Advisory
Commission on Childhood Vaccines Meeting
June
5- 6, 2008
Minutes
June 5, 2008
Members
Present
- Jeffrey
M. Sconyers, J.D., Chair
- Tawny
Buck
- William P. Glass, Jr., J.D. (via teleconference)
- Tamara Tempfer, RN-C, MSN, PNP (via
teleconference)
- Margaret Fisher, M.D., FAAP
- Charlene Gallagher, J.D.
-
Magdalena Castro-Lewis
- Jaime G. Deville
Executive Secretary
- Geoffrey Evans, M.D., Director, DVIC
Staff
Liaison
Introduction and Approval of Minutes
Mr. Sconyers convened the 69th quarterly
meeting of the Advisory Commission of
Childhood Vaccines (ACCV) at 12:08 p.m.
He invited a motion to approve the minutes
of the March 6 - 7, 2008 meeting. Ms.
Buck commented that, pursuant to a discussion
of the availability of thimerosol-free
vaccines to practitioners, she had asked
about the cost compared to vaccines that
contain thimerosol. That question and
the response from staff that the information
would be provided was not reflected in
the minutes. Mr. Sconyers stated that
the minutes would be so amended. On motion
duly made and seconded, the minutes of
the March 2008 meeting, as amended, were
unanimously approved. Ms. Buck added that
it would be helpful to provide access
to ACCV meeting transcripts on the program’s
web site. In addition, she suggested that
contact information be provided in a visible
manner on the web site.
Report from the Division of Vaccine
Injury Compensation (DVIC)
Geoffrey Evans, M.D., Director
Dr. Evans welcomed members and guests
in attendance and reviewed the agenda
for the two-day meeting.
Financial and Statistical Report
Dr. Evans reported that the large bolus
of influenza claims that were anticipated
as the two-year deadline for filing claims
approached had failed to materialize.
Rather than the 500 to 1,000 claims expected,
less than 200 had been filed by the July
2007 deadline. Autism claims had been
in a downtrend from 1,088 claims filed
in 2004 to 167 in FY 2007. However, as
a result of the 2007 autism hearings and
the publicity related to the Hannah Poling
case, claims have been increasing since
the latter half of 2007. Autism claims
filed after June 2007 are required to
undergo jurisdictional screening and DVIC
medical staff review if medical records
are present, as is done routinely for
non-autism claims.
Awards have averaged $62 million for
the past six years, with about $4 million
more in legal fees (which are paid whether
or not the ruling is favorable to the
petitioner). The awards in 2007 were considerably
higher, $97 million, and a similar amount
will probably be awarded in 2008. It should
be noted that one reason for this is that
the Court became fully staffed with special
masers and more cases were processed.
Dr. Evans reported that the Trust Fund
was now over $2.8 billion, and considering
expenditures, the fund is netting about
$300 million a year. Interest contributes
about 27% of that amount. The inclusion
of the flu vaccines has contributed significantly
to the increase (about 130 million doses
have been distributed).
Director’s Activities
Turning to activities since the last
meeting, Dr. Evans reported that he had
provided program briefings to the American
Academy of Allergy, Asthma and Immunology
on March 18th, and the annual meeting
of Vaccine Safety Datalink project on
April 2-3. He also briefed the Committee
on Medical Liability of the American Academy
of Pediatrics, which is especially interested
in appeals decisions of the Federal Circuit.
Dr. Evans noted that he and Ms. Buck are
involved with NVAC Vaccine Safety Working
Group, which is working on an safety plan
for the CDC’s Immunization Safety
Office. Dr. Evans said that he attended
the National Vaccine Advisory Committee
meeting on June 3-4. Finally, the Omnibus
Autism Proceeding began on May 12 and
continued through the end of the month.
Legislative Update
Concerning legislation, two relevant
bills are under consideration on the Hill.
The Federal Advisory Committee Act (FACA)
may be amended to enhance transparency
and accountability (requiring membership
criteria and membership lists to be published,
as well as transcripts of meeting, if
prepared). The Infant Immunization Improvement
Act of 2008 was introduced, which would
support a vaccination program through
the Women, Infants and Children’s
program.
Discussion
In response to a question, Dr. Evans
confirmed that the program has compensated
cases of “autism” in the program’s
20-year history. Compensation was based
on a finding of a Table injury, either
encephaopathy or seizures, with the final
outcome either through a concession by
HHS, or a special master decision. Autism
was not an alleged in these cases, and
all of the cases were adjudicated prior
to creation of the Omnibus Autism proceeding.
Asked about the backlog of claims waiting
to be adjudicated and the trend over time,
Dr. Evans explained the delays were primarily
related to the hepatitis B claims. Over
400 were received in the late 1990’s
when the 2-year deadline for filing retroactive
claims for the newly added vaccine expired.
It’s only within the past 1-2 years
that the Court has been adjudicating these
claims. Dr. Evans thought the trend will
be downward unless a new vaccine safety
issue arises.
Report from the Department of Justice
Vince Matanoski, J.D, Acting Deputy Director
Torts Branch, Civil Division, Department
of Justice
Mr. Matanoski reported that he is serving
as Acting Deputy Director for the Torts
Branch, vaccine section while Mr. Rogers
remains deployed to Iraq.
Personnel
Since the last ACCV meeting, the Department
of Justice (DOJ) has hired one more attorney,
with another attorney joining the office
in the few weeks. The office is still
in the process of trying to expand its
staff in light of the activated autism
cases.
Statistics
Mr. Matanoski reported that since February
1, 2008, there were 177 cases filed, almost
double the filings from his report at
the last meeting. Of those, 52 were non-autism
and 125 autism claims (a bump in autism
claims could have been attributed to the
publicity surrounding autism lately).
Of the pending cases, 101 were resolved
since February 1, 2008, which represented
fewer cases than were filed. Referencing
the 6,000 cases, this presents a challenge
to DOJ to reduce that differential by
processing more cases than are filed.
Of those resolved, 7 claims represented
entitlement decisions by a special master.
During this time period, 53 claims were
resolved through settlement, which means
that the Government and the petitioner
cooperate to reach what is called a litigative
risk settlement, and avoid the unknown
outcome of a trial. Regarding the settled
cases, Mr. Matanoski explained that the
claims are not identified as a Table injury
or off-Table injury settlement as each
claim evolves throughout the entitlement
phase of litigation. However, if the Department
of Health and Human Services (HHS) concedes
a case, that statistic is available. There
were 41 cases dismissed. Of those, 28
claims were entitlement decisions for
the Government and no compensation was
awarded petitioner. Twelve claims were
voluntary dismissals by the petitioners.
Finally, one claim was withdrawn pursuant
to Section 21(b) of the Vaccine Act, which
allows a petitioner to withdraw his case
after the expiration of 240 days B the
result here. If a petitioner withdraws
under that provision, he still has the
option to file a civil action outside
of the Program. Mr. Matanoski was not
familiar with the number of petitioners,
if any, who pursue civil actions after
withdrawing from the Program. He recalled
a number of the earlier autism cases that
withdrew pursuant to Section 21(b) of
the Vaccine Act, but most petitioners
remained in the Program as part of the
Omnibus Autism Proceeding. Ms. Buck questioned
whether DOJ could provide a breakdown
of conceded settlements, litigative risk
settlements, and entitlement decisions
over the years to evaluate any patterns.
Mr. Matanoski offered to look into providing
that information.
Autism
Of the more than 5,000 autism cases pending,
most were filed without any supporting
records. As mentioned at the prior meeting,
the Court has deemed it appropriate to
begin to process those cases. Mr. Matanoski
recalled that the Chief Special Master
has ordered 200 cases per month to be
processed. In those cases, petitioners
are required to provide sufficient documentation
for the Government to review whether the
Court has jurisdiction to proceed with
the case -- was it filed in a timely manner.
So far, the cases are falling into three
categories: 1) cases that were clearly
filed too late; 2) cases that were clearly
filed in a timely manner; and 3) cases
for which either determination is not
clear. In the third category, the gray
area, petitioners are being asked to provide
additional information. In some instances,
the Court is issuing show cause orders
seeking more information.
Over the course of the last five months,
a thousand of the cases have been activated.
Illustrating the procedure, Mr. Matanoski
explained that for each grouping of 200
cases, petitioners have been provided
90 days to compile their records. However,
of the 200 cases roughly 140 need additional
time to compile records. As a result,
while the cases are being activated in
an orderly fashion, the evaluation times
vary depending upon the time it takes
for petitioners to complete their documentation.
Thus, petitioners are seeking extensions,
resulting in a wide variety of deadlines.
Discussing the resolution of the gray
area cases for timely filing, Mr. Matanoski
predicted that many of the cases involving
autism present a subtlety with which the
first symptoms manifest themselves. That
is, the nature of the onset of autism
symptoms can create a question of whether
or not a case is filed in a timely manner,
which in turn may require expert testimony
to sort out the answer. The Government
is considering ways to efficiently address
the issues of timeliness with the Court
and petitioner's counsel.
Mr. Matanoski turned to the autism litigation,
and the three cases representing petitioners
first theory of causation: Cedillo
v. HHS, Hazelhurst v.
HHS and Snyder v. HHS.
He stated that briefing in all three cases
is complete, noting that Petitioners'
Steering Committee (PSC) in the Snyder
case have decided against seeking information
from the United Kingdom. The first theory
is whether the measles-mumps-rubella (MMR)
vaccine combined with Thimerosal act to
modulate the immune system leading to
live measles virus persisting in the body,
particularly the brain, to cause damage
and autism. The second theory is whether
Thimerosal alone causes autism. That theory
was recently tried in May, 2008, with
the following test cases: Mead
v. HHS and King v. HHS.
Notably, one of the three test cases dropped
out so the PSC is seeking a replacement
test case to provide to the special master.
Four experts appeared for petitioners
and twelve experts appeared for respondent.
On the issue of general causation for
the second theory, additional testimony
from two toxicologists for the Government
is scheduled for July, along with the
third test case. The third theory is whether
the MMR vaccine alone causes autism. The
PSC has indicated that the mechanism for
the third theory is the same as the first
theory, i.e., whether live measles virus
persists in the body and in the brain
to cause autism. Thus, no further evidence
on general causation is expected. It appears
that the special masters will apply the
general causation evidence from the test
cases of the first theory to the yet-to-be-chosen
test cases of the third theory.
Appeals
Mr. Matanoski reviewed the decision of
Avera v. HHS, issued
by the U.S. Court of Appeals for the Federal
Circuit (Federal Circuit) on attorneys'
fees and costs. While he discussed this
at the last meeting, it was relatively
new and there has been some development
on the implications of Avera. Avera raised
new issues for the Program:
1) whether the hourly rate for attorneys'
fees was governed by the forum of Washington,
DC and, 2) whether an award of interim
fees is available to petitioners. The
forum rates for Washington, DC are higher
than most forum rates where the attorneys
maintain offices. The petitioners sought
compensation for their attorneys consistent
with their view of Washington, DC rates
instead of rates that their attorneys
received in Cheyenne, Wyoming, where petitioners'
attorneys were located and practiced law.
The Federal Circuit decided that the forum-rule
applied to the Program, however, the Court
applied an exception to the forum-rule,
which looks to where the bulk of the work
was performed. Under the facts of this
case, petitioners' attorneys were not
entitled to the hourly rates of the forum,
which it deemed to be Washington, DC.
Petitioners' attorneys were entitled to
hourly rates consistent with Cheyenne,
Wyoming, where they performed all of the
work in that case. Mr. Matanoski predicted
that most, if not all, of the cases brought
in the Program would fall into an exception
to the forum-rule. In vaccine cases, unlike
traditional tort cases, the hearings are
typically conducted outside of Washington,
DC, and if conducted in Washington, DC,
last approximately six hours (or one day)
so that bulk of time spent by a petitioners'
attorney would be performed outside of
Washington, DC at his/her office. In addition,
many hearings are conducted by telephone,
or the special masters and counsel travel
to the most convenient location for the
petitioner. So far, the Government has
not seen a lot of litigation on the issue
of hourly rates following Avera.
Regarding the second issue in Avera,
the Federal Circuit decided that under
certain circumstances, not defined in
the decision, an award of interim attorneys
fees and costs is appropriate. However,
the Court denied petitioners' request
for attorneys' fees and costs in Avera
even though the case was on appeal. Because
the Court offered little guidance on when
an award of interim fees would be appropriate,
Mr. Matanoski contacted several members
of the petitioners' bar to discuss some
possible parameters for seeking payment
of interim fees. There was a meeting with
some of those attorneys regarding broad
parameters within which they would seek
interim fees. Some ideas included: seeking
fees after a decision issues from the
special master as that presents a natural
break in a case before the damages phase
or appeal and in amounts of at least $25,000.00,
as well as limiting the number of fee
requests. So far, only one case has been
filed seeking interim fees, although Mr.
Matanoski predicted more filings as the
parameters of Avera are
tested. Mr. Matanoski reiterated the Government's
commitment to move the cases toward resolution
without being sidetracked by interim fee
requests. Also still pending before the
Federal Circuit but not yet decided is
Mojica v. HHS, which
was brought by petitioner. In Mojica,
the petition was filed one day late because
of an error entirely attributed to Federal
Express delivery. There, the judge, Court
of Federal Claims, held that the special
master correctly dismissed petitioner's
case for lack of jurisdiction. Even under
those circumstances, the Court of Federal
Claims found that equitable tolling did
not apply afford jurisdiction.
Mr. Matanoski also discussed a case argued
today before the Federal Circuit, DeBazan
v. HHS. Petitioner sought compensation
for a demyelinating condition that manifested
itself eleven hours after vaccination.
Based upon the medical evidence, the special
master denied entitlement to compensation
because the onset of petitioner's injury
occurred too soon after vaccination. On
appeal, the Court of Federal Claims judge
reversed finding that the onset of petitioner's
demyelinating condition within eleven
hours made vaccine causation more likely.
The Government appealed to the Federal
Circuit maintaining that petitioner had
not met her burden of proof in demonstrating
that the vaccine was the most likely cause
of injury. The medical evidence demonstrated
that the onset of petitioner's demyelinating
condition within eleven hours of vaccination
was not attributable to the vaccination.
Early timing of onset is insufficient
to establish causation particularly here,
where the medical evidence contradicted
petitioner's claim.
There are ten cases pending in the Court
of Federal Claims, the first appellate
tier of vaccine cases. The cases were
all appealed by petitioners and involve
either a claim for attorneys' fees or
error by a special master erred in denying
entitlement.
Ms. Buck asked about Zatuchni/Snyder
v. HHS, which was a claim decided
by the Federal Circuit. The Court decided
that if, during the pendency of a vaccine
claim, a petitioner died, petitioner would
be entitled to seek the $250,000.00 death
benefit, as well as additional damages
to include lost wages, pain and suffering
and past unreimbursed expenses up until
the time of death. Mr. Matanoski was unaware
of any pending cases following Zatuchni/Snyder.
The Government did not seek further review
of that decision.
Responding to earlier comments about
how cases were filed, Mr. Matanoski explained
that cases are rarely filed on the basis
of a vaccine Table injury. The pleadings
typically do not provide much information
about the details of a particular injury
other than to aver that a vaccine was
administered and an injury occurred. The
specifics of each case usually emerge
as the facts and case develop and after
petitioner files supporting records and
documentation. Regarding activation of
the autism cases, Mr. Matanoski explained
that typically, the claims are reviewed
by a paralegal for the narrow issue whether
the claim is time-barred and lacks jurisdiction.
Attorneys review the case and, as necessary,
move to dismiss time-barred claims. There
are a lot of cases that fall into the
aforesaid gray area and need further information
(factual and/or expert development) and
documentation to evaluate further for
dismissal.
Report on Omnibus Autism Proceeding
from Petitioner’s Attorney
Tom Powers, J.D.
With regard to the statute of limitations
for filing petitions, there are some cases
that are clearly within the time requirements
and some cases that were clearly filed
too late. But the majority of cases fall
into a gray zone and a lot of effort will
be required to resolve the issues. About
180 attorneys are involved in responding
to issues raised by the Department of
Justice, a significant effort to facilitate
the process of activating what will eventually
be nearly 5,000 cases.
A key issue is when there is agreement
that a medical diagnosis starts the clock
on the 36-month time period during which
a petition may be effectively filed. Autism
has been difficult to diagnose based on
early symptoms. Therefore, some time may
elapse between the first symptoms identified
and the actual confirmed diagnosis of
autism. The assumption that the first
symptom starts the clock, rather than
the firm diagnosis, is an issue that will
apply to many of these cases where the
timing of onset is not clear. The Office
of the Special Masters is seeking a rational
and resource-responsible way to resolve
these issues with petitioners’ attorneys.
Aside from this challenging situation,
the three test cases based on the second
theory (thimerosol alone) are under way,
and hearings in two of these cases have
taken place. The third test case scheduled
dropped out and a search is going on for
a replacement. Hopefully the search will
be successful and the hearing on the third
test case will take place in late July.
The process to identify a viable case
involves reviewing existing cases for
timeliness of filing and determining whether
a table injury could be deemed appropriate
(which would make the case eligible for
a concession). Of the five cases under
review, Mr. Powers felt confident that
one would qualify as the third test case.
In terms of the first theory presented
in 2007 (MMR and thimerosol combined resulting
in autism or Autism Spectrum Disorder),
Mr. Powers noted that the hearings have
been completed, as has the briefing phase,
with the special masters now ready to
render a decision. There was an anticipated
request by petitioners’ attorneys
for an opportunity to obtain information
from sources in Great Britain, but that
request failed to materialize and the
request was withdrawn.
Finally, petitioners’ attorneys
do not anticipate a general causation
hearing in the third theory (MMR vaccine
alone) because the evidence would be essentially
the same as for the first (combined) theory
tried in June 2007. The Petitioner’s
Steering Committee (PSC) is following
a number of possible test cases that could
be heard in the fall, but there have been
no decisions related to that process.
Mr. Powers raised another issue of importance
to petitioner’s attorneys, that
of interim payment of fees. Some attorneys
have worked a number of years on the various
cases, expending significant time and
financial resources pursuing their clients’
interests. Based on the recent Federal
Circuit decision in Avera, those attorneys
may prepare petitions for significant
financial recompense and reimbursement.
The PSC has adopted the position that
conclusion of the prima facie case on
general causation in the autism proceeding
is an appropriate breaking point at which
attorneys should be able to file such
a petition. There are other such breaking
points as the case continues to final
disposition.
As the Omnibus Autism Proceeding advances,
petitioner’s attorneys continue
to expect access the research data and
other information generated by the Vaccine
Safety Datalink. It will be important
to update case information as new science
is published with regard to autism and
vaccine safety.
Vaccine Safety: Overview of Current
Vaccine Safety Activities
Dan Salmon, Ph.D.
National Vaccine Safety Office, HHS
Dr. Salmon described the process by which
a newly developed vaccine becomes approved
for use in humans, which requires specific
approval by the Food and Drug Administration
before it can be routinely recommended
in the U.S. population. Preclinical development
of a new vaccine involves characterization
of its chemical, biological and physical
characteristics. The process usually involves
animal models and includes assessment
of safety. Once the developer of the vaccine
is satisfied that there is a potential
benefit in humans and indication of the
safety of the vaccine, an Investigational
New Drug application (IND) is submitted
to FDA. If the FDA approves the IND application,
a series of clinical trials in humans
follow, beginning with a Phase I trial,
which primarily looks at safety and possible
adverse events related to the vaccine.
Phase I trials are small, with 10 to 30
study participants per dose level. If
no concerns are raised in the Phase I
trial, the developer may initiate Phase
II trials, which are larger (50 to 500
subjects) and evaluate efficacy as well
as safety. There may be several Phase
II trials. When the safety and efficacy
of the candidate vaccine are promising
in Phase II trials, a Phase III trial
is undertaken involving thousands of subjects.
Both safety and efficacy are evaluated
in these trials.
Phase II and Phase III clinical trials
are usually randomized, double-blind,
placebo controlled studies, meaning that
the subjects are randomly divided into
two or more cohorts (e.g., those who will
be given the study vaccine and those who
will be given a placebo), and neither
the study investigators nor the participants
know into which group each subject has
been placed. This is done to reduce the
potential for bias and confounding. Studies
will have inclusion and exclusion criteria
to reduce confounding effects and to minimize
risk in susceptible populations. For example,
an underlying disorder (such as diabetes
or hypertension) might have an effect
on the study outcome, and bias or confound
the results. Also, pregnant women are
usually excluded from initial clinical
trials because of theoretical risks to
the fetus.
An important objective of clinical trials
is to identify possible adverse reactions
to the study vaccine -- from rash or fever
to serious adverse effects like anaphylactic
shock. Common reactions may be evident
in the Phase I and II clinical trials,
but rarer reactions require much larger
study populations. The rarer an event,
the larger the study population of a clinical
trial must be. Therefore, clinical trials
are very useful to identify common adverse
events, but have some limitations in detecting
rare adverse events.
Clinical trials with hundreds of thousands
of participants are costly and not feasible.
Therefore, to identify rare potential
adverse events, the safety of a vaccine
must continually be evaluated after the
vaccine has been licensed. To obtain a
license, the pharmaceutical manufacturer
will submit a Biologic License Application
(BLA) to the FDA, which includes detailed
description of the vaccine’s manufacturing
process and the safety and efficacy data
obtained from the prior clinical trials.
FDA sometimes requires the manufacturer
to conduct a Phase IV surveillance study
that will identify adverse reactions to
the vaccine as it is distributed into
the marketplace for general use. Safety
data is continually gathered by the Vaccine
Adverse Event Reporting System (VAERS).
VAERS is a passive system that collects
reports from anyone, including health
care providers, manufacturers, researchers,
patients and any others who choose to
report such events (although such reports
are mandatory for manufacturers). People
are encouraged to report to VAERS any
potential adverse event caused by a vaccine,
although a report to VAERS does not mean
the vaccine caused the adverse event.
VAERS is important to generate signals
of potential vaccine adverse events that
can be followed up through rigorous scientifically
studies. One limitation of VAERS is that
adverse events are both under-reported,
especially the less serious adverse events,
and over-reported, when reports are made
which are not actually the result of a
vaccine. Nor is VAERS able to specify
a denominator since the total number of
people receiving a vaccine is not known
and therefore rates of adverse health
outcomes among vaccinated and unvaccinated
persons can not be compared using VAERS.
However, there is a system that is useful
for following up signals generated by
VAERS. The Vaccine Safety Datalink (VSD)
relies on cooperative studies involving
8 major managed care organizations representing
1.8% of the entire US populations and
1.5 % of that population under 18. Funded
by CDC, the VSD can develop hypothesis-driven
studies and obtain patient medical records
on the study population, a full range
of adverse medical outcomes, and other
relevant conditions. The strengths of
the VSD include the ability to analyze
emerging vaccine safety issues, and the
ability to assess data in a near real-time
manner. However, even the VSD population
is too small to study cases of very rare
adverse events. Also, the managed care
populations do not perfectly mirror the
entire U.S. population.
When studies are conducted relying on
different definitions and standards they
are difficult to compare and combine for
analysis. The Brighton Collaboration is
an international cooperative organization
supported by the World Health Organization,
the CDC and the European version of the
CDC. Its primary objective is to develop
a set of standards and a common language
so that various studies can be compared.
The Clinical Immunization Safety Assessment
(CISA) is a CDC-sponsored collaboration
involving six major US medical centers
and America’s Health Insurance Plans,
to conduct vaccine-related research on
adverse events. CISA also provides case
management support to individual physicians
who may encounter an adverse event both
on clinical care and subsequent immunization.
Since 1988, on a periodic basis, the
government has asked the Institute of
Medicine of the National Academy of Sciences
to conduct independent reviews that assess
potential causal relationship between
a vaccine(s) and adverse event. Relying
on a multidisciplinary panel of distinguished
experts, in 2004 the IOM looked at thimerosal
in vaccines and the MMR vaccine as causal
factors in autism, and concluded that
the evidence favored rejection of a causal
relationship in both cases.
Finally, CDC undertakes a number of activities
designed to identify patterns of vaccine
usage, demographics, parental attitudes
and beliefs about vaccines, and levels
of understanding about vaccine programs.
CDC also provides a wide variety of educational
and informational resources to parents,
the medical community, and health care
providers. The National Vaccine Program
Office (NVPO) coordinates vaccine safety
activities across all HHS agencies.
Outside HHS and CDC there are a large
number of entities also involved in vaccine
related programs and activities -- the
Department of Defense, academic researchers,
parent and advocacy groups, philanthropic
organizations, and professional organizations,
such as the American Academy of Pediatrics.
In closing, Dr. Salmon presented a case
study of rotavirus vaccines. Historically,
rotavirus affects most children in the
US by age five, causing gastroenteritis.
While rotavirus is rarely fatal in the
U.S., in the developing world rotavirus
illness is a significant cause of death
among children. In the 1990s, clinical
trials of RotaShield, an effective vaccine
against rotavirus, demonstrated a possible
slight increased risk of intussusception,
a compression of the bowel which can be
a serious medical emergency, although
it was not statistically significant.
After RotaShield was licensed in 1998,
VAERS detected a signal of intussusception
following vaccination. This prompted carefully
designed studies that demonstrated a link
between the vaccine and intussusception
about 3 to 14 days after vaccination.
RotaShield was pulled from the market
by the manufacturer in 1999. In 2006 a
new rotavirus vaccine was licensed. Because
of the previous experience with RotaShield,
clinical trials for the new vaccine were
expanded such that the same risk, if present,
would be identified prior to licensure.
Studies showed that this new vaccine did
not cause an increased risk of intussusception.
This example serves to illustrate how
different components of the federal vaccine
safety system work together to maximize
vaccine safety.
During discussion, there was a comment
that the risk-benefit consideration continues
to be an important aspect of vaccine safety.
Asked how the federal agencies affect
the selection of diseases to target for
vaccine development, Dr. Salmon explained
that epidemiological studies often point
to candidates, but that various aspects
of the candidate disease (etiology, mechanisms
of action of the disease vector, etc.)
may make it very difficult to launch a
vaccine development program. It was also
observed that defining the appropriate
target population for the vaccine may
influence a decision to pursue development.
Concerning improvements in the surveillance
system, Dr. Salmon noted that the VSD
is a relatively new improvement that has
greatly increased the effectiveness of
immunization safety research. In addition,
technological advances have made possible
more rapid improvement of vaccines, such
as the acellular pertussis vaccine. In
addition, there are now genomic studies
being undertaken that will expand knowledge
in the vaccine arena. Finally, there was
a brief discussion about the importance
of, and difficulty related to defining
the needs of subpopulations, which include
issues of health disparities and the needs
of special populations. There are also
issues related to the costs of conducting
additional pre-licensure trials in subpopulations
and the delays involved in getting an
effective vaccine into widespread use
when such clinical trials delay the licensing
process. What vaccines are selected for
development not only depends on the various
federal groups concerned with funding
research, but whether or not the pharmaceutical
companies can justify the costly development
process. This is especially true when
relatively small subpopulations are involved.
Industry Role in Vaccine Safety
Bob Sharrar, M.D.
Dr. Sharrar explained that he had spent
the first half of his career, 17 years,
as a public health officer for the City
of Philadelphia, and the second half of
his career monitoring vaccine safety for
a major pharmaceutical company, Merck
and Company. He stated that responsible
pharmaceutical companies develop and manufacture
safe and effective drugs, and continuously
monitor that safety and effectiveness
by maintaining a safety profile for each
product.
As an example of the care taken in developing
safe vaccines, Dr. Sharrar described the
manufacturing of measles virus vaccine,
which is derived from chicken embryo tissue
cultures. At the outset, Merck located
a flock of chickens that were free of
avian flu or other disease, continuously
maintained that flock in a tightly controlled
environment to insure that the original
purity of the strain would be maintained.
In another example, Dr. Sharrar noted
that the original hepatitis B vaccine
was made from plasma collected from homosexual
men who had high titers of hepatitis B
surface antigen. But there was a serious
resistance to using that vaccine because
of a perceived risk, even though multiple
purification steps in the manufacturing
process assured an absolutely safe product.
So Merck developed a recombinant process
that eliminated the need for the plasma.
A similar process was developed for MMR
vaccine that eliminated the need to use
human serum albumin
The removal of thimerosol as a preservative
in multi-dose units of vaccine was prompted
by a public demand for thimerosol-free
vaccine (accomplished by packaging vaccine
in single dose units). But the companies
had to conduct extensive tests to show
that the efficacy and safety profiles
had not changed by the removal of thimerosol.
Dr. Sharrar noted that pharmaceutical
companies were getting better at recruiting
more diverse populations, and they are
conducting clinical trials in other parts
of the world. The drawback is that for
various reasons, when more subpopulation
clinical trials are conducted, the sample
size is reduced, which makes it more difficult
to identify rare adverse reactions to
new drugs. The quality control process
is also very stringent -- Merck conducts
more than 200 tests at different stages
in the MMR manufacturing process. And
if any of those tests fail, the entire
lot is discarded.
To really get at the true safety profile,
including identifying rare adverse effects,
the post-marketing surveillance process
is important. That involves gathering
information on all reported events from
whatever source, and providing that information
to the appropriate Federal offices. Although
the process works well, there are weaknesses
- the process does not make judgments
on causation, but simply develops an adverse
reaction database. In addition, it has
to rely on the diagnoses provided by the
individual reporting the incident, which
may or may not be correct. That process
has been improved by adding a proactive
testing program (the VSD) to the traditional
passive VAERS-type surveillance program.
That means highly specific studies are
conducted in cooperation with major health
care providers, like Kaiser Permanente.
That allows a much more accurate analysis
of more data, including knowledge of the
entire number of individuals receiving
the vaccines.
In some cases laboratory tests can clearly
determine if a particular vaccine was
involved in an adverse reaction. In many
instances that is not possible because
definitive tests are just not available.
For disorders like autism, multiple sclerosis,
and SIDS, there are no markers currently
available that establish a causal link
between the condition and a particular
vaccine. That has to be developed and
perhaps the VSD will be one of the mechanisms
to do that.
During discussion, in response to a question
about how the federal agencies would enhance
the safety profile process in the manufacturing
setting, Dr. Sharrar stated that regulatory
requirements have become burdensome, that
new regulations are piled on top of older
regulations, and the process of conforming
becomes time consuming and expensive.
Streamlining those regulatory requirements
would be a positive step.
Concerning mandatory reporting requirements,
Dr. Sharrar felt that, although pharmaceutical
companies can provide clinical trial data
on adverse events relatively easily, it
is a much different issue with regard
to the huge number of health care providers.
Strict enforcement of such mandatory reporting
requirements might be impractical in that
arena. For instance, there is a federal
mandate that physicians report adverse
events through VAERS, but there is no
practical way to enforce the mandate.
He added that the growing electronic health
record system will make it easier to obtain
adverse event information without going
directly to the physician.
FDA’s Role in Vaccine Safety
Marion Gruber, Ph.D.
Dr. Gruber explained the clinical development
process of an investigational vaccine
by which a manufacturer (sponsor) obtains
FDA approval to market and distribute
the product. One important aspect of the
pre-licensure program is the non-clinical
evaluation of the vaccine which includes
the development of a manufacturing process
that ensures that the vaccine can be made
reproducibly and consistently and conforms
to the established release specifications.
Step one is submission of an investigational
new drug application that describes the
vaccine and contains a proposal for the
first clinical trial, the so-called Phase
I study. The IND includes a description
of the candidate vaccine, its anticipated
use, as well as a description of its manufacturing
process, data on the proof of concept
work, toxicological studies and any other
animal model data available. If FDA does
not identify any safety issues upon review
of the IND submission, the vaccine proceeds
to phase 1 clinical trial which involves
relatively few healthy adult subjects
(usually around 20). This first trial
involves adults even if the ultimate intended
use is for pediatric populations, e.g.
infants. If the adult trial proves successful,
additional Phase I trials may be conducted
in children of younger age groups and
ultimately in the target population, e.g.
infants. The study’s primary purpose
is an initial assessment of safety of
the vaccine in human subjects. Immune
responses may also be assessed.
If the Phase I trial is successful, the
clinical development proceeds to Phase
II clinical trials, which will involve
a larger number of subjects. Phase II
trials are to optimize the dose, dose
schedule and sometimes route of administration.
Immunogenicity of the vaccines is assessed
in these Phase II studies as well as safety
outcomes. During these trials there is
regular communication between the sponsor
and the FDA.
Phase 3 trials typically enroll thousands
of individuals and provide the critical
documentation of effectiveness and important
additional safety data required for licensing.
The primary endpoint is typically prevention
of disease. Effectiveness may also be
inferred through an immune endpoint. The
Phase III trial provides an expanded assessment
of vaccine safety and its potential side
effects. In special cases when it is not
practical or ethical to conduct a trial
in humans (e.g., for anthrax vaccine),
the FDA may approve a vaccine product
based on a demonstration of effectiveness
of the vaccine in animal models. In these
situations, safety studies in humans would
still be required.
CBER has no published guidelines on the
size of vaccine safety studies. The size
of the trial depends on the product under
investigation, the subject population,
the outcomes measured, the disease incidence,
etc. The “rule of three” is
frequently invoked -- that the trial should
be able to detect an adverse reaction
with an incidence rate of one in a thousand,
this would require a sample size of approximately
3,000 subjects.
If successful, the completion of all
three phases of clinical development can
be followed by the submission of a Biologics
License Application (BLA). These applications
contain the complete results of the trials
and all relevant information and aspects
related to manufacturing of the vaccine.
They also include a pharmacovigilance
plan to identify and evaluate potential
safety signals post-licensure. Pre-licensure
safety studies are typically not large
enough to detect rare adverse events or
adverse events occurring in certain subpopulations.
These are more likely detected as part
of post-marketing surveillance.
The Food, Drug and Cosmetics Act and
the Food and Drug Administration Amendment
Act (FDAAA 2007) provide the FDA with
authority for monitoring the progress
of postmarketing studies and, if certain
prerequisites are met, to require holders
of approved products to conduct postmarketing
studies and clinical trials at time of
approval or after approval. CBER has established
various product safety teams (blood products,
cellular and gene therapy products, vaccines)
to improve the acquisition, analysis and
communication of safety information.
During discussion, Dr. Gruber explained
that the FDA works closely with sponsors
during the clinical development process
for a vaccine. Phase I and Phase II studies
are more concerned with detecting adverse
events. However, Phase III studies are
designed to meet the primary endpoint
to establish efficacy and are often large
enough to also establish the safety of
the vaccine in the pre-licensure setting.
Thimerosol and Vaccines: Vaccine Content
Marion Gruber, Ph.D.
Dr. Gruber stated that, except for some
influenza vaccines, thimerosal-preservative
has been removed from pediatric U.S.-licensed
vaccines and from most vaccines indicated
for the adolescent and adult population.
Thimerosol contains organic ethyl mercury.
The mercury compound that has been most
publicized as a human risk in seafood,
breast milk, some cosmetics and dental
amalgams, is methyl mercury, which is
a known neurotoxin to which the fetal
brain is especially receptive and which
can cause severe developmental disabilities.
The Food and Drug Administrative Modernization
Act of 1997 required FDA to identify products
containing organic mercury and to assess
the effects of mercury compound on humans,
especially infants. As part of that review,
the FDA evaluated the amount of mercury
an infant might receive in the form of
ethylmercury from vaccines under the U.S.
recommended childhood immunization schedule
and compared these levels with existing
guidelines for exposure to methylmercury,
as there are no existing guidelines for
ethylmercury. At the time of this review
in 1999, the maximum cumulative exposure
to mercury from vaccines in the recommended
childhood immunization schedule was within
acceptable limits for the methylmercury
exposure guidelines set by FDA, ATSDR,
and WHO. However, depending on the vaccine
formulations used and the weight of the
infant, some infants could have been exposed
to cumulative levels of mercury during
the first six months of life that exceeded
EPA recommended guidelines for safe intake
of methylmercury. There was no evidence
of any adverse reaction related to those
levels of mercury in infants. However,
it seemed reasonable to remove thimerosal
from vaccines intended for pediatric use
and in July 1999, the Public Health Service
published a recommendation to eliminate
thimerosal from vaccines as soon as practicable.
At the same time, the FDA sent a letter
to manufacturers urging the same action.
In 2004, the IOM's Immunization Safety
Review Committee examined the hypothesis
that thimerosal containing vaccines are
causally associated with autism. In this
report, the committee incorporated new
epidemiological evidence from the U.S.,
Denmark, Sweden, and the United Kingdom,
and studies of biologic mechanisms related
to vaccines and autism since its report
in 2001. The committee concluded that
this body of evidence favors rejection
of a causal relationship between thimerosal-containing
vaccines and autism.
Since 2001, all vaccines intended for
pediatric use contain no thimerosal or
only trace amounts that remain when thimerosal
is used in the manufacturing process.
Prior to the initiative to reduce or eliminate
thimerosal from childhood vaccines, the
maximum cumulative exposure to mercury
via routine childhood vaccinations during
the first six months of life was 187.5
micrograms. With the introduction of thimerosal-preservative-free
formulations of pediatric vaccines, the
maximum cumulative exposure from the routinely
recommended childhood vaccines decreased
to less than three micrograms of mercury
in the first 6 months of life. With the
addition in 2004 of influenza vaccine
to the recommended vaccines, an infant
could receive a thimerosal-containing
influenza vaccine at 6 and 7 months of
age. This would result in a maximum exposure
or 28 micrograms via routine childhood
vaccinations. There are thimerosal-free
flu vaccines available but not in sufficient
amounts to supply the whole pediatric
population for which influenza vaccine
is recommended. Also, manufacturers have
stated that a large amount of thimerosal-free
vaccines had to be discarded.
Vaccine Distribution and Utilization
Jeanne Santoli, M.D., M.P.H.
Immunization Services Division, National
Center for Immunization
and Respiratory Diseases, CDC
Dr. Santoli explained that CDC is involved
in making recommendations for vaccine
development and the vaccine program through
the Advisory Committee on Immunization
Practices (ACIP). ACIP collaborates with
the American Academy of Pediatrics, the
American Academy of Family Physicians
and the American College of Physicians
to develop recommendations. Secondly,
CDC plays a major role in tracking the
flu strains that emerge that appear to
be specific threats for the upcoming flu
season. Then a combination (trivalent)
vaccine can be developed to address the
flu strains that most likely will infect
vulnerable populations. CDC supports the
process of purchasing flu vaccines, especially
for children, through 64 immunization
grantees around the country. Distribution
of vaccines is mainly a private sector
function, although CDC does provide some
informational support in coordinating
distribution. CDC also provides education
resources for the administration of the
vaccine program.
In 2004, the first recommendation was
published for the immunization of children
6 to 23 months of age, followed in 2006
by a recommendation to expand coverage
to children 24 to 59 months of age. Then
in 2008, a recommendation was published
to immunize all children 6 months to 18
years of age. Dr. Santoli noted that the
increase in the size of the entire population
who should receive flu shots went from
about 80 million in 1964 to almost 260
million in 2008. CDC contract purchases
of pediatric vaccine accounts for about
half of that market, but only about 10
% of the adult vaccine market.
The actual production of vaccine doses
is smaller -- in 2007, 141 million doses
were produced, 113 million were distributed
(purchased), and therefore 28 million
doses were discarded unused at the end
of the flu season. That unused category
does not include doses purchased by health
care providers but not dispensed and ultimately
discarded. Supply and demand is clearly
not in sync.
Since 2001, thimerosol has not been added
to vaccines except for a few influenza
vaccines distributed in multi-dose vials.
In those it may be added as a preservative
or used in the manufacturing process and
then removed, leaving only trace amounts
in the distributed vaccines. There are
currently 11 influenza vaccines, four
of which contain thimerosol (all sold
in multi-dose vials). Manufacturers have
the capacity to produce 50 million doses
for the next flu season, only 20 million
of which are licensed for children. Although
those numbers would be insufficient for
the two-dose regimen for children, because
of uneven distribution, some of the pediatric
doses will not be used and will be discarded.
During discussion, in response to an
inquiry about the economics of single-dose
versus multi-dose packaging, Dr. Santoli
stated that one problem is storage of
single-dose vials. Concerning the costs,
the federal contract for multi-dose vials
is about $10 per dose, for single-dose
vials about $13 per dose, and for the
intranasal application about $18 per dose.
The costs on the public market are about
one or two dollars more per dose.
Public Comment
Dr. Sconyers announced that Council Member
Dr. Meg Fisher was receiving the Oksana
Korzeniowski Patient Care Award from Drexel
University for her outstanding skills
and commitment in the clinical care of
patients and through her teaching which
has contributed to the skills and knowledge
of residents, students and medical colleagues.
He then invited public participation
in the meeting. There were no requests
by members of the public to comment.
(Whereupon the meeting recessed at 5:10
p.m. to reconvene the following day at
9:00 a.m.)
June 6, 2008
Members Present
Jeffrey M. Sconyers, J.D., Chair
Tawny Buck
William P. Glass, Jr., J.D. (via teleconference)
Tamara Tempfer, RN-C, MSN, PNP (via teleconference)
Charlene Gallagher, J.D.
Magdalena Castro Lewis
Jaime G. Deville, M.D.
Executive Secretary
Geoffrey Evans, M.D., Director, DVIC
Staff Liaison
Michelle Herzog
Review of Vaccine Information Statement
Skip Wolfe
National Immunization Program, CDC
The Commission considered the vaccine
information statement for MMR, and there
was a brief discussion about the use of
the term “provider” or “health
care provider” for “doctor
and/or nurse” and the Commission
agreed that either was appropriate. There
was concern that in referring to response
to adverse events, the term “doctor”
should be used because of the specific
medical implications of such an event.
There was agreement that the term “doctor”
implies a provider and that for consistency
throughout the text, the word “provider”
should be acceptable. There was a suggestion
to consider adding a glossary to the information
sheets if space was available.
Ms. Buck commented that the warning on
the MMR information sheet concerning very
rare, very serious adverse events that
might be attributed to the vaccine, although
not proven, should be explained (especially
whether there is current research to verify
the events). Mentioning events like permanent
brain damage, seizures, and coma could
be frightening to a patient.
Mr. Wolfe noted that Dr. Fisher had submitted
a list of suggestions that included mentioning
acute fulminant hepatitis B as a condition
against which the vaccine was appropriate,
and removing the phrase “chicken
pox is common” since that is no
longer true. On the tetanus, pertussis,
diphtheria information sheet, there was
agreement that the phrase “coughing
episode often lasting weeks to months”
should be added under the pertussis discussion.
Ms. Castro-Lewis noted that the information
sheets contain a statement that there
is a Spanish version available. She suggested
adding that phrase in Spanish. She also
recommended having an independent reviewer
check the translations provided by the
several translation contractors who create
the Spanish language information sheets.
Mr. Wolfe explained the process by which
an information sheet is created -- CDC
creates a draft which is reviewed by an
internal panel, the new VIS goes to the
ACCV and the FDA for review and comment,
the original draft is published in the
Federal Register for public comment, it
goes to one or more provider and/or parent
consultants for comment, it is re-dr |
