year, looking at stockpile issues
and outbreak response issues such as required stockpile size. CDC has
not collaborated much with FDA due to time constraint issues, but they
will collaborate on the regulatory issues and mechanisms for vaccine
use.

CDC has been supporting WHO efforts to rapidly license mOPV and develop
an mOPV stockpile. Some at NIP are more skeptical than their WHO
counterparts over whether Sabin-IPV addresses vaccine manufacturers'
poliovirus containment, but it is still the route for safety and
efficacy. They are actively collaborating to assess the potential use of
an antiviral drug and to determine appropriate global stockpile size,
composition, and regulation.

The committee also recommended developing polio outbreak response plans
in collaboration with state and local counterparts. That plan is being
drafted, and they plan to involve CSTE, NACCHO, and others in the
development this year.

In the post-eradication era, it is not sufficient for true polio
eradication to eliminate wild virus transmission; the risks of
polioviruses from any source must be minimized. For biocontainment,
there is hope that Sabin strains, if release inadvertently, will be less
likely to establish transmission. Whether these strains can be grown to
provide as an efficacious vaccine as wild type IPV is unknown. It is
also not known if these strains will maintain their attenuation type if
produced under conditions for IPV manufacture. WHO is evaluating these
issues. The issue for the IPV stockpile in the United States will be
whether they need to shift to a Sabin-IPV stockpile. At the moment, it
is only a potential product. If WHO moves ahead with the shifting
biocontainment issues to encourage manufacturers to shift from wild type
IPV to Sabin-IPV production, there will be licensing issues with
Sabin-IPV in the United States.

Currently, there is no licensed and effective antiviral for polio. An
antiviral could potentially serve two useful purposes: to eliminate
excretion in individuals with immunodeficiencies and to act as a
component of an outbreak response strategy. Over the last year, WHO and
CDC staff, laboratory scientists, and advocates for antivirals have been
working together to look at this process and wanted to bring this
process into wider consideration. Recently, Dr. Jafari sent a proposal
to the director of NAS for a meeting to consider the feasibility and
technical and regulatory issues for an effective polio antiviral drug.
Pleconaril showed that a caps inhibitor class of drugs has effectiveness
against enteroviruses and rhinoviruses. There is no particular drug that
has an affinity for the poliovirus, but several candidates may be
useful.

Bringing wider discussion of this issue through an NAS-sponsored meeting
would be helpful. Should they change their thinking from a polio vaccine
stockpile to a stockpile with both vaccines and antivirals? NVAC's
comments are invited on these issues.

In conclusion, their stockpile does not have the optimal size,
composition, and use. Even with the IPV stockpile, they have not moved
much from last year.

**Discussion**

Dr. Helms commented that he is more concerned this year than he was last
year with the potential funding difficulties with the inactivated
vaccine and the emerging movement to develop monovalent polio vaccine on
the outside. They have distance to go in the eradication effort,
although the progress is definable. The antivirals sound like they are
worth trying, but how do you get the momentum started?

Dr. Hinman supported the meeting to consider a polio antiviral agent. If
an antiviral could be developed, it would be an appropriate component of
the stockpile. If there were an outbreak, he doubted there would be any
uptake of an unlicensed OPV given under an IND in the United States.
They would be asking people to take an unlicensed vaccine that carries
some risk and is no more effective in providing protection than the
licensed product that carries no risk. He encouraged an examination of
antivirals and assuring an adequate supply of inactivated polio vaccine.

Dr. Levin asked if there were any good candidates for antivirals. He
knew about pleconaril, but are there others?

Dr. Alexander replied yes. Dr. Marc Collett, a laboratory scientist who
used to work for ViroPharma, the developer of pleconaril, was present
and could respond. There is a basic structure to these caps inhibitor
drugs for the rhinoviruses, enteroviruses, and polioviruses. There are
several that have good in-vitro activity against polioviruses. However,
their bio-availability is not good. There would have to be more adoption
to make them available. Then, there are safety and clinical efficacy
issues.

Dr. Collett added that issue is that no one has had any motivation to
optimize a pharmaceutical for polio. It can be done technologically, but
some incentive has to be created for someone to do it.

Dr. Schaffner asked how an antiviral might be used---in therapy or more
in contacts of people who have been shown to have poliomyelitis? Would
it be given to people who are presumably infected but healthy?

Dr. Alexander explained that there are two purposes. One would be
clinical treatment of the immunodeficients who are known chronic
excretors. Mark Pallansch in CDC's polio and antivirus lab has been
interested in this for years and has spoken to the American Society of
Immunology and Rheumatology. Immunologists and rheumatologists would be
interested in looking at their patient populations that are at high risk
for chronic excretion, but they are not interested until there is a
therapy. If there were such a drug available, they could elicit
involvement. This effort would be very focused since these individuals
would be under very specialized care. They could possibly improve
surveillance and double the number that Dr. Cochi shared; they could
eliminate the excretion and this potential source of poliovirus
circulation.

Dr. Alexander added that the other component is an outbreak response
strategy. For example, in a couple of years after polio eradication, the
wild virus might appear to be gone from India. In this scenario, OPV
would still be in use and immunization coverage falling when a
circulating vaccine-derived virus and an outbreak develop. Hopefully, at
that point, they would have a directed monovalent response to type 1 or
type 2. But that virus may also have its own circulation in the
community. If this were to occur, they would like to implement a ring
vaccination strategy, potentially using IPV and an antiviral drug to
limit the circulation of OPV used to stop the outbreak to the affected
region.

Dr. Overturf commented that in addition to trying to create incentives,
when they screen for drugs, they should screen for broad activity
against the whole gamut of related viruses. There was strong support
from the Pediatric Infectious Disease Society specifically for
pleconaril and for continuing to look for alternative treatments for
other enteroviruses. There may be incentives for manufacturers for other
viruses besides polio with the antivirals.

Dr. Curlin noted that while optimization of this polio drug is a
feasible strategy, they should not forget that it poses some real
problems to check the efficacy of a polio antiviral. It is not
necessarily easy to evaluate the drug when little wild polio exists.

Dr. Alexander agreed with Dr. Curlin, and this is part of the reason for
wanting a broader array of experts thinking about these issues and
raising these tough questions. Pleconaril made it through phase 3 trials
and was on the way to be licensed as an oral drug. However, they
identified some drug interactions because a very large oral dose had to
be given to get enough in the excretions to eliminate rhinoviruses. He
believes Scherring Plough has obtained the rights to pleconaril and has
developed a nasal spray variation. It looks like they might move forward
with it. In the nasal passages, there is good availability, less general
availability, and decreased problems.

Dr. Cochi explained that they wrote a letter to NAS to propose this
meeting. Dr. Ellie Ehrenfeld, a member of the academy and the WHO
Advisory Committee for Polio Eradication, is willing to serve as a focal
point for this effort. Getting a consensus endorsement that it is
desirable to proceed with the meeting on antivirals would be useful.

ACTION: A motion was made to endorse a meeting of the IOM to discuss the
feasibility and technical and regulatory issues for an effective polio
antiviral drug. The motion was seconded and all voted in favor the
resolution.

**[IND Influenza Vaccine Shortage Program]{.smallcaps}**

**-- *Dr. Stuart Nightingale -- Program Director (OPHEP)***

The IND Influenza Vaccine Shortage Program is a work in progress.
Although the program has not been used, but it may be a useful model for
enabling the use of the investigational new drug (IND) in the future. It
is also a model of interagency cooperation and collaboration. Because it
has not been used, some issues may only be clear once it has been.
Acceptability is a large issue; how will the public respond to the use
of IND products in this situation?

Dr. Nightingale would provide an overview of the program; Dr. Robin
Robinson would address the IND vaccine procurement process; Dr. Baylor
would discuss the FDA response to the vaccine shortage; and Dr. Melinda
Wharton would review the CDC plan for distribution and administration.
Then, Dr. Nightingale would review lessons learned.

The HHS Interagency IND Team was formed on October 11, 2004 when the
Assistant Secretary of Public Health and Emergency Preparedness, Stewart
Simonson, asked them to develop and implement a plan, if necessary, to
import influenza vaccines from foreign manufacturers for use under IND.
It was not until November when a final decision was made that the Chiron
vaccine would not be available. HHS took a multi-agency approach that
included a number of offices including: the Office of the Secretary,
CMS, HRSA, CDC, and FDA. The team held conference calls twice a week
throughout this time period.

They considered the options for availability of investigational products
at this scale (IND mechanisms, treatment IND, and emergency use
authorization). Some options were more limited than others. They decided
to develop an evolving plan for acquisition, distribution, and
administration of foreign influenza vaccine. This is very similar to
some of the contingency protocol approaches that are used for products
in the stockpile that are either unapproved or unlabeled. In addition,
they kept constant communication across HHS on these issues, which was
important.

There were many challenges in this situation. Timing and coordination
were extremely important because they used an evolving approach. They
had a target that they met, but it was late in the season. Purchase of
an IND product was a novel issue because a waiver is required. In
addition, determining how to inform the public and healthcare
professionals on the nature of influenza IND vaccine for use in a
shortage was a challenge. Any mention in the newspapers about
experimentation could threaten the program, though this did not come to
pass. There were coverage and reimbursement issues, and Medicare was
organized to cover the vaccine. Deciding on sites to administer IND
vaccine was an issue, which was dependent on the demand location and
other factors.

Agencies also had to make modifications to existing systems to
accommodate changes needed for IND vaccine administration and
monitoring, including adverse reaction reporting and monitoring.
Targeting and sequencing was another issue---how this would be used
vis-à-vis licensed product? This was all being done without knowing the
severity of the 2004-2005 flu season. The potential variations in ACIP
recommendations would also influence when and where IND vaccine would be
used.

In conclusion, Dr. Nightingale shared a schematic of the program to show
its different activities through different phases. The acquisition was
complicated and dependent on a lot of activities. Key questions related
to distribution systems were: How would IND vaccine be stored? How would
it be distributed? Where would it be distributed for administration---
community health clinics, state operated public health facilities, or
other approaches? They finally decided on a CRO-related activity.

**Procurement -- *Dr. Robin Robinson (OPHEP)***

The procurement process occurred in 4 or 5 weeks, rather than the
typical 6 months. First in the inquiry process was a step similar to an
RFI, except it was done in 2 weeks. They selected 14 international
influenza vaccine manufacturers that met several criteria established by
the Influenza IND Team. The manufacturers would, at a minimum, have the
capabilities to bring in a vaccine under an IND or another mechanism.
They developed an initial set of questions that quickly evolved into
absolute criteria:

-   Vaccine type, composition, and manufacturing stage.

-   Vaccine availability.

-   Manufacturer's interest.

-   Future vaccine production capabilities.

A JOFOC was established on October 22, 2004, identifying 14
manufacturers that were the only ones with the capability. On November
4, 2004, they issued an RFP (HHS2005-B-00355) that included the
following absolute criteria.

-   Independent organization, not an agent of a government.

-   Licensed influenza vaccine for human use in the country of origin.

-   Member of the WHO's list of pre-qualified vaccine manufacturers *or*
    subject to regulatory oversight by the government of countries in
    FDA's list (Section 802 of FDA Reform and Enhancement Act of 1996
    (21 U.S.C. 382).

-   Minimum availability of 500,000 doses of egg-based, trivalent
    inactivated influenza vaccine.

-   Vaccine composition compatible with WHO-recommended virus strains
    for the 2004-2005 influenza season in the Northern Hemisphere.

-   Submission of drug master files (DMF), licensing dossiers, and other
    documents for licensing.

-   Submission and maintenance of a special usage IND application.

-   Agreement to CDC IRB approval of IND clinical protocol.

-   Permission for FDA field inspections of manufacturing facilities.

-   Shipment of vaccine to a Strategic National Stockpile
    (SNS)-designated site through staged shipments no later than January
    15, 2005, unless otherwise arranged.

Two companies fulfilled all of these requirements. On December 10, 2004,
GSK was awarded a contract for 1.24 million doses of Fluarix influenza
vaccine with an option to purchase up to 3.4 million doses total. On
January 31, 2005, a contract was awarded to Berna Biotech for 0.25
million doses of Inflexal V influenza vaccine.

GSK vaccine shipped under normal GMP shipping protocols to validated
storage sites and the vaccine distributor, LHI. These vaccine
manufacturers were afforded limited product liability protection through
VCIP. SNS provided help with inspecting and accepting the vaccine
shipment and storage, and in the case of Berna, it was the project
officer.

**FDA Role -- Dr. Norman Baylor**

Once they were told that that Chiron's license had been suspended, FDA
dedicated a large number of staff to this issue and worked in close
collaboration with CDC, other parts of HHS, and the private sector to
explore all viable options to secure additional doses of influenza
vaccine. They worked with sanofi pasteur and MedImmune to secure
additional doses of U.S.-licensed vaccine. Sanofi pasteur increased
their doses to 58 million, and MedImmune increased theirs to 3 million
doses for a total of 61 million doses for the year. In addition, they
were able to rapidly identify suppliers of approximately 5 million doses
of additional vaccine that were licensed in other countries and could
potentially be used under an IND.

They received cooperation from several companies as well as with other
regulatory agencies such as the Paul Ehrlich Institute in Germany, the
Therapeutic Goods Administration in Australia, Swiss Medic, and Health
Canada. They immediately sent inspectors and scientists to manufacturing
facilities of potential IND sponsors to evaluate the manufacturing
processes. Coupled with these efforts, they inspected the facilities,
assessed the chain of custody and storage/transport conditions, and
obtained lot release from some of the foreign regulatory authorities. In
addition, they reviewed a large volume of manufacturing and clinical
data. All of these activities were done within weeks and resulted in the
potential use of approximately 4 million doses of vaccine from GSK and 1
million from Berna Biotech.

There were complications under an IND. For example, who will hold the
IND? In this situation, it was the manufacturer. Another issue is who
would be the principal investigator and how would it be arranged? CDC
played this role. There were also protocols such as the evaluation of
safety monitoring, as well as product labeling and cost recovery issues.

FDA has been doing everything possible to stimulate interested foreign
licensed manufacturers to provide or, where needed, develop safety and
efficacy data required to pursue U.S. licensure in the future. Where
appropriate, FDA has informed manufacturers of its willingness to
consider licensing approaches such as accelerated approval, where
licensure is based on a likely surrogate. The bar was not being lowered
to use this technique. In fact, going to accelerated approval requires
post-approval confirmatory studies that are clinical efficacy studies.
GSK has stated that it would use this approach and, with clinical
studies to be done by the National Institute of Virology and Infectious
Diseases, may be able to seek licensure under the accelerated approval
mechanism. GSK may be granted licensure in time for the 2005-2006
season.

Finally, FDA is currently assisting both Chiron and GSK to have
additional vaccine for next year.

**CDC Role -- *Dr. Melinda Wharton***

Dr. Wharton discussed plans for distribution and administration of
CDC-developed vaccine. An important part of CDC's proposal for vaccine
use under IND is the use of the CDC institutional review board (IRB) as
a national IRB. This would allow localities using vaccine under the IND
to use CDC IRB approval to meet FDA requirements for IRB review. The
rationale was that the actual scope of needed use could not be
determined. It was possible that vaccine would have to be used
nationally, and there could be great urgency to implement it. Therefore,
having an iterative process going through multiple local IRBs was not
feasible. The determination for use of the CDC IRB as a national IRB
included the statement, "Unless precluded by local law or institutional
policy, each local site may rely on CDC IRB to meet FDA requirements for
IRB review." The CDC IRB approved the protocols, including the consent
forms and patient recruitment messages. This became an iterative process
due to the evolving recommendations over the last few months.

To provide the capacity to meet IND requirements without a burdensome
process for public health, CDC contracted with LHI, a contract research
organization, to provide nationwide access to IND vaccine. LHI could
provide clinic sites in many locations around the country and licensed
physicians to serve as co-PIs or sub-investigators and other clinic
personnel to administer vaccine in compliance with IND conditions. LHI
were to administer vaccine in accordance with IND protocol, which
included assuring eligibility, obtaining informed consent, administering
one pre-filled dose IM, entering data into the vaccinee database, and
completing required paperwork.

The informed consent form is four pages long, and focus groups convened
in January 2005 found the form alarming. It raised questions not only
about receiving the proposed investigational influenza vaccine but any
vaccine again. In response to these concerns, the form was revised and
IRB approval obtained. This was an inherently difficult task, however.
For the future, this area requires careful thought and planning to
balance their efforts to make vaccine available to people who will
voluntarily accept it in a fully informed way. Signatures are also
required as part of IND protocol. A parent/guardian signature is
sufficient for children 3 to 13 years old. For those aged 14 to 17
years, signatures are required from both the vaccinee and
parent/guardian.

INDs are generally written to be congruent with ACIP recommendations at
a given time. Currently, the program is congruent with the January 3
interim recommendations. Under the IND, children under 3 years old are
excluded. The vaccines are licensed in their home countries for use in
these age groups. This was a decision made early because of the nature
of this particular vaccine shortage. Chiron vaccine is not licensed for
use in young children; CDC anticipated that supply for this age group
would be sufficient to meet pediatric demand. In addition, the GSK IND
product is in a .5 mil syringe without a mark for a .25 mil dose, so it
was not feasible for use for the pediatric population. As part of the
allocation plans, sanofi pasteur filled all pediatric orders.

There were also minor differences between the protocol and ACIP
recommendations for use in pregnant women. They tried to be consistent
with product labeling, which confined use among women in their first
trimester of pregnancy and among those with underlying high-risk
conditions.

For adverse events reporting under the IND, there is a requirement to
report serious adverse events as defined in a regulatory sense (those
that are life threatening or lead to hospitalization or death). The GSK
IND also requires reporting certain adverse reactions independent of
severity, including allergic reactions; vasculitis, with or without
renal involvement; thrombocytopenia; and certain neurologic disorders
(encephalomyelitis, neuritis, neuralgia, paresthesia, seizures,
Guillain-Barré syndrome).

In the patient information, there is a specific statement explaining
that certain adverse effects are expected, such as sore arms, minor
local reaction, and mild systemic symptoms. Those need not be reported
unless they meet the serious adverse events criteria.

Under the IND, the Vaccine Adverse Effects Reporting System (VAERS) is
the primary reporting system for adverse events among recipients of IND
vaccine. All vaccinees would be provided with a pre-printed VAERS form
containing vaccine information such as IND number, vaccine, and lot
number. Patients would also be given instructions for reporting unusual
or severe adverse events by mail, online, or by telephone, and
800-numbers would be available for patients and physicians with
questions.

Once a report is received by VAERS, it is forwarded in real time to both
the CDC medical reviewer and FDA. At the same time, CDC would forward
the information to the contract research organization and the CDC
medical monitor. It would also be provided in a timely manner to the CDC
Data Safety Monitoring Board and the sponsor.

They recruited a Data Safety Monitoring Board composed of five persons
knowledgeable about immunization. Should they need to use the vaccine,
the board would review program safety data periodically and make
recommendations regarding the continuation, modification, or termination
of the program. They would render individual expert opinions and report
to the sponsor and principal investigator, who would then report to FDA
and the CDC IRB.

They also developed a training approach in anticipation of implementing
the IND. An investigator's handbook and a training module have been
developed. Should they decide to implement nationally, the training
would probably be done via web cast. They could quickly provide
simultaneous training to clinic personnel at different sites and have a
mechanism in place to answer questions and collect feedback. The
training could be archived online, and a certification process could
allow people to go through the training and print out a certificate.

Given that the IND vaccine has not been used, there has been no vaccine
distribution to clinic sites. The training has been limited, but they
are ready to do it if necessary. Some members of LHI's Clinician
Information Line staff were trained on January 14, and LHI clinical
staff in six clinics in three to four states were trained today. Once
trained, they can complete FDA paperwork to become investigators on the
IND. At that point, requirements to ship vaccine to these sites will be
met.

There have been many challenges in this process, but none was more
challenging than communication. There are inherent difficulties in
dealing with use of a product under IND protocol. Legal and ethical
requirements exist to fully inform people that the product is not
licensed and is investigational, which raises questions in people's
minds about safety and acceptability. At the same time, they are
offering these products because of the importance of receiving influenza
vaccine, and last season, they were concerned about not having enough
vaccine. This is a delicate balance between fully informing people while
conveying the benefits of vaccination. The message was a difficult one
to develop, and they ended up with two documents, both of which were
cleared by CDC IRB, to address these issues: the informed consent form
and the recruitment messages. It is not enough to simply put up posters
announcing the availability of IND vaccine and encouraging vaccination.
Recruitment messages for potential IND participants have to be approved
by an IRB. To make these messages available without having to engage
local IRBs, they developed recruitment messages stating: CDC has
acquired flu vaccine from GSK, Germany; the vaccine will help ensure
that people at high risk will have access to flu vaccine; and people
should get the vaccine if they or people around them are at high risk
for serious problems from the flu. They also developed templates for
recruitment materials that would allow individual sites to add
information.

**Lessons Learned -- *Dr. Nightingale***

There are many lessons learned from the program so far, and although it
is too early for some lessons, they have a model for future use of IND
influenza vaccine under shortage conditions. The messaging challenge is
important; negative messages about experimentation in the media could
ruin a whole program. They need positive messages, while avoiding
comments that would be problematic. Unlike other IND treatment
situations, the product has widespread or global acceptance. They cannot
say what would happen with the approval process, but there was no time
to go through whole process given the cycles and necessities. There are
issues in this situation that are different from other IND uses in both
treatment or prevention situations.

Another lesson learned is that timing is critical. Efforts should be
completed early. That requires going through many parts of the scenario,
and they now have templates for future years.

**Discussion**

Dr. Black expressed some concern about IND vaccines. Though it has been
used in several countries, the safety surveillance of adverse events in
many of these countries is either nonexistent or not up to standards.
There have been cases where drugs were used in other countries and
adverse events were identified later. He is concerned about a tone of
underplaying that this is an IND drug or an experiment or that the
safety has not been demonstrated in this country. All of these
statements are true, which is why they are in the consent form and raise
people's alarm. He favors developing another pathway, but they do not
want to confuse people as to what the IND process is. There are articles
in newspapers about investigators being investigated and facing criminal
charges for misleading people to participate in trials. These
investigators were not clear with participants that it was research. If
something is done under an IND, it is by definition an unproven research
product. This may be a reason to try another mechanism. He does not want
to undermine the whole process to develop an expeditious means to bring
vaccine forward.

Dr. Black then asked Dr. Wharton about reporting adverse events through
VAERS. Normally, FDA expects that capturing adverse events is complete
or near complete, but they all know that there is underreporting. He
asked how this was going to be addressed.

Dr. Wharton explained that under some of the INDs they anticipated using
from CDC, FDA has been wiling to accept reporting via VAERS. This
undoubtedly results in less complete reporting compared to one in which
they have a clinical trial with active follow-up with every vaccinee.
They hope to pick up significant adverse events through the stimulated
passive reporting system being proposed. She noted that the FDA
perspective may be more critical.

Dr. Baylor commented that he understood Dr. Black's comments. They were
dealing with what was perceived as a potential critical emergency
situation in the country. They had to find a mechanism to locate and use
other vaccine sources. Some of the FDA activities were much more
extensive than what they normally do for a Phase I IND. While it was not
the same rigorous review that a licensing procedure would have, they
felt it was an adequate enough review to assure the American people that
these products could be used safely. They do not have another mechanism,
and he appreciated the comments about the need for one. The American
people can be assured that they evaluated these products the best they
could in the time available, and this was an emergency.

Dr. Young asked for a description of the targeted clinics for the
program and what populations they expected to reach.

Dr. Wharton explained that she cannot address the specific clinics, but
the contract research organization has national scope with established
fixed locations in many cities that provide patient care. It may be
predominantly in the occupational health arena, but she was not certain.
If there were demand in an area without a fixed clinic location, they
anticipated that the contractor would establish a temporary clinic
location, perhaps to be determined by the state or local health
department. The contractor would fully staff and equip the clinic so
that vaccine could be provided. They never got far enough into the
program to identify specific locations where clinics were needed.

Dr. Nightingale noted that this effort was done based on what they
needed to prepare now, but future approaches could be flexible. The
model could substitute different clinic sites. Another approach could be
to leave the site selection to the states and to use public health
clinics, for example. This

Ms. Koslap-Petraco commented that they seem to have invested a lot of
time and money into this program. She asked what data they have showing
that people would accept this.

Dr. Nightingale noted that CDC conducted some research. This is an issue
with the media, informed consent, and the state/local health officers'
views. He does not know the current situation, but handing out a CDC
form listing the risks and benefits of any vaccine had been standard
practice in the past. The difference would be whether or not people
signed it. The signing would be different, but the concept is that they
want to fully inform the person---whether it is in a formal way through
informed consent or a leaflet providing an explanation. They never
focused on some of these issues.

Ms. Koslap-Petraco shared that she knows they have to explain that it is
an IND. Their experience this year was that as soon as the reported
press that the United States was seeking IND vaccine from other
countries, they got nonstop calls from people asking for vaccine. The
number one question they asked was whether they would be getting the
experimental or regular one.

Dr. Black commented that they can educate people as part of the
consenting process. His major logistical concern is not whether people
are afraid, since they can explain the vaccine and have a brochure,
video, or other materials available. Rather, it is the time required
with a 4-page consent form. At most flu clinics, people come in and out
in a 2-minute process; this is not a 2-minute process. If it takes 15 to
30 minutes to do this, even if it is done with dedicated contract
personnel, he questioned how feasible it would be to use this existing
mechanism to vaccinate a substantial number of people---either because
they refuse based on fear or the logistics of going through the system.

Ms. Koslap-Petraco agreed. When they finally got vaccine, they
vaccinated 3,000 people in a day. Her biggest concern is that all people
need to hear is the word "experimental" to say they will take the risk
of not getting vaccinated, especially when there is a 4-page consent
form. They are very good at explaining things to people, but she does
not think they have enough data to spend this amount of money on
something when they do not know whether people will accept it.

Dr. Black shared that they have done experimental flu studies at their
site, and they get a 50 to 60 percent participation rate. This is good
for an experimental study but bad for a public health program since they
miss half of the people. The nurses for these studies think it is
successful if they enroll three or four people a day, which is another
problem.

Dr. Raymond noted that this is an issue of risk versus benefit. When
people were telling Ms. Koslap-Petraco that they did not want an
experimental drug, there was little influenza going around the country.
Last year in mid-December, if he had gotten IND vaccine for the children
for the Fujian strain, parents would have flocked to get it. He does not
know how they are going to take 15 minutes to explain the vaccine to
people. How are they going to do it for pandemic influenza when it will
be the same situation? People will be dying, and they will have a new
vaccine that has not been tested in human beings. They have to figure
out a way, which was done with smallpox a few years ago. They knew the
side effects of that vaccine, and people still came to get it. They
could bring 30 people into a room, have them watch a video, and get a
sign-off that they watched the video and had their questions answered.
They do not have to spend 15 minutes with people individually.

Dr. Helms commented that he is thankful that the IND team arrived at a
system to get vaccine onboard in the United States. It was important to
happen, and the team found a way to get it done. At the same time, as
they look at the program in retrospect, there probably is a better way
to achieve this. NVAC will think about how to do it in the future,
counting on those on the IND team to fill in any other gaps that might
occur in the interim. The program was critical and necessary and
important for the national endeavor.

**Rabies Vaccine Supply -- *Dr. Charles Rupprecht (CDC)***

Rabies is not a human contagion, but it is a common disease. All animals
are susceptible. They report more cases of rabid animals through passive
surveillance than any other country in the world. The disease is common,
and although most cases are caused by bites, they are still learning new
things in terms of how it can be transmitted and the repercussions. They
had the first organ transplantation case from an unrecognized donor in
2004. In addition, rabies is not one-to-one; it is episodic. Even a
single rabid animal can have dramatic consequences as they found out
from one suspect sheep at a petting zoo with over 600 exposures. Members
of public who are anxious to help also bring in infected stray animals
from Asia and other places. They are constantly contending with new
variants of the disease.

In addition, the virus is dynamic; it is an RNA virus with many
reservoirs, which continues to evolve. They know from molecular clocking
that this virus was here before Europeans brought more of it. They know
from little vignettes in time that viruses are spilling over and finding
new hosts. Rabies will continue to present challenges.

Currently, they are primarily examining rabies prophylaxis or treatment.
That is, most of the biologicals are used after a person is bitten. It
consists of wound care, immune globulin that has infiltrated in the
wound, and five doses of vaccine. They estimate approximately 20,000 to
40,000 annual people exposures the United States. Each event costs
approximately \$1,500 per person; this is just for the cost of the
biological and does not include time lost from work, administration, or
other costs.

They are also currently facing indigent care usage. These persons fall
into vacuum, and currently, CDC is being asked to work directly with the
state health departments to overcome some of these indigent situations
that are not currently covered. The 1999 ACIP recommendations are the
most current for human rabies prevention biologicals in the United
States. Three licensed vaccines are Human Diploid Cell Vaccine (HDCV),
Purified Chick Embryo Cell Vaccine (PCEC), and Rabies Vaccine Absorbed
(RVA), which was previously the only rabies vaccine produced in the
United States. However, RVA is no longer produced, so two biologicals
are available. There are also two manufacturers of immune globulins,
Bayrab and Imogam that are infiltrated at 20 IU/kg.

During an active year for rabies in the United States in 2004, they had
a voluntary recall by sanofi pasteur of the major vaccine, HDCV. The
recall immediately created a vacuum for the second manufacturer that was
not well prepared to meet the demand. This highlights drawbacks to
globalization and the vicarious nature of the market, as well as the
unpredictability and volatility of the disease itself. There were times
when it was difficult dealing with supply and demand and distribution at
the end of last year as the second manufacturer of PCEC vaccine was able
to fill that gap. The dilemma in 2005 is that they expected IMOVAX to be
back on market but it is not, though they have assurances that it will
be by the end of the year. They also have assurances from the PCEC
manufacturer that they should be able to fill the market left vacant
from the temporary issue with IMOVAX.

However, assurances are one thing and actualities are another. They have
considerable anxiety in the agency and in the public health community
about whether or not current supplies will meet demands. When there is a
vacuum created by one manufacturer, there are global ramifications, and
when that market niche opens, then the manufacturer supplying the United
States has to consider global needs. They also have to recognize
incentive. With only two global manufacturers for an orphan product,
there is no great incentive for anyone to produce a rabies vaccine
globally. In addition, without having a nationally produced vaccine,
given the endemic nature of the virus here, they have concerns.

They are currently considering rabies vaccine stockpiles with a 3 to 6
month order of magnitude, which includes approximately 50,000 doses if
models, support, and supplies can be found and recommended. In addition,
a manufacturer-managed portfolio stockpile could be used to fill a void
if a given lot is withdrawn or a given manufacturer decides to no longer
produce the biological. This addresses longer-range plans and how to
compel people to produce biologicals needed for a disease that has the
highest case fatality of any infectious disease. There are a variety of
other licensed products that exist but are not licensed in the United
States. Some are licensed for Canada or Europe, and these could be the
same or new vaccines that would need to be contended with using a
VAERS-like system, similar to an influenza-like IND model.

They also need a plan to resolve indigent concerns where people are not
covered by third-party payments. It is currently an onerous process to
ask providers or states to come up with verification or an affidavit
that says 1) the person was exposed and 2) there is no program covering
their needs to receive rabies vaccines. Often, recent immigrants are not
covered for biologicals, and there are language and cultural
difficulties.

They have also renewed discussions with FDA about how to resolve some of
the stockpile and IND issues, using influenza as a model. The situation
is complicated by the use of rabies immune globulins in addition to
vaccine. They have focused on rabies vaccine as their primary concern
because of the expected needs. Since they are not addressing immune
globulin supplies, they are only dealing with half of the problem. They
have been assured that immune globulin supplies are adequate, but they
have to look at this much more closely.

One of NVAC's mandates is not only to look at vaccine and supply issues,
but to also promote and advocate for new biologicals and research.
Rabies biologicals that are on the market are 40 years old in terms of
any paradigm shifts. Immune globulins using people for hyperimmune serum
is close to a century old in terms of the paradigm. The long-term
solution is to think about orphan products that are critically needed.
They need renewed advocacy for such research, such as monoclonal
antibodies as a potential alternative to immune globulin from a global
perspective. This is an issue that just HHS is grappling with. They had
an expert consultation with WHO last fall. They wanted to bring this to
NVAC's attention for their support and further discussions.

**Discussion**

Dr. Hinman noted that the presentation seemed to imply the need for a
lot of research for improved vaccines, but his recollection is that
existing human vaccines are 100 percent effective pre-exposure. Many
other vaccines that they continue to use are 40 years old or older and
work well. He asked Dr. Rupprecht for a better sense of why there is
particular urgency for improvements in rabies vaccine or immune globulin
compared to other vaccine preventable diseases or diseases for which
there is no vaccine.

Dr. Rupprecht replied that the way rabies vaccines are produced are
outmoded. Looking at the HDCV vaccine, the time from initiation to
production to final release is too long to meet emergency needs. While
it is debatable whether new rabies vaccine is needed, the developing
world cannot afford the vaccines they have now.

Dr. Clem Lewin commented from the perspective of Chiron Vaccines, the
second rabies vaccine manufacturer mentioned by Dr. Rupprecht and the
producer of RavaVert. With last year's supply issue, his understanding
was that Chiron was able to supply all of the needed doses for the
United States. There may have been a perception of short supply because,
in an effort to prevent panicked stockpiling, doses to the distributors
were limited to what they ordered previously. There was rationing put
into controlled distribution and very close collaboration between sanofi
pasteur, FDA, and CDC in discussing the issue and assuring the supply
was maintained. Chiron has been in discussions again about the supply
situation and will be able to supply the United States. They have also
been able to supply other markets in Europe. Outside of Europe, there
are other manufacturers in the developing world; Chiron, for example,
has a facility. With respect to indigents, he shares Dr. Rupprecht's
comments. Chiron instituted a program that provides vaccine to
indigents. It has become slightly more complicated over the last month
because of the vendor that was providing the services. They are in the
process of reorganizing the program. As Dr. Rupprecht stated, there is a
requirement to show that that the person needs the vaccine and is
indigent. It does not seem right in our society that they cannot provide
vaccine for a relatively small number of cases.

Dr. Rupprecht noted that they are putatively at least 11 genotypes of
virus that cause the disease. All of the rabies vaccines, both human and
veterinary, are based on a handful that do not cross-protect against
others. In fact, for new viruses that were discovered in Eurasia over
the last 2 years, there is little cross-protection. To say that there is
no need for rabies research or advocacy pales in comparison to the facts
about the emerging pathogens being found and the ease of their
translocation.

Dr. Helms noted that this is an example of where redundancy in the
system filled a gap and made a situation easier. They always worry and
ask if there is sufficient redundancy. What if both manufacturers went
down or there were only one manufacturer? It is a benefit to discuss
what went well.

Dr. Hinman suggested they no longer use the term, redundancy.
"Redundancy" has a pejorative connotation and they are discussing
multiple suppliers being able to assure continuing supply. Redundancy
suggests they have too many.

**Resolutions (continued)**

Dr. Helms revisited the resolutions brought forward by Dr. Hinman,
explaining that they elected to wait until Dr. Baylor had the
opportunity to engage in the discussion.

Dr. Baylor commented that he read the resolution and they have to be
careful. He asked what they want and are really asking for. It is good
to establish a working group to explore legislation, but what type of
legislation do they want? FDA's mandate is to assure that vaccines
undergo a review and are safe and effective. The resolution says, "to
explore the legislative and regulatory changes that would be required to
allow licensure of vaccines licensed for use in other industrialized
countries." They have to first understand how vaccines are licensed in
other industrialized countries, what kind of requirements are or have
been established in these countries, and if they are adequate to meet
the requirements of people in the United States. Or, do they want to go
to the extreme and say that since these vaccines have been licensed,
there is no need to review those vaccines at all? He asked for
clarification of what they would want FDA to examine in these types of
products.

Dr. Hinman explained that he was not trying to prejudge anything. U.S.
regulations have protected us well over the last century from when the
law was put in effect. There are other countries that also have good
regulatory mechanisms, but they are not the same as ours. However, if
they had an outbreak of poliomyelitis in the United States, for example,
and wanted to use OPV that has been administered in billions of doses,
they would have to bring it in under an IND. They would not be able to
grant it a license, which does not make a lot of sense. Similarly, there
are other vaccines that are comparable to those used in the United
States. Since NVAC is concerned about having single manufacturers for
many vaccines, the manufacturers have said that one of the impediments
to entering the U.S. marketplace is the requirement to redo a series of
clinical trials to meet slightly different requirements. There ought to
be a way to harmonize or align things so as not to create artificial,
unnecessary barriers to the importation of safe and effective vaccines.
He does not know what this would be, but he has talked to people at FDA
and elsewhere about this for 20 years and has not seen any major
progress. He was pleased to see from Dr. Baylor's presentation about
achievements with accelerated review and similar activities. Absent an
explicit approach, things will not change, and he would like to see some
action.

Dr. Black noted there are two issues being raised, and they need to be
separated. The first is to have a mechanism that could be activated in
response to a specific need such as a vaccine shortage or the lack of
available vaccine, as with rabies. There would be a more positive
response to something urgent that needs to be dealt with in a relatively
short amount of time compared to the other issue Dr. Hinman raised. The
other issue is harmonization among regulatory agencies and the ability
to accept vaccines manufactured in other countries, which is also a
valid issue. He suggested they keep the issues separate if the
resolution is approved. The first issue is a higher priority.

Dr. Hinman noted that they are related but not identical issues. The
more important task is to figure out how they can respond in times of
emergency and crisis. It is related to the larger issue, however, and
they cannot be totally separated.

Dr. Baylor agreed with Dr. Black. They need to put these things into
categories. With the polio example, they had a licensed manufacturer in
this country, and for a number of reasons, that manufacturer is not
producing OPV. FDA is not necessarily the reason the company is no
longer producing the vaccine. There are a lot of questions, and a
working group would be a good place to raise them. For example, why are
there not more manufacturers entering? Unless there is dialogue, they do
not know if FDA is a barrier. They hear that it is, but numerous
offshore companies are not approaching him to dialogue with FDA about
the regulatory process is in the United States. The dialogue has to
happen with offshore companies as well. This is a big issue.

Dr. Walt Orenstein noted that Dr. Baylor helped stimulate this issue
through the vaccine supply meeting that occurred in recent weeks. Dr.
Baylor made a statement during the meeting about certain regulations
that FDA is required to abide by. A number of people at that meeting,
such as a representative of the Infectious Disease Society of America,
suggested they take a look at what those regulation and legislation
issues are, see whether they should be changed, and maybe make some
legislative remedies. A number of the companies at that meeting were
concerned about the difficulties they face in trying to get licensure
under different authorities. A working group would be helpful in trying
to examine these issues and there may be aspects of legislation that
they do not agree with that could possibly be changed through a
legislative initiative.

Dr. Overturf commented that he is not sure what this discussion is about
since the motion on the surface is nothing more than a request for
information (RFI) to identify what, if anything, could clarify the
regulatory process for offshore products. This discussion is useful, but
it is being done in the absence of information. They keep hearing about
these regulations and legislation, and they have not identified what
they are. This seems to be a request for a working group to begin
identifying those issues.

Dr. Helms commented that Dr. Baylor's admonitions are that once that
group is constituted, it needs to focus. This did not seem to be out of
Dr. Hinman's intent with the resolution.

Dr. Baylor noted that Dr. Orenstein was correct in how the issue was
brought up at the supply meeting, and it would be useful to look at the
issue. In one slide he presented, FDA did eliminate the additional
standards for bacterial and viral products to help bring some
flexibility into the regulatory process. He agreed that a working group
would be useful.

ACTION: A vote was called on the resolution, and all voted in favor.

RESOLUTION: The NVAC establish a working group to explore the
legislative and regulatory changes that would be required to allow
licensure of vaccines licensed for use in other industrialized countries
in order to meet vaccine needs in the US. The working group should
provide recommendations back to NVAC at its September 2005 meeting.

Dr. Gellin asked Dr. Overturf if there would be any value in integrating
this effort with VRBPAC.

Dr. Overturf explained that the only significant activity he would
discuss in his report is that they were going to review this process in
more detail next week. He did not think they will request this
information, but it may come up in the VRBPAC discussions about the
perceived barriers in the accelerated licensing process. VRBPAC might
get involved with this since FDA might eventually use VRBPAC as a way to
set up bypasses for individual vaccines.

Dr. Gellin noted that as they begin to structure this effort, it would
be worth using the different set of talents looking at these issues from
a different perspective.

**CMS Report**

Dr. Helms noted that Dr. Randy Farris was not present to give a CMS
report. He noted that CMS raised the reimbursement rate for
administering influenza pneumococcal vaccine by more than double. Dr.
Helms added that there is a handout in the materials about this issue.

Dr. Schaffner wanted to congratulate Dr. Farris and CMS on this issue
but noted that CMS still does not cover tetanus diphtheria vaccine.

Dr. Gellin explained that his understanding is that CMS does not have a
ready way to evaluate the impact of the changes they are making. This is
a significant change, and he is not sure how they came up with this
number and if they have the ability to go back and figure out the right
point to incite desired behaviors. They need to clarify if this is the
case with Dr. Farris, and if it is, maybe they can inspire CMS to take a
more critical look at these changes and their actual impact.

**ACIP/NIP Report -- *Dr. Melinda Wharton***

Dr. Wharton explained that Dr. Cochi had to leave for another meeting
but asked her to provide a brief update on what they think is going to
happen at the ACIP meeting tomorrow and Friday. She highlighted two
issues:

1.  Since their October meeting, the sanofi pasteur meningococcal
    conjugate vaccine has been licensed, and they expect the
    Meningococcal Working Group to present options to the committee for
    recommendations---most likely for routine use of the vaccine either
    at the pre-adolescent immunization visit, high school entry, or
    both.

2.  Regarding the prioritization of high risk groups for receiving
    influenza vaccine in the event of a shortage next year. They will
    also address whether they should have abundant supply of acceptable
    vaccines available under an IND or some other alternative mechanism.
    The Influenza Vaccine Working Group has been actively engaged in
    this issue and is reviewing data regarding health impact for various
    risk groups, effectiveness, etc. They expect some recommendation to
    be made to HHS in case a shortage occurs.

**ACCV/DVIC Report -- *Dr. Geoff Evans***

Dr. Evans did not review the news about autism claims and litigation
since they heard this at the supply workshop.

After NVAC's last meeting, Congress passed the American Jobs Creation
Act of 2004. That bill, which was enacted on October 22, 2004, imposed
excise taxes of \$.75 on hepatitis A and trivalent influenza vaccines.
The language for the hepatitis A vaccine was straightforward. The excess
tax was to go into effect the first day of the first month that begins
more than 4 weeks from the day of enactment, which turned out to be
December 1, 2004. On December 1, HHS published the tax enactment date in
the *Federal Register*. There is 8 years of retroactive coverage from
the effective date of the excise tax and a 2-year window in which to
file "older" injury or death claims.

The situation with the influenza vaccine is more complicated since
Congress included the language about the first day and first month but
provided a second option that allows the Secretary to decide when to
impose the excise tax. This was done because of the unique nature of
influenza vaccine with the specific season and new products produced
every year.

Would it be advantageous to be able to control the day-to-day excise
tax? Imposing the burden on the manufacturer to collect tax on supplies
that have already been pre-purchased, might prove to be additionally
difficult. The Secretary, understanding the unique situation, solicited
feedback from manufacturers and the public through the Advisory
Commission on Childhood Vaccines meeting in November. Both manufacturers
were in favor of a July 1, 2005 excise tax start date, and this was
unanimously voted in as such by the commission. The current season's
vaccine expires on June 30, which is a good demarcation for sales
purposes. That recommendation has gone to HHS, and they are still
waiting for approval, which will be published in the *Federal Register*.
He will let NVAC know the date. Again, there will be retroactive
application for coverage.

All of this allows hepatitis A and influenza vaccine to be added in the
last box listing in the vaccine injury table in the provisional
category. People can file claims that can be adjudicated. If they look
at the latest iteration of the vaccine injury table, it will show that
the vaccine is listed as an asterisk in the last box, which is the
provisional box for any vaccine recommended by CDC for routine
administration to children. It will have separate listing in the table
only after the Secretary goes through rulemaking, publication in the
*Federal Register*, 6 months of public comment and hearing, and
publication of final rule. It will be another year or more before this
happens. Rulemaking also entails whether they will be adding any
conditions or injuries that would be associated with either vaccine. The
Advisory Commission on Childhood Vaccines began to address this issue in
its November session, and they will continue the discussion in March,
hopefully finishing in June with votes on what conditions, if any,
should be added to the table when they go through rulemaking.

In addition, Senate bill 3, which was provided to NVAC members, has a
section on a program that would require the Secretary and Attorney
General to make recommendations to Congress regarding necessary
modifications to the compensation program and Federal rules regarding
litigation involving vaccines. This is a result of the autism litigation
and the need to prevent claims from going outside of the program. As one
industry person put it to Dr. Evans, they thought this was more of a
placeholder to see what kinds of events will eventually be put into the
bill as it goes forward during this Congressional session.

Dr. Gellin noted that the Senate bill was provided to NVAC because the
news emerged last week. There are many other bills like this in
pipeline. As Dr. Evans highlighted, there are pieces that are relevant
to the Committee's work.

**VRBPAC/FDA Report -- *Dr. Gary Overturf***

There are two major agenda items at VRBPAC next week. One is to select
the influenza strains for this year, which he believed WHO was doing
this week. The data are very clear for H1 and the H3 strains, as well as
for type A and B strains. The biggest issue will be how much data there
are. They will also discuss accelerated processes for influenza vaccine
in more detail. There is another meeting already scheduled for March
where they will examine versions of other vaccines, including DTAP and
some of the combined vaccines.

There are two subcommittee meetings scheduled for review of the
Laboratory of Biophysics and the Laboratory of Pediatric Respiratory
Viral Infection. VRBPAC is charged with constantly reviewing research
and regulatory processes and various components of laboratories.

He anticipated that there would be at least two other vaccines that come
to the committee's attention during the year.

**NIH Report -- *Dr. Barbara Mulach***

Dr. Mulach expanded on a point made briefly in Dr. Baylor's presentation
on the influenza shortage. In December, NIAID collaborated with
GlaxoSmithKline and went through their vaccine networks to get data on
Fluarix vaccine in the U.S. population. Within a 5-day period, they were
able to enroll 950 people in a study in mid-December. Data should be
finalized soon, which will hopefully help inform any decision makers and
provide information on the U.S. population with that vaccine.

**Discussion & Public Comment**

Dr. Whitley-Williams commented on the need to include various
populations in these trials. There is more heterogeneity in the United
States than in some of the European countries, although this is
changing. She hoped that some of the trials, even though they are small,
included gender and ethnic differences.

Dr. Helms asked if there were additional public comments, and there were
none.

**Adjournment**

Dr. Helms thanked NVPO staff and the meeting attendees and adjourned the
meeting.