[Senate Hearing 105-660]
[From the U.S. Government Publishing Office]
S. Hrg. 105-660
NATIONAL IMMUNIZATION PROGRAM
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HEARING
before a
SUBCOMMITTEE OF THE
COMMITTEE ON APPROPRIATIONS UNITED STATES SENATE
ONE HUNDRED FIFTH CONGRESS
FIRST SESSION
__________
SPECIAL HEARING
__________
Printed for the use of the Committee on Appropriations
Available via the World Wide Web: http://www.access.gpo.gov/congress/
senate
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U.S. GOVERNMENT PRINTING OFFICE
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For sale by the U.S. Government Printing Office
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COMMITTEE ON APPROPRIATIONS
TED STEVENS, Alaska, Chairman
THAD COCHRAN, Mississippi ROBERT C. BYRD, West Virginia
ARLEN SPECTER, Pennsylvania DANIEL K. INOUYE, Hawaii
PETE V. DOMENICI, New Mexico ERNEST F. HOLLINGS, South Carolina
CHRISTOPHER S. BOND, Missouri PATRICK J. LEAHY, Vermont
SLADE GORTON, Washington DALE BUMPERS, Arkansas
MITCH McCONNELL, Kentucky FRANK R. LAUTENBERG, New Jersey
CONRAD BURNS, Montana TOM HARKIN, Iowa
RICHARD C. SHELBY, Alabama BARBARA A. MIKULSKI, Maryland
JUDD GREGG, New Hampshire HARRY REID, Nevada
ROBERT F. BENNETT, Utah HERB KOHL, Wisconsin
BEN NIGHTHORSE CAMPBELL, Colorado PATTY MURRAY, Washington
LARRY CRAIG, Idaho BYRON DORGAN, North Dakota
LAUCH FAIRCLOTH, North Carolina BARBARA BOXER, California
KAY BAILEY HUTCHISON, Texas
Steven J. Cortese, Staff Director
Lisa Sutherland, Deputy Staff Director
James H. English, Minority Staff Director
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Subcommittee on Departments of Labor, Health and Human Services, and
Education, and Related Agencies
ARLEN SPECTER, Pennsylvania, Chairman
THAD COCHRAN, Mississippi TOM HARKIN, Iowa
SLADE GORTON, Washington ERNEST F. HOLLINGS, South Carolina
CHRISTOPHER S. BOND, Missouri DANIEL K. INOUYE, Hawaii
JUDD GREGG, New Hampshire DALE BUMPERS, Arkansas
LAUCH FAIRCLOTH, North Carolina HARRY REID, Nevada
LARRY CRAIG, Idaho HERB KOHL, Wisconsin
KAY BAILEY HUTCHISON, Texas PATTY MURRAY, Washington
TED STEVENS, Alaska ROBERT C. BYRD, West Virginia
(Ex officio) (Ex officio)
Majority Professional Staff
Craig A. Higgins and Bettilou Taylor
Minority Professional Staff
Marsha Simon
Administrative Support
Jim Sourwine
C O N T E N T S
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Opening remarks of Senator Dale Bumpers.......................... 1
Statement of Peter Paradiso, vice president of scientific affairs
and research strategy, Wyeth-Lederle Vaccines and Pediatrics... 3
Prepared statement........................................... 5
Hib vaccine on trial in Gambia................................... 14
Statement of Walter A. Orenstein, M.D., Director, National
Immunization Program, Centers for Disease Control and
Prevention, Department of Health and Human Services............ 17
Achievements in child immunization initiative.................... 17
Vaccine development.............................................. 18
Accomplishments with new vaccines................................ 18
Challenges posed by new vaccines................................. 19
Safety and efficacy issues....................................... 19
Issues to stocking vaccines...................................... 20
Prepared statement of Dr. Walter A. Orenstein.................... 21
Statement of Dr. Michael Osterholm, State epidemiologist and
chief, acute disease epidemiology section, Minnesota Department
of Health...................................................... 26
Prepared statement........................................... 29
Remarks of Senator Bumpers....................................... 34
Testing efficacy of vaccines..................................... 34
Antigen compatibility............................................ 35
New vaccines and ease of delivery................................ 36
Issues related to manufacturing combination vaccines............. 36
Postmarketing surveillance of vaccines........................... 37
Adult immunization............................................... 38
Progress in links of immunization and WIC programs............... 38
Outreach activities.............................................. 39
Measles eradication.............................................. 40
State carryover balances from prior years........................ 41
Confusion caused by number of vaccines on the market............. 42
Bar coding of vaccines........................................... 42
Immunization registries.......................................... 42
Tracking immunization of children................................ 43
Cost benefit of vaccines......................................... 44
Problems related to vaccine delivery............................. 45
Members of ACIP.................................................. 46
Vaccine delivery issues.......................................... 46
ACIP recommendations............................................. 46
Advantages of tracking immunizations of children................. 47
New application for FDA approval................................. 48
Standardization of vaccine delivery.............................. 49
NATIONAL IMMUNIZATION PROGRAM
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WEDNESDAY, JULY 16, 1997
U.S. Senate,
Subcommitte on Labor, Health and Human
Services, and Education, and Related Agencies,
Committee on Appropriations,
Washington, DC.
The subcommittee met at 10:33 a.m., in room SD-124, Dirksen
Senate Office Building, Hon. Dale Bumpers presiding.
Present: Senator Bumpers.
NONDEPARTMENTAL WITNESSES
STATEMENT OF PETER PARADISO, VICE PRESIDENT OF
SCIENTIFIC AFFAIRS AND RESEARCH STRATEGY,
WYETH-LEDERLE VACCINES AND PEDIATRICS
opening remarks of senator dale bumpers
Senator Bumpers. First I want to thank the chairman,
Senator Specter, for calling today's hearing to discuss the
development of new pediatric vaccines and the role industry and
Government should take in ensuring that these new vaccines are
made available to our Nation's children. I know he shares my
commitment to improved preventive health care for children and
to make the investments necessary to ensure that all children
have ready access to vaccines that protect them from illness
and death.
Today's hearing is an opportunity to celebrate
breakthroughs on several fronts. In 1992 the public health
community was reeling in the aftermath of a 3-year measles
epidemic that resulted in 55,000 cases of measles and 132
deaths, mostly among preschool aged children. Coverage rates
for preschoolers were abysmally low in many areas and this
committee was struggling to find the resources to provide CDC
with the tools to respond to the crisis.
Today, just 5 years later, we will hear testimony that the
United States has achieved the highest coverage rates in
recorded history. Even better news is that disease rates are at
a new low and there is evidence that measles transmission in
this country has been interrupted.
We will also hear exciting news about development of new
vaccines that will protect our children against deadly and
other costly diseases. One of the most promising products in
the pipeline is a rotavirus vaccine that will have a dramatic
effect on illness and death in young children. Worldwide,
rotavirus kills 2,000 children every single day. In the United
States alone, rotavirus is responsible every year for 50,000
hospitalizations and 20 deaths among children under age 5.
Two vaccine manufacturers have rotavirus vaccines in the
late stages of development and it is likely that at least one
of those vaccines will be available as early as next year. We
will hear today about these and other exciting developments
that hold the promise of preventing thousands of cases of
diseases and death among our young children.
As new vaccines have been introduced, industry has also
made considerable progress in combining vaccines as a way of
reducing the need for doctor visits and additional injections.
Two combinations have come onto the market in the last year and
at least 12 additional combinations are in some stage of
development. Even beyond the human costs associated with death
and disease in young children, the benefits of new vaccines and
new combinations are clear. Immunization is still the most
cost-effective preventive health strategy available. The cost-
benefit ratio for vaccines varies from $2.60 saved for every $1
spent for pertussis vaccines to $14.40--let me reread that.
The cost-benefit ratio for vaccines varies from $2.60 saved
for $1 spent for pertussis vaccines to $14.40 saved for $1
spent for measles, mumps, and rubella vaccine.
But along with the benefits of this new generation of
vaccines, there are new challenges. How can we maintain our
high coverage levels in the face of a far more complex
schedule? How can industry and Government improve collaboration
to ensure that products are brought to market in a timely way?
What steps should we take to reduce the risks of complications
associated with a new generation of overlapping combination
vaccines?
In this era of tightening budgets at the State and Federal
level, how can we accommodate the increased costs associated
with new products? How can the Federal Government make
purchasing decisions in a way that provides maximum flexibility
to the States and at the same time ensures competitive prices
for new products?
We will not be able to answer all of these questions this
morning, but I know that our witnesses will have a great deal
to offer as we debate these issues over the next several years.
I have asked Dr. Peter Paradiso of Wyeth-Lederle to lead off
with an overview of where industry is today in development of
new products. Dr. Walter Orenstein will follow with an update
on coverage and disease rates and a summary of the challenges
CDC has identified in implementing an improved and much
expanded vaccination schedule. Then Dr. Michael Osterholm
brings us the perspective of the State health community, which
along with private pediatricians is on the frontline in
delivering an increasingly complex regimen of vaccines.
After each of the witnesses has delivered his testimony, I
will ask each of them to remain on the panel so we can discuss
a number of the questions. I want to personally thank all of
you on behalf of myself, the subcommittee, and, frankly, the
American people for being here this morning and taking the time
to prepare testimony on an increasingly new set of complex
problems that we are faced with.
summary statement of dr. peter paradiso
Dr. Paradiso, please lead off.
Dr. Paradiso. Thank you. Mr. Chairman, I am Dr. Peter
Paradiso, vice president of scientific affairs and research
strategy for Wyeth-Lederle Vaccines and Pediatrics, one of four
companies in the childhood vaccine market. Before I begin, I
would like to especially thank you, Senator Bumpers, for your
long-time involvement and interest in childhood immunization
issues. All of us who work to develop childhood vaccines will
surely miss you and your input when you retire.
I will condense my submitted remarks to focus on three
major topics: first, the positive effect that newly developed
vaccines are currently having in the prevention of childhood
disease; second, the promise of control of even more vaccine-
preventable diseases over the course of the next decade; and
third, to the extent time permits, the influence of Vaccines
for Children [VFC] Program on vaccine research and development.
A decade ago, if I were sitting in this witness chair I
would be able to discuss three very good childhood vaccines--
OPV, MMR, and DTP. These vaccines have saved the taxpayers
countless billions of dollars in direct and indirect costs over
the years. They have now been joined by an impressive array of
new products made possible by biotechnology that continue the
tradition of safe and effective vaccines. These include a new
acellular pertussis vaccine that responds to parent and
provider concerns about adverse reactions, hepatitis B vaccine
for infants that is greatly increasing protection against liver
disease, and most recently a varicella vaccine to protect
children against chicken pox.
All these vaccines are extremely safe, effective, and, an
important consideration in the new world of managed care, also
highly cost effective.
I would like to spend a few minutes discussing another of
the new vaccines, the Haemophilus influenza type b, [Hib],
conjugate vaccine whose development I was intimately involved
in, as an example of the benefits attainable for society
through childhood immunization. Prior to the development of the
Haemophilus influenza type b conjugate vaccine, Hib infected 1
of out every 250 infants, 5 percent of patients died, and 30
percent suffered permanent central nervous system injury. Hib
was the predominant cause of childhood meningitis, the leading
cause of acquired mental retardation, and a major source of
deafness and other neurological defects in children.
It was known for many years that antibody directed at the
sugar saccharide coating on the surface of the bacteria would
protect against disease. Unfortunately, young infants at the
highest risk for disease are unable to respond to saccharide.
If you look at the first chart, you will see a cartoon of
conjugate technology that was used to develop the Hib conjugate
and that is now being used to develop vaccines for pneumococcus
and meningococcus, which we will hear more about today. The two
components are the protein, with the big ``P'' there on the
top--and that is a component because children as young as 2
months of age can respond to protein vaccines, like diphtheria,
tetanus, and pertussis vaccines. The squiggly green line is a
representation of the sugar that coats the surface of the
bacteria. If you make antibody to the sugar, then you will kill
the bacteria and protect the children.
Unfortunately, children under 2 years of age cannot make or
respond to the sugar. So what the conjugate technology did was
to take the protein and attach it covalently to the sugar in a
permanent way, so that when the child recognized the protein it
also recognized the sugar because it was attached. The result
was that infants were able to make a response to the sugar and
protect against the Haemophilus b disease by attacking the
surface of the bacteria.
This conjugate technology actually resulted in an immune
response that nature did not naturally do from an infection and
so children were unable to be protected.
The next chart shows the chronology of the development of
Haemophilus vaccine. The bacteria was recognized in the late
1800's and it was really in the 1930's that people recognized
that it was the sugar on the surface that was the important
part of the bacteria to try to make a response to. But you can
see there were many years in the use of that knowledge, and in
1973 it was shown that the sugar would work in older children,
but would not work in younger children, and that something
different was needed if you were going to protect the youngest
infants who were at the greatest risk.
So in 1990 a vaccine that used that conjugate technology
was shown to be effective in very young infants, and within a
very short period of time--and here I have listed 1994--the
disease was under control in the United States.
You can see on the next chart what I mean by that. In the
United States in the 1980's, analysis by the Centers for
Disease Control showed that there were approximately 20,000
cases of Haemophilus b disease every year and about 12,000 of
those were meningitis. You can see that in the year 1991, a
year after the introduction of conjugate vaccines, there was
already a dramatic reduction in the total number of cases of
Haemophilus disease, and that continued to go down, so that by
1993-94 about 95 percent of the disease was gone.
In 1992 they started recording the cases in children under
5 where the majority of these 20,000 cases were, and you can
see that impact is even more dramatic.
The next slide shows you why the impact for this conjugate
vaccine was even more dramatic than we would have expected by
the amount of vaccine that was used. This is a population in
northern California, where we did our efficacy trial for the
conjugate vaccine. You can see that it shows from the year 1984
to the year 1995 the cases of Haemophilus b disease in various
age groups within the population. The first arrow, red arrow,
shows the time at which the polysaccharide vaccine was used,
and it did not have much of an impact on total disease. The
second arrow, the middle arrow there, shows when we started
doing our efficacy trial, and now you can start to see a
reduction in the number of cases of disease.
The yellow line here is the highest incidence in kids 17 to
18 months of age. The third red line is when the vaccine was
actually introduced universally around the country in this
population. What is really remarkable about this slide and what
it illustrates is that not only are the kids who were targeted
protected, but also the kids who were not vaccinated or only
partially vaccinated, and you can see that from the blue line,
as well as the older children from the green line, who were
also protected from disease.
prepared statement
The reason that they were protected was because the vaccine
eliminated the carriage of the bacteria in the population. This
effect is known as herd immunity, where you actually by
vaccinating a majority of the population can protect the whole
population because you have eliminated the bacteria. Those
children are not carrying it, they do not spread it to their
friends and siblings. So what you get here is a far more
dramatic effect than you measured initially in your efficacy
trials because you are protecting people in contact with those
who have been vaccinated.
[The statement follows:]
Prepared Statement of Peter Paradiso
Mr. Chairman and members of the subcommittee, thank you for the
opportunity to testify today regarding vaccine research and development
and the pipeline of new vaccines that will be introduced in the next
decade and beyond. I am Dr. Peter Paradiso, Vice President of
Scientific Affairs and Research Strategy for Wyeth-Lederle Vaccines and
Pediatrics. Together with its predecessor companies, Wyeth-Lederle has
developed and manufactured childhood vaccines for more than a century.
Wyeth-Lederle is part of Wyeth-Ayerst, a division of American Home
Products, which is one of the world's largest research-based
pharmaceutical and health care products companies. American Home is a
leader in the discovery, development, manufacturing, and marketing of
prescription drugs and over-the-counter medications. It has a global
presence in vaccines, biotechnology, agricultural products, animal
health care and medical devices.
the biotechnology revolution
The 1990's have been an era of great progress in vaccine research
and development. If I were sitting before this Subcommittee a decade
ago, the story I would tell would be quite different. In the mid-
1980's, the question was not which vaccines would be available in the
future, but whether vaccines would be available at all. The industry
confronted a severe liability crisis which threatened not only its
financial well-being but public confidence in childhood immunization.
Action taken by Congress at that time provided a measure of relief from
the cloud of vaccine liability, and the advent of managed care has
placed a new premium on preventive interventions like vaccines.
As a result of these changes in the environment, the vaccine
industry is healthier than at any time during the past several decades.
Nevertheless, there are still only four companies serving the American
childhood vaccine market--Wyeth-Lederle and Merck (both U.S.
companies), Pasteur Merieux Connaught, and SmithKline Beecham. In spite
of being the most cost-effective approach to health care, vaccines
account for only 1 to 2 percent of the U.S. pharmaceutical market, and
even with robust growth over the next decade, vaccines will still
account for only a small portion of the pharmaceutical market.
Congressional action and changes in the marketplace have been key
elements of the progress in immunization. The primary impetus for new
vaccine development, however, has been the availability of new tools
provided by biotechnology. A decade ago most vaccines consisted of
either inactivated or attenuated live organisms. For many diseases,
these relatively straightforward approaches were adequate to stimulate
immune responses. But for other diseases, the infant immune system did
not respond to products manufactured in the traditional ways. New
techniques, such as the use of recombinant or conjugation technology,
have opened up many new possibilities for development of vaccines to
deal with this problem.
An example with which this Subcommittee is familiar is the use of
conjugation technology to prevent Haemophilus influenzae type b (Hib)
disease--most notably meningitis--in infants. In the 1980's, several
companies developed and brought to the market Hib polysaccharide
vaccines. These vaccines were purified capsular polysaccharide vaccines
similar to the pneumococcal polysaccharide vaccines that are currently
used in adults. Although the Hib polysaccharide vaccines were very
safe, they were not effective in children younger than 18 to 24 months
of age. Because Hib disease occurred mostly in children younger than 18
months, particularly those in day care settings, the polysaccharide
vaccine was of limited utility. Therefore, it became a public health
priority to develop a Hib vaccine that would benefit young infants who
are at greatest risk of the disease.
In the second generation of Hib vaccines, a protein carrier is
conjugated, or chemically linked, to the Hib polysaccharide. The
benefit of these vaccines is that they can be effectively administered
to infants as young as two months of age, thereby offering protection
at the time of greatest exposure to disease. Prior to the development
of conjugation technology, protecting young children from this disease
was simply a dream. The conjugation technology that is necessary for
the production of these Hib vaccines is now being used in the
development of other new vaccines, including one that will protect
against Streptococcus pneumoniae, also known as pneumococcus, which
causes meningitis, bacteremia, pneumonia, and nearly 50 percent of
childhood ear infections.
Although the principal explanation for progress in vaccine
development lies in new scientific methods, government policies do
matter. A favorable environment for vaccine research depends on a
productive relationship between industry and government. Because the
federal government is the largest single purchaser of childhood
vaccines and also sets policy for the use of childhood vaccines, its
power to influence vaccine development is great.
In order to maintain a healthy environment for vaccine research and
development, we believe the government should coordinate with industry
in the establishment of research priorities and in the conduct of
research; pay a fair price for vaccines; support the use of preventive
vaccines by the public; encourage a diversity of scientific approaches
to the development of vaccines; support industry efforts to market
vaccines globally; and strongly defend the safety of government-
approved vaccines.
Industry, in turn, must respond to public health priorities in
setting its research agenda; supply vaccine reliably and at a
reasonable price; respond to provider concerns about immunization
schedule confusion; and responsibly address public concerns about
vaccine safety. I will return to our vision of an appropriate
relationship between industry and government in more detail after
reviewing vaccines recently introduced to the market and those that
soon will be introduced.
new vaccines
For many years after the initiation of the Section 317 immunization
program, the federal government purchased only measles-mumps-rubella
(MMR) vaccine, diphtheria-tetanus-pertussis (DTP) vaccine, and oral
polio vaccine (OPV), and the task of fully immunizing a child was a
matter of administering six shots and five oral doses of vaccine during
the first five years of life. The members of the Subcommittee are well-
acquainted with those vaccines and their benefits. Those vaccines have
prevented much illness and loss of life, and they also have impressive
cost-benefit ratios--1:11 for DTP and 1:14 for MMR. \1\ It is also
worth noting that the worldwide use of OPV has resulted in the
eradication of wild polio disease from the Western Hemisphere and great
progress in the global effort to eradicate polio by the year 2000.
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\1\ Hinman A.R., Koplan J.R., Pertussis and pertussis vaccines.
JAMA 1984;251:3109-3113; White C.G., Koplan J.P., Orenstein W.A.
Benefits, risks and costs of immunization for measles, mumps, and
rubella. AJPH 1985;75:739-744.
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Since 1990, four new vaccines and several new combination products
have been introduced, and the potential to prevent childhood disease
and save health care dollars has expanded dramatically. However, the
introduction of new products has also created problems for the federal
and state governments, pediatricians, public health officials, and
parents. Providers and parents sometimes express concerns about the
``confusion'' created by a multitude of new vaccines and suggest they
need a ``simpler'' schedule. While we agree that combination vaccines
would simplify the immunization schedule, some thought should be paid
to efforts to improve parent and provider education regarding changes
and additions to the immunization schedule so that acceptance of new
products occurs promptly. The use of new vaccines prevents children
from suffering from disease and saves the health care system millions
of dollars. Surely we can find a way to educate parents and providers
concerning appropriate use of these life-saving products.
Recently-introduced vaccines and their benefits are:
Haemophilus influenzas type b vaccine
Prior to the development of a Hib conjugate vaccine, Haemophilus
influenzae type b, or Hib, infected one of every 250 infants; 5 percent
of patients died; and 30 percent suffered permanent central nervous
system injury. Hib was the predominant cause of childhood meningitis,
the leading cause of acquired mental retardation, and a major source of
deafness and other neurological defects in children. In the early
1990's, introduction of several Hib conjugate vaccines, including one
developed and manufactured by Wyeth-Lederle, virtually eliminated Hib
meningitis. In addition, the vaccine has resulted in savings of
approximately $2.5 billion annually in direct and indirect costs
associated with Hib disease. As discussed above, this vaccine is the
result of conjugate technology that was perfected only a few years
before the vaccine's introduction.
Acellular pertussis vaccine
For decades, we have used a very effective whole cell pertussis
vaccine to protect children against whooping cough. In the mid-1980's,
parents began to refuse use of the whole cell pertussis vaccine because
of the perception of adverse events associated with the vaccine.
Declines in immunization rates led to pertussis outbreaks. It later
became clear that whole cell pertussis vaccine posed little if any risk
of serious reactions, but public confidence in the vaccine was damaged.
Accordingly, public health experts identified their number one
immunization priority to be the development of a pertussis vaccine that
was composed of purified parts of the bacterium, rather than the entire
inactivated organism. This acellular pertussis product was thought to
be safer than the whole cell vaccine. The vaccine industry responded by
developing a number of new acellular vaccines. Three acellular products
for infant use have been introduced in the last year, and additional
entrants to the market are possible. The new acellular pertussis
vaccines have fewer side effects--both local ones like redness and
swelling and systemic ones like fever--than the whole cell pertussis
vaccine, and their development was seen as critical to ensuring
continued parent and public confidence in the childhood immunization
program.
Hepatitis B vaccine
Hepatitis B is a very serious liver disease, predisposing infected
individuals to liver cancer. A plasma-derived hepatitis B vaccine has
been available in the United States since the 1970's, but the vaccine
was not widely accepted because of concerns about its safety and the
reliability of supply. Development of a recombinant product began in
1975, and the recombinant vaccine was introduced to the market in 1986
by Merck and SmithKline Beecham. This vaccine was originally
recommended for use in high risk individuals, including infants, or
those born to mothers infected with hepatitis B, but this strategy was
not effective at reaching all of those at risk.
In the United States, hepatitis B is most commonly transmitted
through sexual contact or intravenous drug use. It is not routinely
considered a disease of childhood. However, the absence of a routine
adolescent immunization program has convinced many public health
experts that administration of hepatitis B vaccine at infancy is
appropriate to ensure vaccination compliance. After initial resistance
to use of the vaccine, most pediatricians and others immunizing infants
have added it to the infant schedule. A recent report indicates some
problems in tracking and monitoring the infants born to hepatitis B
mothers and recommends stronger centralized tracking and case
management systems. The difficulties associated with the perinatal
immunization program for these mothers and infants underscore the need
for universal hepatitis B immunization as part of routine immunization
services. \2\ The importance of this vaccine is further supported by a
study that documented the reduction in incidence of liver cancer in
Taiwanese children since the institution of a universal hepatitis B
vaccination program. \3\
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\2\ CDC. Program to prevent perinatal hepatitis B virus
transmission in a health-maintenance organization--Northern California,
1990-1995. MMWR 1997;46:378-380.
\3\ Mei-Hwei Chang, et al. Universal hepatitis B vaccination in
Taiwan and the incidence of hepatocellular carcinoma in children. NEJM
1997;336: 1855-1859.
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Varicella vaccine
In 1995, after more than twenty years in development, Merck's
varicella, or chickenpox, vaccine was approved by the Food and Drug
Administration (FDA). The vaccine is now recommended for routine use to
protect children from chickenpox. Although normally a relatively mild
disease, chickenpox afflicts a small fraction of patients with much
more serious symptoms, including bacterial infections of skin lesions,
pneumonia, dehydration, encephalitis, and hepatitis. Parents lose a
considerable number of work days when their children have chickenpox,
and use of the vaccine prevents not only the disease but also parents'
lost work days. An analysis of the vaccine's cost-effectiveness
concluded that routine use of the vaccine will save $400 million a year
in total societal costs. \4\ Hospitalizations for varicella and the
costs of those hospitalizations have been found to be greater than
estimated in the original cost-effectiveness study, \5\ so the total
savings associated with use of the vaccine are probably also higher
than the initial calculation.
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\4\ Lieu TA, et al. Cost-effectiveness of a routine varicella
vaccination program of U.S. children. JAMA 1994;271:375-381.
\5\ Seward presentation on varicella vaccine, Advisory Committee on
Immunization Practices, June 16, 1997.
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Hepatitis A
Hepatitis A is a highly contagious disease which is usually spread
by fecal-oral transmission. In the U.S., hepatitis A is cyclical, but
the rate of incidence has increased gradually since the early 1980's.
Disease symptoms may vary considerably, from mild and transient to
severe and prolonged, and may include fever, nausea, vomiting, and
diarrhea, followed by jaundice in many adults. A new hepatitis A
vaccine has been approved for use in the United States, but this
vaccine is not recommended for routine use in young children. The
vaccine is recommended for use by travelers to countries where
hepatitis A is endemic and for certain other populations.
the vaccine pipeline
The promise of the vaccine pipeline is truly impressive. New
products will protect children and adults against an increasing number
of diseases; influence the practice of pediatric and adult medicine;
meet the challenge of antibiotic-resistant infections; and revise our
thinking about vaccines, which may be used as therapy rather than just
as prevention.
I will confine my remarks today primarily to pediatric vaccines.
Although several of the pediatric vaccine companies also have active
HIV, herpes, Helicobacter pylori, and melanoma vaccine development
efforts, to name a few, I will not discuss those R&D pipelines today.
Among the new pediatric vaccines that are in the pipeline are:
--Rotavirus.--Rotavirus is the most common cause of severe diarrhea
among children and strikes virtually every child by the age of
four. The direct medical costs associated with rotavirus are
more than $400 million annually--primarily the result of the
fact that young children can get dangerously dehydrated very
quickly--and the total societal costs are over one billion
dollars annually. In less developed countries, rotavirus is a
major killer of young children. My company has recently filed
an application for a new vaccine that will protect children
against 80 percent or more of serious diarrhea caused by
rotavirus.
--Streptococcus pneumoniae.--Perhaps the most pressing issue facing
pediatricians today is the emergence of antibiotic-resistant
strains of Streptococcus pneumoniae, which is a major cause of
pneumonia and meningitis in infants and the number one cause of
otitis media, or ear infection, in all children. According to
the Centers for Disease Control and Prevention (CDC), the way
to address the looming problem of antibiotic resistance in S.
pneumoniae is to develop vaccines which will prevent infection
with the organism.\6\ Industry is committed to the development
of a pneumococcus vaccine for infants, and this vaccine will
respond to the public health crisis of antibiotic-resistant
strains of S. pneumoniae.
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\6\ Breiman R.F., et al. Emergence of drug-resistant pneumococcal
infections in the United States. JAMA 1994;271:1831-1835; CDC. Defining
the public health impact of drug resistant Streptococcus pneumoniae:
report of a working group. MMWR 1996;45 (no.-RR-1).
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Vaccines to protect against S. pneumoniae will have a significant
impact on pediatric practice, because as many as half of all
sick-child visits are attributed to ear infections, and as many
as half of those infections are caused by S. pneumoniae.
Globally, S. pneumoniae is the largest cause of pneumonia in
young infants, and pneumonia is the single largest cause of
deaths.
--Sexually transmitted disease vaccines.--Several companies are
pursuing vaccines that will protect adolescents against
sexually transmitted diseases. The vaccine that is probably
closest to the market is the herpes simplex vaccine, although
work on a vaccine to prevent human papilloma virus disease--
including cervical cancer--is also proceeding. Some have
suggested that hepatitis B vaccine, which is now given to
infants, should instead be routinely delivered to older
children, as is done in Canada, and serve as the ``anchor'' for
a combination vaccine product to protect against sexually
transmitted diseases.
While some are concerned that it will be difficult to achieve
high vaccination compliance among adolescents, others believe
vaccines present an opportunity to keep adolescents in the
health care system or to make schools the site for preventive
care for adolescents. Additional vaccines that might be
administered in adolescence--but which are not as far along in
development--include vaccines to protect against Epstein-Barr
virus and cytomegalovirus.
--Respiratory syncytial virus.--Respiratory syncytial virus (RSV) is
the major cause of lower respiratory tract illness in infants
and young children. It is often associated with pneumonia and
bronchiolitis. RSV produces sizable epidemics in major urban
centers during the winter season, resulting in an average of
100,000 hospitalizations and approximately 5,000 deaths
annually. Several companies have research efforts directed at
development of an RSV vaccine, and clinical trials are
underway.
--Lyme disease and rabies.--At the most recent meeting of the
Advisory Committee on Immunization Practices (ACIP), there were
presentations from vaccine companies regarding the development
of a vaccine to prevent Lyme disease and a vaccine to prevent
rabies. These vaccines are outside the group of products that
might be commonly thought of as childhood vaccines, but I
mention them to illustrate the range of research on new
preventive vaccines.
--Influenza vaccine.--There is also ongoing research on an influenza
vaccine for children. This project is noteworthy not only
because it would be the first flu vaccine that is effective in
children but also because of its route of delivery. One
promising candidate vaccine could be administered as a nasal
spray instead of an injection, thereby easing its
administration and perhaps improving compliance with the
requirement of annual reimmunization against influenza.
--Adult immunization.--An area of great interest is the development
of new vaccines and improvement of existing vaccines for adult
use. Currently, influenza vaccine and pneumococcal vaccine are
recommended for use in adults, although compliance with the
adult recommendations--despite ready Medicare payment for
senior citizens--is still low. Research is concentrated on
improving those vaccines so that usage could be encouraged. In
addition, there is a great deal of interest in use of the
acellular pertussis vaccines--only recently approved for
infants--as a booster in adults. There are still several
thousand cases of pertussis in the United States annually, and
many believe the disease will not be brought under control
until adults are immunized and no longer carry the organism.
--Other age-appropriate immunization strategies.--Aside from adult
immunization, there are other cohorts who are legitimate
targets for immunization beyond those currently contemplated in
the immunization program. One way of dealing with the
proliferation of new antigens and the accompanying increase in
injections is to identify certain diseases as preventable
through either maternal--i.e., prenatal--or adolescent
immunization. Infections with organisms like Group B
streptococcus and RSV in infants during the first months of
life may be preventable through maternal immunization, and
vaccines to prevent sexually transmitted diseases could be
delivered in adolescence.
--Combination vaccines.--All vaccine companies are investing
considerable resources in the development of new combination
products that will reduce the number of injections required for
full immunization. Several of the vaccines you are familiar
with are combination vaccines--for example, diphtheria-tetanus-
pertussis vaccine and measles-mumps-rubella vaccine are
combination vaccines. Even polio vaccine is technically a
combination vaccine because it contains three strains of polio
virus. Public health experts are pressing for more antigens to
be combined into one shot.
Vaccine companies enjoyed great success when we combined
diphtheria-tetanus-whole cell pertussis vaccine with Hib vaccine, and
pediatricians and public health providers enthusiastically accepted
that new combination, which simplified the immunization schedule by
reducing the number of injections required at the 2-month, 4-month, and
6-month visits. Our success on that combination might have left
pediatricians and others with the impression that developing
combination vaccines is a relatively straightforward and easy process.
Instead, we have found the next logical combination product to be a
real scientific challenge. When acellular pertussis vaccines were
introduced for toddlers--and recently for infants--vaccine companies
turned their attention to developing a Hib-containing combination that
would include acellular pertussis vaccine in place of the whole cell
pertussis vaccine.
Those vaccines have posed very difficult development problems.
Although we are not certain of the mechanism of interference, in most
cases the acellular pertussis component of the vaccine seems to
decrease the immunogenicity of the Hib component in infants who are
administered the combination product, compared to those who receive the
vaccines separately. Companies are trying new strategies to eliminate
this interference problem and are also developing combinations of Hib
with vaccines other than DTaP that will not result in decreased
protection, compared to separate vaccines.
Because of the complexity of the infant immunization schedule,
companies now evaluate new candidate vaccines in ways we did not in the
past. We look closely at the route of administration of the vaccine: is
it possible to administer the vaccine orally, in order to avoid an
additional injection, and is the vaccine a good candidate for
combination with other antigens? Vaccine companies are developing new
technologies for vaccine development, including new adjuvants that will
enhance the responses to vaccines and reduce the number of doses
required for protection against disease, and time release mechanisms
that will allow delivery of a full immunization series in a single
shot. I am confident that we will be successful in keeping the schedule
as simple as possible while enhancing its medical value.
role of the government in vaccine research and development
There has been a great deal of rhetoric in recent years about how
government and industry must be partners in the vaccine development
process. As a vaccine researcher and developer for 13 years--in a
start-up biotechnology company and in a vaccine division that has been
part of two large corporations--I have strong views about how
government policies affect the ability of private vaccine companies to
provide a reliable supply of vaccines and develop new vaccines. If
public-private collaboration is to be successful, there must be balance
and predictability in the relationship between industry and government.
The Federal Government as Vaccine Purchaser
Prior to enactment of the Vaccines for Children (VFC) program in
1993, the federal government had been for many years the single largest
purchaser of vaccines in the U.S., with federal purchases, at
dramatically discounted prices, ranging up to 50 percent of the total
market. The equilibrium that existed prior to VFC no longer exists, and
the federal share of vaccine purchase appears to be steadily
increasing. Aside from the volume of VFC purchases, other elements of
the program are having an impact on industry sales and revenue, with an
almost inevitable future effect on vaccine research and development.
Whether a vaccine company is a small start-up operation or an
existing division of a large corporation, development of new vaccines
will occur only if revenues from vaccine sales are available to support
the R&D effort. The imposition of outright price controls on vaccines
under contract with CDC as of May 1993 has been a cause of concern
among vaccine developers, both for its immediate impact and for its
precedential effect. This concern has been voiced not only by the major
manufacturers but also by smaller biotechnology companies with vaccines
or vaccine-related products in development.
When VFC was enacted, there were specific inducements to industry
included in the legislation. The prices of new vaccines were to be
controlled by the market, not by government. Moreover, industry was
promised rapid uptake of new vaccines by virtue of the fact that the
VFC entitlement did not require congressional action. In addition,
rather than the former winner-take-all practice in federal contracting,
the legislation provided for multiple suppliers, a measure that was
intended to provide stability in market share where more than one
company had an approved vaccine.
With respect to decisions to cover new vaccines, the VFC statute
gave unusual authority to the CDC's ACIP in order to ensure that
decisions would be based not on budgetary considerations but on the
public health. The VFC Conferees stated: The Conferees intend that the
Advisory Committee on Immunization Practices be allowed to conduct its
work in an objective manner, concerned only with issues of public
health and medicine. While decisions regarding the list of recommended
vaccines will, undoubtedly, have some budget implications for the
program and the Secretary, it is the Conferees' intention that the
ACIP's work be rigorously separated from such concerns. \7\
---------------------------------------------------------------------------
\7\ 139 Cong. Rec. H6173 (daily ed. Aug. 5, 1993).
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Intent on avoiding previous circumstances in which vaccines had
been recommended by the ACIP but not purchased promptly by the federal
government because of budgetary concerns, Congress effectively made the
decision to cover vaccines under VFC automatic once the ACIP had made
its recommendation. In fact, the Conferees stated their specific
intention ``that the Secretary provide for Federally vaccine-eligible
children the same vaccines that are recommended for children with their
own source of payment.'' \8\
---------------------------------------------------------------------------
\8\ 139 Cong. Rec. H6173 (daily ed. Aug. 5, 1993).
---------------------------------------------------------------------------
Unfortunately, at some point in the implementation of the VFC
program, this congressional intent appears to have been lost. Now, the
ACIP is being encouraged to conduct a rigorous cost-benefit analysis
before making a decision about VFC purchase. A consideration of the
costs and benefits of a vaccine is routinely part of the ACIP
discussions surrounding the development of a recommendation for general
usage of a vaccine, but the advisory committee is now repeating that
analysis--in fact, in some cases asking for additional data on costs
and benefits--before making a purchase decision. This approach has
resulted in a delay in the acceptance of certain new vaccines--most
recently, the varicella vaccine--while ACIP weighs matters of cost.
This is troubling to manufacturers because we now have a very large
purchaser of vaccines that does not necessarily accept its own
decisions regarding routine vaccine usage and delays the uptake of new
products. The whole idea undergirding the VFC program was to make the
same vaccines available to all of America's children, whether rich or
poor, whether in the private or the public sector. Yet the two-step
process by which the ACIP is reviewing new vaccines--first making a
general recommendation, then proceeding to consider whether the vaccine
should be covered by VFC--is inherently creating a two-tiered
immunization system. With respect to varicella vaccine, the ACIP has
issued a very broad recommendation, but has bridled at the same scope
of coverage for purposes of VFC purchase. We hope Congress will give
the CDC and ACIP some direction about its intent when it drafted the
VFC program and its hope that new vaccines would be quickly integrated
into the new program.
Another potentially troubling aspect of VFC implementation involves
contracting approaches or ACIP policy statements that might serve to
restrict availability of individual vaccine products to providers. This
stems from a desire to lessen perceived ``confusion'' among providers
regarding new vaccines and the new vaccine schedule. Either through
restrictive contracting or through encouragement to limit choices, the
prospect is raised that providers may not have the full range of
options in selecting specific vaccines. Industry regards this as a
potential breach of the legislation's promise of multiple suppliers for
each antigen. In our experience, providers are able to make sound
choices among the available products. Like any prudent purchasers,
providers reward quality and convenience in use while keeping an eye on
product price. Restricting provider choice is a step backward that is
inconsistent with the spirit of VFC.
The Federal Government as a Research Funder
An ideal theoretical division of research responsibility between
the public and private sectors would have the federal government fund
basic research while industry supports clinical or applied research. In
practice, however, the relationship is more complicated. Vaccine
companies perform a substantial amount of basic research, especially in
areas that have generally not been explored by others. At the same
time, the federal government has been a major funder of a variety of
clinical vaccine research.
As a general proposition, industry should take responsibility for
financing and conducting the clinical trials that lead to FDA approval
of vaccines for routine use in children. We believe that the federal
government has a role to play in some clinical research. For example,
certain clinical trials would not be undertaken if the federal
government did not choose to fund them. The trial of adult acellular
pertussis vaccines that the National Institute of Allergy and
Infectious Diseases (NIAID) has recently agreed to fund may be one such
example. Federal maintenance of a clinical trials network has also
contributed to the high degree of clinical trials expertise and ready
availability of an infrastructure for conducting trials, and that
effort could not be readily duplicated in the private sector.
However, the federal government should not fund trials of products
where companies are willing to support the trials. This is an
unnecessary commitment of federal resources, and it creates a situation
in which the government may give one company an advantage over others.
The advantage is not restricted to the results of the trial but also to
what amounts to an endorsement of a product. In addition to providing
an immediate advantage in terms of avoiding the substantial cost of a
clinical trial, government funding creates a perception that one
product may be favored over others in the process of review and
approval by other government agencies, including both FDA and the ACIP.
The Federal Government As Defender of Childhood Immunization
Despite the fact that public confidence in the safety of childhood
vaccines is much higher than prior to enactment of the injury
compensation system, there remain small but vocal groups who are quick
to exaggerate problems with these products, which are overwhelmingly
safe and effective. It does not take much misinformation to dissuade
parents from immunizing their infants. Several years ago, for example,
the selection of a hearing-impaired Miss America led to public
statements that her disability was the result of a DTP shot in infancy.
Fortunately, her pediatrician corrected the public record by noting
that in fact Miss America was deaf as a result of a childhood Hib
infection. Now, of course, Hib conjugate vaccines make this condition
largely a thing of the past.
We believe the federal government should take as one of its primary
responsibilities the defense of childhood immunization against
irrational fears unsupported by data. At present, vaccines are under
attack from a variety of sources who are willing to take advantage of
the most remote theoretical possibility of adverse reactions. Federal
agencies should utilize their not insubstantial public relations
capacities to deal promptly and aggressively with scientifically
unsound assertions that threaten public confidence in vaccines.
The Federal Government's Role in Global Immunization
As important as childhood immunization is in the United States, it
can no doubt accomplish even more in developing countries around the
globe. Financial aid from the U.S. and the significant private sector
support of organizations like Rotary International will never be
adequate to address all the global opportunities for prevention of
disease through immunization. Wyeth-Lederle, which has been mostly a
domestic supplier of vaccines, would like to do our part to prevent
disease in developing countries where the need is most acute.
Several of our new vaccine products could have their greatest
impact in the developing world, but there are many hurdles before we
can become an effective global vaccine company. One concern that could
be alleviated by U.S. governmental action is that relating to
differential pricing of products between developing and developed
countries. During the 1993 debate over the VFC program, vaccine
companies were unfairly targeted as selling products in the U.S. at a
higher price than abroad. Our company, which at that time sold very
little vaccine internationally, could truthfully say that our prices in
the U.S. were no higher than in other countries.
For the future, however, that cannot be the case if we expect life-
saving vaccines to reach the developing world. Those countries simply
lack the resources to pay fair value for new vaccines like those to
prevent rotavirus or pneumococcal disease. As a result, prices in the
United States and other developed countries must be high enough
essentially to subsidize the cost of delivering the same vaccines to
developing countries. In fact, European-based vaccine companies have
long supplied vaccines like DTP, OPV and measles to world health
agencies at greatly discounted prices. Polio eradication would not be
possible if this had not been true. The practice of subsidizing
revenues from sales in less developed countries with revenues from
sales in developed countries should not subject a company like mine,
which is seeking to globalize what has been a domestic business, to
unfair criticism. U.S. government policy should specifically recognize
the legitimacy of differential pricing as a way of meeting our moral
obligation to the less fortunate countries of the world. Furthermore,
as the global polio eradication campaign demonstrates, control of
diseases overseas can have a direct beneficial impact on disease levels
in the U.S.
conclusion
This is an exciting time for vaccine research and development. Over
the course of the next few years, there will be a number of new
vaccines that will protect American children from dreaded diseases. A
decade ago, Members of this Subcommittee were concerned that suppliers
of the three childhood vaccines then in use would desert the market and
the federal government would be searching for emergency vaccine
supplies.
Now, providers' and consumers' complaints relate more often to the
wealth of new products and the confusion of the immunization schedule.
Industry is confronting the challenge of schedule confusion by working
hard to develop new combinations that will not compromise the
effectiveness of the separate products, and the federal and state
governments must be very involved in educational efforts regarding
schedule additions and changes.
From time to time, there are proposals to develop comprehensive
research and development plans for new vaccines under the auspices of
this or that government agency. The history of vaccine research and
development does not support the notion that government planning makes
a significant contribution to the process. Instead, vaccines have been
developed as a result of solid basic science forming a foundation for
clinical development. When the science is ready, the vaccines will
follow--and not before.
In my testimony, I have recounted only research successes or
promising avenues of exploration. For all these successes, there are
many more projects that have not borne fruit in the form of new
products. Vaccine research is risky and can thrive only when those
supporting it--including both the federal government and the investment
community--understand and accept those risks.
For the industry to remain a reliable supplier of vaccines and
developer of new products to protect against additional disease, we
must have a stable, predictable, and cooperative relationship with the
government if it remains the major purchaser of vaccines. We believe
that a true partnership can produce exciting new possibilities for
preventing childhood disease.
______
Appendix 1
high-risk populations are protected
Improvements in immunization coverage have reached populations with
a high burden of vaccine-preventable diseases and low immunization
coverage. Measles among preschool children has been a marker for
underimmunization. The disease had disproportionately affected urban
areas and racial and ethnic minority populations during the resurgence
of 1989-1991 as a result of undervaccination of preschool children.
However, measles has now virtually disappeared from these populations.
Between 1989 and 1991, 55,622 cases were reported across the country.
In contrast, between 1993 and 1996, 2,072 cases were reported. In New
York City during the 1989 to 1991 resurgence, there were 3,144 reported
measles cases, but only 51 cases were reported from 1993 to 1996.
Improved immunization coverage against measles is a major reason
for these decreases. Studies of children who were two years of age
during the mid to late 1980's in 15 large urban areas, documented a
median measles vaccination coverage of 67 percent, ranging from 52 to
78 percent. In contrast, data from the same 15 urban areas from the
1995 NIS documented a median coverage of 89 percent, ranging from 81 to
97 percent.
Successful Strategies
CDC and its partners are implementing strategies that work.
Improved coverage is a result of State and local areas' implementing
proven strategies that increase immunization rates. In Chicago, for
example, a 1994 survey of five Housing Authority units showed that MMR
coverage among 19- to 35-month-old children was 62 percent. A 1996
follow-up survey showed that MMR coverage had increased to 76 percent.
This increase intensified linkages with the U.S. Department of
Agriculture's Special Supplemental Nutrition Program for Women,
Infants, and Children (WIC), using outreach workers to bring children
into the health care system, and using a mobile van to improve access
to care.
Linking the WIC program with assessment of immunization status has
been highly effective in increasing coverage in areas of
underimmunization. For example, data from three cities, between June
1995 and May 1996, found that immunization coverage of WIC participants
improved 24 to 33 percentage points within 12-15 months of starting
interventions (Table 4).
TABLE 4.--RESULTS OF WIC/IMMUNIZATION LINKAGE EFFORTS IN SELECTED CITIES
----------------------------------------------------------------------------------------------------------------
Percent of
Location Number of births in Preintervention Postintervention Project
sites WIC results results period
----------------------------------------------------------------------------------------------------------------
Chattanooga........................... 4 55 57 84 12
Boston................................ 12 35 39 63 15
Chicago............................... 48 55 56 89 12
----------------------------------------------------------------------------------------------------------------
Note: Children 24 to 27 months of age.
Despite these successes, underimmunized populations continue to
exist, and we must continue efforts to further address these areas.
Pockets of need are being identified and addressed
CDC has been working closely with States and urban areas to improve
coverage. In 1997, all States were required to describe how they will
identify concentrations of underimmunized populations and the measures
they will take to improve coverage. CDC suggests various means of
identifying underimmunized populations, such as use of coverage data
from local surveys, clinic assessments, and/or use of surrogate
measures including poverty status, which has been shown to correlate
with low immunization coverage. Proven approaches, such as linking
immunization with the WIC Program, clinic and provider assessments with
feedback of results to decisionmakers who can improve performance,
reminder and recall systems, and immunization registries are being
employed by States and urban areas. In addition, they are implementing
other innovative strategies, such as increased outreach and education.
Other CDC activities are also aimed at improving coverage and
reducing disease. At the direction of Congress, CDC awarded funds last
year to support childhood demonstration projects in community health
networks in three urban areas, Detroit, San Diego, and New York City,
and one rural area consisting of four counties in Colorado. These
projects will demonstrate whether an academic medical center, as a
leader of a community health network, can raise immunization coverage
by using interventions to improve clinic immunization practices and
conducting outreach.
Also at the direction of Congress, CDC awarded inununization funds
to four school-based demonstration clinics in New York, West Virginia,
South Dakota, and Wisconsin to determine if these school-based clinics
can help raise immunization rates in their communities. Finally, in
collaboration with the U.S. Department of Housing and Urban
Development, CDC recently awarded funds to support immunization
demonstration projects in public housing authorities, where children at
risk of underimmunization are likely to reside. Selected cities include
Kansas City, Little Rock, Chicago, and Philadelphia. These projects
will be important in determining methods to improve immunization
coverage among children living in public housing.
hib vaccine on trial in gambia
Senator Bumpers. Dr. Paradiso, I am reluctant to interrupt
you, but I just read a thing in the World Health Organization
where the Hib vaccine is on trial in Gambia.
Dr. Paradiso. Yes.
Senator Bumpers. Why--and it says that from all appearances
it is going to be as effective in African countries as it is in
industrialized nations.
Dr. Paradiso. Yes.
Senator Bumpers. What is the difference? I found that
intriguing.
Dr. Paradiso. The major difference is that Haemophilus b in
developing countries and in Africa, where this was done in the
Gambia, the biggest problem is in pneumonia, and Haemophilus b
causes pneumonia in that population. So the question was, first
of all, whether in that population those children would respond
to conjugates at a very young age the same way people in
developed countries do, and the answer to that was yes, and you
do prevent the same kind of disease we see here.
But what they also found out was that they also prevented
against pneumonia, and they found out that a large portion of
pneumonia was from Haemophilus on the basis of how much
pneumonia went down as a result of vaccinations.
So the World Health Organization has now targeted
Haemophilus conjugate as the next vaccine to add to their
program, along with hepatitis B, for global immunization.
The vaccine pipeline contains a wealth of new products,
which I have described in some detail in my written statement.
We also have prepared a few charts for the research pipeline
for the four vaccine companies currently serving the U.S.
pediatric population.
The first charts shows the products that are under
development at SmithKline Beecham and at Wyeth-Lederle
Vaccines, my company. The second chart, on the other side, show
the vaccine development for Merck Co., as well as Pasteur
Merieux Connaught.
I am not going to go over this list of vaccines, but it
shows you the impressive array of vaccines that are currently
in some point of research and development within these
companies. They include vaccines, for instance, they include
vaccines for adolescents, for sexually transmitted diseases,
for elderly where we are recognizing that they become
susceptible to childhood diseases again as they get older and
their immune systems become compromised. So there is an
impressive array of vaccines that all these companies are
working on and that the public sector is working on to take
advantage of the cost effectiveness of vaccines.
Because I have limited time today, I will discuss only the
two new antigens which will probably be introduced into the
childhood immunization schedule soon. The conjugation
technology which I spoke to you about and that was necessary
for the production of the Hib vaccines is now being used to
develop several new vaccines, including one that will protect
against streptococcus pneumoniae, also known as pneumococcus,
which causes meningitis, bacteremia pneumonia, and nearly 50
percent of childhood ear infections.
One of the most pressing issues facing pediatricians today
is the emergence of antibiotic-resistant strains of
pneumococcus. In some locations nearly 40 percent of strains
are resistant. According to the Centers for Disease Control,
the way to address the looming problem of antibiotic resistance
to pneumococcus is to develop vaccines that will prevent
infections by the organism. Industry is committed to developing
these vaccines. Several companies are dedicating considerable
resources to this effort and a number of candidate vaccines are
already in clinical trials.
The pneumococcal vaccine will include seven or more strains
of streptococcus pneumoniae, thereby providing protection from
a broad spectrum of pneumococcal infections.
Streptococcus pneumoniae vaccines were identified in 1986
by a special panel of the Institute of Medicine as one of the
five high priority category vaccines for the developing world.
This designation is explained by the fact that pneumococcus is
the largest cause of pneumonia in young infants globally and
pneumonia is the single largest cause of deaths worldwide.
Another vaccine that the Institute of Medicine panel
included in the high priority category for the developing world
as a candidate for accelerated development in the United States
is the rotavirus vaccine. Rotavirus is the most common cause of
severe diarrhea among children and strikes virtually every
child by the age of 4. The direct medical costs associated with
rotavirus are more than $400 million annually, primarily the
result of the fact that young children can get dangerous
dehydrated very quickly, and the total societal costs are over
$1 billion annually.
The impact of rotavirus goes beyond our borders. In less
developed countries rotavirus is a major killer of young
children.
The rotavirus vaccine also answers the concern of
immunization providers that researchers reduce the number of
injections required for full vaccination and utilize oral and
other routes of delivery whenever possible. My company has
recently filed an application for a new oral rotavirus vaccine
that will protect children against 80 percent or more of
serious diarrhea caused by rotavirus.
This is an exciting time for vaccine research and
development. Over the course of the next few years there will
be a number of new vaccines that will protect American children
from dreaded diseases. A decade ago, members of this
subcommittee were concerned that suppliers of the three
childhood vaccines then in use would desert the market and the
Federal Government would be searching for emergency vaccine
supplies. Now, in contrast, there is reference to an
embarrassment of riches as the question is how to smoothly
integrate the new life-saving products into the childhood
immunization schedule.
As these comments suggest, biotechnology is revolutionizing
childhood immunization. Another important influence on the
vaccine research and development is the increased participation
of the Federal Government. No example of Government involvement
in the process has made a greater impression on vaccine
companies than the Vaccines for Children Program enacted in
1993. As you know, the VFC Program was of great concern to the
vaccine industry because it gave the Government unprecedented
power to purchase vaccines and impose price caps. We argued at
the time of the enactment of VFC that the combination of price
controls and expanded public market might have a devastating
impact on vaccine research and development.
In response, the administration offered and Congress
incorporated into VFC certain features intended to allay these
concerns. In order to provide stability in the marketplace and
support vaccine research and development, VFC envisions
contracts with multiple suppliers and promises that new
vaccines will not be subject to a price cap. Moreover,
companies introducing new vaccines were led to believe that
their products would have the benefit of immediate uptake by
the VFC program as coverage would be virtually automatic once
an ACIP recommendation had been issued.
To avoid a repeat of situations where the Federal
Government failed for extended periods of time to purchase new
recommended vaccines, notable examples being hepatitis B,
acellular pertussis for toddlers, and combination DTP-Hib,
coverage decisions were delegated to the ACIP. Congress
believed that the ACIP would be driven only by public health
and medicine and not by budgetary considerations. Therefore,
Congress directed the Secretary to ensure that those children
who are eligible for VFC would automatically receive the same
vaccines as those generally recommended by the ACIP and
received by children in both the public and the private sector.
Unfortunately, at some point in the implementation of the
VFC program this congressional intent appears to have been
lost. In implementing VFC, CDC has instructed the ACIP to
follow a two-step process. This has resulted in a very
difficult task for committee members, whose expertise is in
medicine and public health. Their decisions should be based on
their expertise.
Rather than relying on general recommendations developed
strictly on public health grounds, the ACIP now engages in a
second evaluation that seems to involve reconsideration of cost
effectiveness. This approach has resulted in delay in the
acceptance of certain new vaccines, most recently the varicella
vaccine, while ACIP weighs matters of costs.
We do not believe that Congress intended the current two-
step process that CDC is employing for VFC coverage decisions.
How does this affect vaccine research and development? The lead
time for the development of new vaccines is extremely long.
Companies can expect to wait a decade or more before new basic
research is translated into vaccines in the marketplace. Before
investors will dedicate resources to potential new products,
they must have some assurance that there will be a market for
them.
With the advent of managed care, most of us are secure that
our products will be welcomed in the private sector as cost-
effective alternatives to hospitalization and other expensive
treatment interventions. We need to also be confident that the
Federal Government will be a stable and reliable purchaser of
our new vaccine products and accept new vaccines at a fair
price, at least as long as the Government remains our major
customer.
The promise of new vaccine R&D is impressive. Vaccines are
among our most humane and effective medical tools and, unlike
most other interventions, are not only cost effective but cost
beneficial. However, they will save neither children nor costs
if they are not used. Industry is doing its part by making
vaccines available. Government's role should be to ensure that
they are used through public education, support for vaccine
research where appropriate, and a reasonable and balanced
purchase program.
Thank you for this opportunity, and I welcome your
questions.
Senator Bumpers. Thank you very much, Dr. Paradiso, for
that excellent statement.
STATEMENT OF WALTER A. ORENSTEIN, M.D., DIRECTOR,
NATIONAL IMMUNIZATION PROGRAM, CENTERS FOR
DISEASE CONTROL AND PREVENTION, DEPARTMENT
OF HEALTH AND HUMAN SERVICES
Senator Bumpers. Dr. Orenstein.
Dr. Orenstein. Thank you very much, Mr. Chairman. I am Dr.
Walt Orenstein, Director of the National Immunization Program
at the CDC. I am pleased to appear before the subcommittee to
discuss future vaccine development.
I want to thank you personally and the subcommittee for the
support and leadership you have provided to assure that our
Nation's children are fully protected against vaccine-
preventable diseases. Your support has contributed much to our
success.
achievements in child immunization initiative
As you mentioned in your opening statement, this Nation has
made unprecedented progress toward our goals of eliminating or
reducing vaccine-preventable diseases. Provisional data for
1996 show that record low levels were set or tied for mumps,
tetanus, polio caused by wild viruses, and invasive Haemophilus
influenza. Fewer than 500 measles cases were reported, down
from almost 28,000 cases in 1990, and all of the cases in 1996
are believed to be due to recent importations from abroad.
We also have high immunization coverage among 2-year-old
children. Data from the 1995 national immunization survey show
that 95 percent of 2-year-old children received three or more
doses of the DTP vaccine, 88 percent received three doses of
polio vaccine, 90 percent received a dose of a measles-
containing vaccine, and 92 percent received three or more doses
of Haemophilus influenzae type b vaccine. The national coverage
rate for the 4-3-1 series was 76 percent in 1995, the highest
level ever achieved.
vaccine development
The pace of progress in the area of vaccine development is
quickening, as we have highlighted in our first chart, which
depicts the cumulative number of changes to the routine
immunization schedule since 1975. The schedule has been
changing dramatically since the late 1980's. Each vial
represents a single change. In the 10 years between 1975 and
1984 only one change to the schedule was made. In contrast, in
the 10 years between 1988 and 1997 more than 10 changes were
made.
Several new vaccines may become available in the next few
years to prevent death and disability from other infectious
diseases and, as has already been mentioned, will be considered
for universal childhood immunization. These include a vaccine
for rotavirus diarrhea, a vaccine against strep pneumoniae,
which causes an estimated 7 million ear infections each year in
the United States, and even a vaccine for meningococcal
disease, another cause of serious meningitis.
accomplishments with new vaccines
These are wonderful fruits of the revolution in
biotechnology, but they pose challenges for those of us in
public health who have to implement them.
If you could put on the next chart, please.
As you can see in this chart, in 1987, just 10 years ago,
there were just six injections required through 2 years of age.
Now in 1997, as shown by the blue shots on the chart, there is
a minimum of 11 injections if certain combinations of vaccines
are used and as many as 4 more shots, as shown in yellow, if
other vaccines are used.
The number of injections can result in three or four
separate injections at some visits to one's provider, or more
visits, which might compromise compliance.
Next chart, please.
The vaccine manufacturers have responded to this problem by
working to combine antigens developed to prevent multiple
diseases into combination vaccines. As you mentioned in your
opening statement and as shown in the top part of this chart,
in 1996 two new combinations were introduced, the DTaP-Hib for
toddlers, shown here at the top left, and the Hib-HepB for
infants 6 weeks of age or older, shown on the top right.
Possibly appearing in the years ahead are many more vaccines,
including some which could prevent seven diseases with a single
product.
Senator Bumpers. Let me interrupt you just a moment, Walt.
Dr. Orenstein. Sure.
Senator Bumpers. Are you saying that those combinations are
in existence now?
Dr. Orenstein. That is correct. The Hib-HepB is in
existence right now, the one on the top right. The one on the
top left is in existence for the fourth dose of the schedule.
It is not yet licensed for doses one, two, and three, although
we expect that in the near future.
Senator Bumpers. I understood you to say we had a
combination of DTaP, Hib, and HepB.
Dr. Orenstein. No; that is not yet available.
Senator Bumpers. OK.
Dr. Orenstein. The ones on the----
Senator Bumpers. I misunderstood this. I had looked at that
chart.
Dr. Orenstein. OK. The ones on the bottom are ones that
various companies have told us at one point or another that
they are seriously considering. I would imagine only a few of
these may actually reach the market, but these are the ones
that are potentially in the pipeline that we have to be
prepared for.
challenges posed by new vaccines
As I said, this is a list of up to 20 products. The
benefits of such combination vaccines are clear. More diseases
can be prevented with fewer shots. We can decrease immunization
visits and increase parental and provider acceptance of new
vaccines.
However, we face several challenges, including the
potential increased cost of combination vaccines. Developing
combination vaccines is neither simple nor cheap, because it
must be demonstrated that there are not any potential chemical
incompatibilities between ingredients, nor immunologic
interference, and that the overall safety and efficacy is not
compromised compared to the individual products. Development of
combination vaccines may require greater collaboration among
vaccine manufacturers. Since not all manufacturers currently
make all vaccines, companies will have to acquire rights to
include certain components in their new combination vaccines,
which could add to the cost of these vaccines.
Actual production costs may be higher because it is
necessary to assure all components, both individually and when
combined, meet safety and efficacy requirements. Although these
vaccines may be shown to be cost saving compared to existing
vaccines, some resistance to a higher price may exist. This may
occur since the budgetary pocket that purchases the vaccine is
often not the pocket which accrues the cost savings in reduced
numbers of doctor's visits, parental time lost from work, and
reduced costs of caring for prevented diseases.
safety and efficacy issues
Individual vaccines may be cheaper to purchase, but more
expensive to deliver.
An important challenge for all new vaccines, particularly
new combination vaccines, will be to monitor safety and
effectiveness after licensure. New vaccines are usually tested
in up to 10,000 people prior to licensure to assure basic
vaccine safety and efficacy. These studies are unlikely,
however, to detect less frequent adverse reactions that still
may be of public health importance when these vaccines are used
in millions of children.
To monitor the safety of new and combination vaccines,
surveillance of adverse events following licensure must occur
to ensure that if new unanticipated adverse events occur, they
are detected. In addition, it is critical to scientifically
evaluate whether rare adverse events observed following
vaccination are actually caused by the vaccine or represent
coincidental illness that would have occurred anyway.
The CDC has developed the vaccine safety datalink project,
in which four health maintenance organizations link vaccination
and medical records of more than 1 million children to provide
exactly this scientific basis for evaluation of causation of
adverse events.
The effectiveness of new combinations must also be
monitored. It may not always be predictable when vaccines can
be combined together. We will have to maintain strong disease
surveillance to look for evidence that these new vaccines
really work by reducing the actual occurrence of disease.
issues related to stocking vaccines
Another issue related to combination vaccines is the need
to determine which vaccines to stock among many potential
options.
If you could go to the next chart, please.
For example, the licensure of combined Hib-HepB, shown here
at the top of refrigerator 1, and combined DTaP-Hib, shown at
the top of refrigerator 2, represented a turning point in
immunization practice, as these two products contain
overlapping, noncomplementary antigens. They both contain Hib.
In refrigerator 1 on the chart, if HepB-Hib is stocked, a
child can be fully vaccinated against five diseases with this
vaccine and DTaP alone. That is all that would need to be
stocked in that refrigerator. DTaP-Hib is not needed, even when
it becomes available for infant vaccination, and in fact using
this combination with Hib-HepB would give extra, unneeded doses
of Hib, because you can see that Hib is in both vaccines and
you only need one Hib.
In contrast, as shown in refrigerator 2, if DTaP-Hib is
stocked, HepB alone is needed, rather than the combination Hib-
HepB, and DTaP alone is needed.
Choosing what to stock for the individual physician would
be easy if the patient stayed with that physician.
Unfortunately, patients switch and may have been started on one
regimen and then moved into another practice. Thus, until
combinations are available containing all the vaccines,
physicians and clinics will be confronted with the choice of
stocking all vaccines to meet every possibility, as shown in
refrigerator 3 here, or stocking a limited number of vaccines,
as shown in refrigerators 1 or 2, to help simplify the
inventory in a given clinic, and thus occasionally having to
give extra doses of some vaccine components.
These choices have cost implications both for the
individual physician or clinic and for public health programs.
An additional challenge for CDC in the future will be to create
procurement strategies which are as economical as possible,
while continuing to encourage vaccine manufacturers in the
research and development of innovative vaccine technologies.
CDC is testing a procurement strategy for DTaP vaccines
which more closely approximates the private sector market. As
long as the ACIP considers each manufacturer's products
essentially equivalent from a public health perspective,
manufacturers of all licensed vaccines are given access to the
public vaccine market and States can then choose which product
or products they want to use.
A contract was established with each licensed manufacturer
with low guaranteed minimum purchase requirements and
manufacturers are able to change the negotiated price every 3
months as long as the price does not exceed the original
negotiated price.
In conclusion, a remarkable record of success has been
achieved. Vaccine-preventable diseases are at or near record
low levels and immunization coverage is at record high levels.
New vaccines offer the promise of preventing more and more
infectious diseases. Combination vaccines offer the promise of
simplifying vaccine delivery so we can assure that children
will benefit from all these vaccines.
However, future challenges lie ahead. The development of
new and combination vaccines raises issues related to cost,
assuring safety and efficacy, and product choices. We welcome
these challenges, however. The short-term costs and
difficulties should be more than compensated for by the
additional protection against diseases conferred by these new
vaccines.
prepared statement
With your help and working with our partners in industry,
public health, the provider community and others, we are
confident that we can overcome obstacles and take advantage of
opportunities.
Thank you and I would be happy to answer any questions you
may have.
Senator Bumpers. Thank you very much, Dr. Orenstein, for a
highly enlightening statement.
[The statement follows:]
Prepared Statement of Walter A. Orenstein, M.D.
introduction
Mr. Chairman, I am Dr. Walter Orenstein, Director, National
Immunization Program, for Disease Control and Prevention (CDC). I am
pleased to appear before the Subcommittee to discuss fixture vaccine
development.
I want to thank you and the Subcommittee for the support and
leadership you have provided to assure that our Nation's children are
fully protected against vaccine-preventable diseases. I am happy to
report great progress, we have record low disease levels and record
high immunization rates. Your support has contributed significantly to
our success.
Record low levels of vaccine preventable diseases
This Nation has made unprecedented progress toward our goals of
eliminating or reducing vaccine-preventable diseases. Reported cases of
eight vaccine-preventable diseases have declined by at least 97 percent
from prevaccine era peaks (Table 1). Provisional data for 1996 show
that record low levels were set or tied for mumps, tetanus, polio
(caused by wild viruses), and invasive Haemophilus influenzae (for
children under 5 years of age). Only one case of diphtheria was
reported, and fewer than 500 measles cases were reported. (All of the
measles cases are believed to be connected to recent importations.)
Pertussis, even though occurring at levels more than 97 percent below
prevaccine era rates, is occurring at levels higher than we would wish.
It is now, however, predominately occurring in older children,
adolescents, and adults, for whom, there are no currently licensed
pertussis vaccines. The National Institutes of Health has recently
undertaken a study to determine whether new acellular pertussis
vaccines available for children can safely protect adults.
TABLE 1.--COMPARISON OF MAXIMUM AND 1996 PROVISIONAL MORBIDITY VACCINE-PREVENTABLE DISEASES
----------------------------------------------------------------------------------------------------------------
1996
Maximum cases provisional Percent change
cases
----------------------------------------------------------------------------------------------------------------
Diphtheria...................................................... 206,939 1 -99.99
H. influenzae, invasive disease (less than 5 years)............. \1\ 20,000 276 -98.62
Measles......................................................... 894,134 488 -99.95
Mumps........................................................... 152,209 658 -99.57
Pertussis....................................................... 265,269 6,467 -97.56
Polio (paralytic)............................................... 21,269 .............. -100.00
Rubella......................................................... 57,686 210 -99.64
Congenital Rubella syndrome..................................... \1\ 20,000 2 -99.99
Tetanus......................................................... \2\ 1,560 27 -98.27
----------------------------------------------------------------------------------------------------------------
\1\ Estimated.
\2\ Mortality.
Record High Immunization Coverage
We have record high immunization coverage among 2-year-old
children. The 1995 National Immunization Survey (NIS) (Table 2), the
latest data available, shows that 95 percent of 2-year-old children
received three or more doses of the diphtheria/tetanus/pertussis (DTP)
vaccine, 88 percent received three doses of polio vaccine (OPV), 90
percent received one dose of a measles-containing vaccine, and 92
percent received three or more doses of the Haemophilus influenzae type
b (Hib) vaccine. The national coverage rate for the 4:3:1 series (4
DTP/3OPV/1MMR), a common measure of the basic series of vaccines, was
76 percent in 1995, the highest level ever achieved.
TABLE 2.--1995 IMMUNIZATION LEVELS OF 19- TO 35-MONTH-OLD CHILDREN AND 1996 IMMUNIZATION GOALS
----------------------------------------------------------------------------------------------------------------
Percentages
---------------------------------------------------------------
Vaccine Oct.-Dec. 1995
1992 baseline 1996 goals 1995 coverage coverage
----------------------------------------------------------------------------------------------------------------
DTP 3+.......................................... 83 90 95 95
OPV 3........................................... 72 90 88 90
MCV \1\......................................... 83 90 90 91
Hib 3+.......................................... .............. 90 92 92
Hepatitis B3.................................... .............. 70 68 78
4DTP/3OPV/1MMR.................................. 55 .............. 76 78
----------------------------------------------------------------------------------------------------------------
\1\ Measles-containing vaccine.
Source: 1992 Baseline: National Health Interview Survey, 1992.
1995 Data: National Immunization Survey (NIS), January-December 1995.
Information on successful strategies for achieving high
immunization coverage and low disease rates is contained in Appendix 1.
Prospects for future vaccines
We are on the way to reducing or eliminating the vaccine-
preventable diseases of today. While continuing to do this, we must
also consider the challenges and opportunities of tomorrow.
A thoughtful biology-watcher, Lewis Thomas, predicted that a
thousand years from now our era will be known as the Age of
Biotechnology, because of our growing ability to purposefully
manipulate the molecular structures of living organisms to serve our
needs. Nowhere is this technology more evident than in the current
arena of vaccine development. Almost a century passed between the very
first vaccine--Edward Jenners preventive for smallpox in 1796--and the
second one for rabies by Louis Pasteur in the 1880's. In the hundred
years since Pasteur, vaccines for another two dozen diseases--from
diphtheria to polio to measles were introduced. Now, the pace of that
progress is quickening.
Since 1990, several major changes have been made to the routine
childhood immunization schedule, including infant vaccination with
Haemophilus influenzae type b, hepatitis B. routine early childhood
immunization against varicella (chickenpox), and replacement of older
pertussis vaccines with safer vaccines. The new ``acellular'' pertussis
vaccines will decrease the fever, soreness, and fussiness that
sometimes have followed whole-cell pertussis vaccines, as well as some
of the rare but more serious adverse events.
Several new vaccines may become available in the next few years to
prevent death and disability from other infectious diseases. These
vaccines will also be considered for universal childhood vaccination.
Such vaccines include a vaccine for rotavirus diarrhea, which each year
results in an estimated 500,000 doctor visits, 50,000 hospitalizations,
and approximately 20 deaths among children under 5 years of age.
Studies are also underway to develop vaccine for Streptococcus
pneumoniae that will work in infants under 2 years of age, for whom
current pneumococcal vaccines do not provide protection. The
pneumococcus causes an estimated 7 million ear infections, 9,000
serious bloodstream infections, and 1,500 cases of meningitis in
American children under the age of 2 years. With the trend toward
increased resistance to antibiotics by these bacteria, such new
vaccines, if safe and effective, would be very useful. In addition,
strains of another bacterium, meningococcus, cause approximately 2,600
cases of meningitis in the United States each year, often in epidemics
that frighten the public and require emergency control efforts to
diagnose and treat cases and give antibiotic prophylaxis to exposed
persons. About 13 percent of those infected die from this devastating
disease. Incidence rates are highest in young children. New
``conjugated'' vaccines for some of these strains show promise to
prevent this disease in infants.
Also, on the horizon are potential vaccine technologies that would
have been considered science fiction just a decade ago. Small pieces of
synthetic DNA have worked as experimental vaccines in animals, and are
producing promising immune responses in human volunteers. Plants have
been bioengineered to become vaccine factories, potentially reducing
manufacturing costs. Even tomatoes, corn, and potatoes have been
genetically engineered to express vaccine antigens. Oral vaccine made
from re-engineered benign strains of typhoid bacteria has protected
against this disease. The benign typhoid strains have also been
modified and given orally to protect experimentally against other
diseases as well, offering an alternative to shots. Experimental
vaccines have been enclosed in microscopic capsules, which might permit
them to be released slowly over time to avoid the need for booster
shots, or to be taken orally. Adjuvants can increase the effectiveness
of some vaccines.
The challenges ahead
These are wonderful fruits of the revolution in biotechnology, but
they pose challenges for those of us in public health responsible for
putting new vaccines to use in preventing disease and reducing the
costs of health care to society. For example, the recommended
immunization schedule is getting very complex. Just 10 years ago in
1987, the nationally recommended immunization schedule for children
through 2 years of age required just 6 injections. The 1997 schedule,
however, requires 11 to 15 injections for children through 2 years of
age depending on which vaccine combinations are used.
This number of injections can result in 3 or 4 separate injections
at some visits to one's health care provider. Anecdotally, we know that
some doctors and some parents may be reluctant to immunize children
with more than 2 or 3 injections during one visit. So, some injections
may get deferred, resulting in additional time and costs for the extra
visits, some of which may not be kept, and thereby, potentially
decreasing the proportion of children fully protected from disease in a
timely manner. Simply increasing the number of visits in the routine
schedule could add to costs, including both the direct medical expenses
incurred and the indirect costs when parents must take time off from
work for the visit.
Combination vaccines--benefits and challenges
The vaccine companies have responded to this problem by working to
combine antigens for multiple diseases into combination vaccines. In
1996, two new combinations were introduced: DTaP-Hib for toddlers
(recommended at 12-18 months of age) and Hib-HepB for infants 6 weeks
and older. Possibly appearing in the years ahead are up to 20 various
combination vaccines, such as MMR-Varcella, or DTaP-Hib-HepB.
The benefits of such combination vaccines are clear. More diseases
can be prevented while reducing the number of shots, thereby
eliminating additional doctor visits, and decreasing related medical
costs and parental costs. Along with the benefits of new combination
vaccines comes new challenges related to cost, assuring vaccine safety
and efficacy, and choices among products.
Cost of combination vaccines
The potential increased cost of combination vaccines will be a
major challenge for the future. Developing combination vaccines is
neither simple nor cheap, because it must be demonstrated that there
are not any potential chemical incompatibilities nor immunologic
interference between the ingredients, and that safety and efficacy will
not be compromised. (For example, such interference has delayed the
licensure of the DTaP-Hib combination vaccine for use in infants.)
Development of combination vaccines may require greater
collaboration among vaccine manufacturers. The most desirable vaccine
combination would contain the greatest number of components. Since not
all manufacturers currently make all different vaccines, vaccine
companies will have to acquire rights to include certain components in
their new combination vaccines, which could add to the cost of these
vaccines. Furthermore, actual production costs to combine these
vaccines may be higher than the individual vaccines because it is
necessary to assure all components, both individually and when
combined, meet safety and efficacy requirements. Also, the product
lifetimes may be short as newer, larger combinations replace
combination vaccines with fewer components.
Although these vaccines may be shown to be cost-saving compared to
existing vaccines, some resistance to a higher price may exist. This
may occur since the budgetary packet that purchases the vaccine is
often not the pocket which accrues the cost savings in reduced numbers
of doctor's visits, parental time lost from work, and reduced costs of
caring for prevented diseases. Individual vaccines may be cheaper to
purchase but more expensive to deliver.
assuring safety and efficacy
An important challenge for all new vaccines, particularly new
combination vaccines, will be to monitor safety and effectiveness after
licensure. New vaccines are usually tested in up to 10,000 people prior
to licensure to assure basic vaccine safety and effectiveness. These
studies may not, however, detect less frequent adverse reactions that
may still be of public health importance when these vaccines are used
in millions of children. Furthermore, new combination vaccines are
generally tested in smaller numbers of people prior to licensure. As a
hypothetical example, for a vaccine that causes serious reactions once
per 20,000 doses, approximately 200 children, in a birth, cohort of
approximately 4 million, may suffer a reaction. To monitor the safety
of new combination vaccines, surveillance of adverse events after
licensure must occur to ensure that if new, unanticipated adverse
events occur, they are detected. In addition, it is critical to
scientifically evaluate whether rare adverse events observed following
vaccination are actually caused by the vaccine or represent coincidence
of an illness that would have occurred anyway.
CDC has developed the Vaccine Safety Datalink, in which four health
maintenance organizations link vaccination and medical records of more
than 1 million children, to provide exactly this scientific basis for
evaluating causation of adverse events. With the addition of new and
combination vaccines, this project will play a critical role in
assuring the safety of vaccines.
The effectiveness of new combination vaccines must also be
monitored. It may not always be predictable which vaccines can be
combined together. For example, researchers were surprised recently
when they discovered interference in immune response to Hib vaccine
when combined with some acellular pertussis vaccines even though none
existed between the whole-cell pertussis and Hib vaccines. For some
vaccines such as pertussis-containing vaccines, there is no laboratory
test to measure how well a person is protected by the vaccine. When
acellular pertussis vaccines are named with other vaccines, chemical
alterations may occur which could decrease effectiveness. This is not
detectable by tests that are currently available. Therefore, we will
have to maintain strong disease surveillance to look for evidence that
these new vaccines really work by reducing the occurrence of disease,
and be prepared to do more detailed scientific studies if surveillance
suggests they are not as effective as expected. CDC can play a major
role in these efforts, through its collaborative surveillance efforts
with States, using projects such as the Vaccine Safety Datalink to
evaluate vaccine efficacy, and by providing technical and epidemiologic
skills.
product choices
Another issue related to combination vaccines is the need to
determine which vaccines to stock among many potential options. For
example, the licensure of Hib HepB and DTaP-Hib represented a turning
point in immunization practice, as these two products contain
overlapping, non-complementary antigens. If Hib/Hep B is stocked, a
child can be fully vaccinated against five diseases with this vaccine
and DTaP alone. DTaP/Hib is not needed, even when it becomes available
for infant vaccination; in fact, using this vaccine combination would
give extra, unneeded doses of Hib since it is in both products. In
contrast, if DTaP/Hib is stocked, Hep B alone is needed rather than
Hib/Hep B. DTaP alone is also needed. These choices could be easy to
make if children stayed with the same provider, but many switch. Thus,
until there are combinations containing all the vaccines, physicians
and clinics will be confronted with the choice of stocking all vaccines
to meet every possibility, or giving extra doses of some vaccines to
help keep the inventory in a given clinic or office simple. These
choices have cost implications both for the individual physician or
clinic and for public health programs. Giving extra doses of some
vaccines as parts of combinations will require more resources; however,
having to stock all preparations, including some that may be
infrequently used, could lead to some vaccine expiration.
An additional challenge for CDC in the future will be to create
procurement strategies which are as economical as possible while
continuing to encourage vaccine manufacturers in the research and
development of innovative vaccine technologies. Since 1994, CDC has
established guaranteed minimum purchase contracts with each licensed
manufacturer of a childhood vaccine recommended by the Advisory
Committee on Immunization Practices (ACIP) for routine use. To ensure
that each licensed manufacturer received a portion of the public sector
market, the low bidder receives 50 percent of Vaccines for Children
Program (VFC) orders, as well as all vaccine orders purchased with
Section 317 or State funds. The other bidder receives the other 50
percent of VFC orders, but does not receive any orders with State or
317 funds. Until recently, there had not been more than two licensed
manufacturers for any particular product. However, there are now three
licensed manufacturers of DTaP vaccine, and ultimately there could be 5
licensed manufacturers. Therefore, it was clear a new approach to
vaccine procurement was needed.
CDC is testing a procurement strategy for DTaP vaccines which more
closely approximates the private-sector market. As long as the ACIP
considers each manufacturer's products essentially equivalent from a
public health perspective, manufacturers of all licensed vaccines are
given access to the public market, and States can then choose which
product or products they want to use. A contract was established with
each licensed manufacturer with low guaranteed minimum purchase
requirements, and manufacturers are able to change the negotiated price
every 3 months, as long as the price does not exceed the originally
negotiated price. It is hoped that this procurement strategy will
further encourage innovation in vaccine development while providing
product choice to States, where choice did not exist in previous
contracts.
We are working to anticipate the issues posed by new and
combination vaccines. This involves cooperation with our many partners
in the diverse community involved in disease prevention through
immunization, including public health agencies at local, State,
Federal, and international levels; non-governmental organizations of
medical providers and others promoting health; managed care groups;
vaccine manufacturers; those in academia who provide their expertise
and advice; parental advocacy groups; and others.
conclusion
A remarkable record of success has been achieved. Vaccine-
preventable diseases are at, or near, record low levels, and
immunization coverage is at record high levels. But our effective
vaccines are only as good as our ability to deliver them to children
and adults in need. By continuing to build a comprehensive system, much
as we developed methods to ensure our school-age children are
vaccinated, we as a society, and we as individuals, can gain the full
benefits vaccines have to offer. Never again should epidemics be the
primary motivation of immunization errors of our current vaccines.
The Childhood Immunization Initiative (CII) was designed to
increase immunization rates now, and build a system for sustaining
gains into the future. As you know, the CII includes five key
strategies to improve preschool vaccination rates improving the quality
and quantity of vaccination delivery services; reducing vaccine costs;
increasing awareness, community participation, and partnerships;
improving the monitoring of disease and vaccination coverage, and
improving vaccines and vaccine use.
New vaccines offer the promise of preventing more infectious
diseases. Combination vaccines offer the promise of simplifying vaccine
delivery so we can ensure that children will benefit from all these
vaccines. Future challenges do, however, lie ahead. The development of
new and combination vaccines raises issues related to cost, assuring
safety and efficacy, and product choices. Immunization schedules are
becoming increasingly complex as new vaccines are added. We welcome
these challenges, however. The additional protection against diseases
conferred by these new vaccines will more than compensate for the
short-term costs and difficulties associated with new vaccines. With
your help, and working with our partners in industry and public health,
we are confident that we can overcome obstacles and take advantage of
fixture opportunities.
Thank you. I would be happy to answer any questions you or other
Members of the Subcommittee may have.
STATEMENT OF DR. MICHAEL OSTERHOLM, STATE
EPIDEMIOLOGIST AND CHIEF, ACUTE DISEASE
EPIDEMIOLOGY SECTION, MINNESOTA DEPARTMENT
OF HEALTH
Senator Bumpers. Dr. Osterholm, welcome to the committee.
Dr. Osterholm. Thank you, Mr. Chairman. Mr. Chairman, I am
Dr. Michael Osterholm, State epidemiologist and chief of the
acute disease epidemiology section, Minnesota Department of
Health. I welcome the opportunity to appear before the
subcommittee to discuss both the potential and challenges of
the new generation of vaccines that will be available for
public and private providers.
Like my colleagues here on the panel, I, too, want to
acknowledge you and the subcommittee for your ongoing vision
and support of our efforts to protect children against vaccine-
preventable diseases. One of the sad days in public health is
the day that we heard of your decision not to run again, and a
heartfelt thank you to you for all that you have done.
Senator Bumpers. Thank you very much.
Dr. Osterholm. As you have heard this morning in testimony
from my distinguished colleagues, we have made unprecedented
progress toward our goals of eliminating or reducing childhood
vaccine-preventable disease in this country. No other country
in the world has realized this same success. Our most recent
track record in protecting the health of our children should
give us cause for great celebration.
But we all realize that vaccine-preventable disease efforts
are everyday, ongoing, and ever needed if we are to continue to
realize that current success. As we anticipate the future, we
all recognize this effort will be affected by the increasing
availability and use of combination vaccines. At the outset, it
would seem that combination vaccines will be a major step
forward in reducing the number of injections that a child must
receive. This will be particularly important as new and
significant public health problems, such as rotavirus, strep
pneumo, and Neisseria meningitides infections are addressed in
the future.
However, I am here to share with you as a State
epidemiologist that the future of vaccine-preventable diseases
as viewed from the availability of an ever-increasing number of
combination vaccines represents both the best of times and the
worst of times.
Some of the challenges and opportunities of combination
vaccines have been shared with you by other members of the
panel. I concur completely with the recent comments made by Dr.
Orenstein regarding some of the issues and these vaccines.
However, let me share with you some additional concerns.
Some 5 years ago as a State epidemiologist and someone
involved in immunization research, particularly that
surrounding Haemophilus influenza type b vaccines, I felt
confident that I could describe with clarity and personal
understanding the recommended childhood immunization schedule
for Minnesota children. This would include all possible
combinations and permutations of necessary immunizations based
on the age of the child and previous immunization history.
Today, despite the fact that I do this for a living, I find
that the same discussion is extremely difficult.
In fact, at a recent meeting that we had among our senior
immunization personnel at the Minnesota Department of Health,
we all agreed that we have great difficulty in answering
questions for both providers and parents when they share with
us a child's previous immunization history and request advice
on those vaccines needed in the future to comply with the
recommended immunization schedule and minimize doses and
product number.
If this activity is difficult for those of us who do this
for a living, I can only imagine how difficult and frustrating
it has become for the private practitioner and the parent.
I have included a copy of a document prepared at the
Minnesota Department of Health outlining vaccine product
options available for preschool children to meet the
recommended immunization schedule. As you can see in this
enclosed handout, there are any number of different
immunizations that are available to meet specific antigen
requirements for a given age. However, one must first determine
if we are attempting to optimize in the fewest number of
injections for that child or use the fewest number of products
by the medical practice or public health clinic.
Depending on which of those two options you decide, it will
dictate which product you will give at a given age for that
child. In addition, you must consider whether you are providing
an immunization for a child with a high risk versus a low risk
for hepatitis B virus infection. If one could optimize among
the current 19 licensed immunization products available through
the Minnesota VFC program, you could provide the fewest number
of injections per child at both low and high risk for hepatitis
B by using 9 different products. On the other hand, if you are
trying to optimize in the fewest number of products, which is
7, this will result in 16 injections, plus two oral doses of
vaccine for both high- and low-risk infants for hepatitis B
infection.
The vaccines to use become extremely complicated when a
child enters a medical practice after having received initial
immunizations from a different provider source. Now the
original provider source may not have used the vaccines chosen
by the current provider. What are the options and what are the
possibilities?
Today we have staff at our department that literally spend
hours on calls to our immunization hotline assisting clinicians
and parents as they wade through this complicated maze of
immunization possibilities. In effect, we have become a victim
of our own success.
As noted above, as part of the VFC program in Minnesota we
currently supply 19 different vaccines to our providers.
Enclosed you will find a copy of our vaccine order form. This
compares, of course, to the 29 different CDC contracts for
vaccines and biologics. All of these vaccine orders are handled
by a single pharmacy warehouse under State contract. When this
contract was originally initiated, less than one-half of the
currently available products were on the market.
Today we find ourselves stocking redundant antigens and
multiple vaccine products, of which not all are needed to fully
immunize a child. Nonetheless, if you are a provider today you
may order any or all of these products, depending on the
previous history of immunization among your current patients
and your own medical practice protocol.
Not only does the polypharmacy issue become a problem for
the State people, but now it becomes a major issue within
individual clinics as it relates to needs, space, and equipment
for storage of the vaccines. Is this issue really a problem
and, if so, why?
It is in Minnesota, believe me. Today over 90 percent of
our State's population is in some form of managed care,
something that you have heard originally mentioned earlier
today as a positive area for vaccine use. This includes
different options of managed care, which are the closed panel
practices or staff models, or loosely connected preferred
provider organizations or PPO's. In Minnesota we have found
that as purchasers of health care, particularly large employer
groups, change health plans almost on an annual basis due to
cost differentials, people are frequently changing their
primary health care provider.
Last year in our State, we estimate that more than 25
percent of all individuals in managed care settings, which
again is 90 percent of our total population, changed their
primary health care provider. We have labeled this population
as the churning population. This extremely large number of
migrating consumers of health care are bringing with them to
their new medical clinics their previous immunization
histories, both documented and undocumented.
For the new provider to try to address this maze of
previous immunization histories and match them up with future
needs is beginning to overwhelm our system. We have documented
an ever-increasing number of errors in vaccine administration,
errors in vaccine ordering, wasted nursing time in attempting
to understand the confusion, high levels of both provider and
parent frustration, and last but not least, wasted vaccine.
As they would say back in rural Minnesota, all change is
not progress. This is taking a real toll on our public health
staff. We have seen a dramatic increase in the number and
complexity of our hotline calls, an increased need for
satellite or other types of training sessions, for complex
algorithms for vaccine administration, and for widespread
distribution of provider manuals and guides. And as new and
additional vaccines come online, regardless of their VFC
status, all this material needs immediate updating.
All this has placed great stress on our public health
infrastructure and our ability to assist the community in
maintaining age-appropriate immunization levels.
Finally, while immunization levels are at an all-time high,
we are witnessing increasing frustration among our medical care
providers that is extremely counterproductive to achieving
those same overall goals of high immunization, childhood
immunization, in the future. As more combination vaccines
become available and the number of possibilities and
permutations for who gets what vaccine and when, we can expect
further stress in this system and I believe substantial
reductions in our current immunization levels.
I might add that this is continuing to occur even with the
recently harmonized immunization schedule.
So where do we go from here? Unless there are some timely
and critical changes to our current national agenda for
childhood immunizations, I fear our current success will begin
to implode upon itself. What I see as a State epidemiologist
for the future is the need to dramatically improve upon our
current data management aspects of childhood immunization,
particularly as it relates to timely and automated registry
systems which follow the child regardless of provider, the need
for the automation of vaccine delivery, including the need for
necessary equipment and technology for such things as bar code
reading of vaccine vials in every physician's office and public
health clinic in the country, and, most of all, a need for a
standardized antigen package for combination vaccines.
This latter recommendation relates to the need for some
type of understanding, going, or at the very least regulation,
which requires manufacturers to include a core set of antigens
in a specified combination vaccine. I recognize this latter
recommendation has many obstacles and many opponents. The
obstacles include the current licensure process for vaccines
via the FDA, concern regarding the incentive for industry to
develop new vaccines and economic return, antitrust issues
related to collaborative industry efforts, and concern that the
Government begin directing vaccine development in a procurement
manner similar to that currently used by such agencies as the
Department of Defense for other contract items.
However, I can tell you, if we do not address all three of
these above issues immediately, the future for childhood
immunization in this country will be problematic. In addition,
I might add, less crucial but helpful areas that we need to
address include State flexibility for ordering among all
possible immunization products for VFC and our need for
continued 317 grant support for staff to provide the kind of
technical assistance to providers and parents I just outlined.
prepared statement
I believe that this subcommittee as part of its ongoing
effort to maintain the highest possible levels of immunization
among our children can play a role in helping direct us through
both the future opportunities and challenges regarding this
problem.
Thank you. I will be happy to answer any questions you or
other members of the subcommittee may have.
[The statement follows:]
Prepared Statement of Michael T. Osterholm
Mr. Chairman, I am Dr. Michael Osterholm, State Epidemiologist and
Chief, Acute Disease Epidemiology Section, Minnesota Department of
Health (MDH). I welcome this opportunity to appear before the
Subcommittee to discuss both the potential and challenges of the new
generation of vaccines that will be available for public and private
providers. I want to acknowledge you and the Subcommittee for your
ongoing vision and support for our efforts to protect children against
vaccine-preventable diseases.
Future of Childhood Vaccination from a State Health Department
Perspective
As you have heard this morning in the testimony from my colleague,
Dr. Walter Orenstein, we have made unprecedented progress towards our
goals of eliminating or reducing childhood vaccine-preventable diseases
in this country. No other country in the world has realized this same
success. Our most recent track record in protecting the health of our
children should give us cause for great celebration. But we all realize
that vaccine-preventable disease efforts are everyday, ongoing and
ever-needed if we are to continue to realize our current success. As we
anticipate the future, we all recognize this effort will be affected by
the increasing availability and use of combination vaccines. At the
outset, it would seem that combination vaccines will be a major step
forward in reducing the number of injections that a child must receive.
This will be particularly important as new and significant public
health problems such as rotavirus, Streptococcus pneumonia, and
Neisseria meningitidis infections are addressed. However, I'm here to
share with you as a State Epidemiologist that the future of vaccine-
preventable diseases as viewed from the availability of an ever
increasing number of combination vaccines represents both the ``best of
times and the worst of times.''
Some of the challenges and opportunities of combination vaccines
have also been shared with you by Dr. Orenstein. I concur completely
with his conclusions regarding these vaccines. Let me share with you
some additional issues.
Five years ago, as a State Epidemiologist and someone involved in
immunization research, particularly that surrounding the Haemophilus
influenzae type b vaccines, I felt confident that I could describe with
clarity and personal understanding, the recommended childhood
immunization schedule for Minnesota children. This would include all
the possible combinations and permutations of necessary immunizations
based on the age of the child and previous immunization history. Today,
despite the fact that I do this for a living, I find that same
discussion extremely difficult. And in fact, at a recent meeting of our
senior immunization program personnel at the MDH, we all agreed that we
have great difficulty in answering questions for both providers and
parents when they share with us a child's previous immunization history
and request advice on those vaccines needed in the future to comply
with the recommended immunization schedule. If this activity is this
difficult for those of us who do this for a living, I can only imagine
how difficult and frustrating it has become for the private
practitioner and the parent.
I have included a copy of a document prepared at the MDH outlining
vaccine product options available for preschool children to meet
recommended immunization schedules. As you can see, there are any
number of different immunizations that are available to meet specific
antigen requirements for a given age. However, one must first determine
if we are attempting to optimize on the fewest number of injections for
that child or the use of the fewest number of products by the medical
practice or public health clinic. Depending on which of those two
options you decide, it will dictate which product we'll use at a given
age for that child. In addition, you must consider whether you are
providing an immunization for a child with a high-risk versus a low-
risk for hepatitis B virus infection. If one could optimize among the
current 23 licensed immunization products on the market, you could
provide the fewest number of injections for children at both low- and
high-risk for hepatitis B by using nine different products. On the
other hand, if you are trying to optimize on the fewest number of
products, which is seven, this will result in 16 injections plus two
oral doses of vaccines for both high- and low-risk infants for
hepatitis B virus infection. The vaccines to use become extremely
complicated when a child enters a medical practice after having
received initial immunizations from a different provider source. Now,
the original provider source may not have used the vaccines chosen by
the current provider. What are the options and what are the
possibilities? Today we have staff at the MDH that literally spend
hours on calls to our immunization hotline assisting clinicians and
parents as they wade through this complicated maze of immunization
possibilities. In effect, we have become a victim of our own success.
In Minnesota, as part of our immunization program, we currently
provide 18 different vaccines to our providers. Enclosed you will find
a copy of our vaccine order form. All of these vaccine orders are
handled by a single pharmacy warehouse under state contract. When this
contract was originally initiated, less than half of the currently
available products were on the market. Today we find ourselves stocking
redundant antigens and multiple vaccine products of which not all are
needed to fully immunize a child. Nonetheless, if yow are a provider
today, you may order any or all of these products depending on the
previous history of immunization among your current patients and your
own medical practice protocol. Not only does the polypharmacy issue
become a problem for the state depot, but now it becomes a major issue
within an individual clinic as it relates to needs, space and equipment
for storage of these vaccines.
Is this issue really a problem and, if so, why? In Minnesota it is!
Today, over 90 percent of our state's population is in some form of
managed care. This includes the different options of managed care which
are closed panel practices or loosely connected PPOs, staff models or
preferred providers. In Minnesota, we have found that as purchasers of
health care, particularly large employer groups, change health plans
almost on an annual basis due to cost differentials, people are
frequently changing their primary health care provider. Last year in
our state, we estimate that more than 25 percent of individuals in
managed care settings changed their primary health care provider. We
have labeled this population as the ``churning population.'' This
extremely large number of migrating consumers of health care, are
bringing with them to their new medical clinics, their previous
immunization histories, both documented and undocumented. For the new
provider to try to address this maze of previous immunization histories
and match them up with future needs, is begining to overwhelm our
system. We have documented an increasing number of errors in vaccine
administration, errors in vaccine ordering, wasted nursing time in
attempting to understand this confusion, high levels of provider and
parent frustration, and last but not least, wasted vaccine. As they
would say back in rural Minnesota, ``all change is not progress.''
This is taking a real toll on our public health staff. We have seen
a dramatic increase in the number and complexity of our hotline calls,
the increased need for satellite or other types of training sessions,
for complex algorithms for vaccine administration, and for widespread
distribution provider manuals and guides. And as new vaccines come on
line, regardless of their VFC status, all this material needs immediate
updating. All of this has placed a great stress on our public health
infrastructure and our ability to assist the community in maintaining
age-appropriate immunization levels. Finally, we are witnessing
increasing frustration among our medical care providers that is
extremely counter productive to achieving an overall goal of high
levels of childhood immunization. As more combination vaccines become
available and the number of possibilities and permutations for who gets
what vaccine and when, we can expect further stress on this system. I
might add that this is continuing to occur even with the recently
harmonized immunization schedules.
The future
So where do we go from here? Unless there are some timely and
critical changes to our current national agenda for childhood
immunizations, I fear our current success will be short lived. Frankly,
the system will begin to implode upon itself. What I see, as a State
Epidemiologist, for the future, is the need to dramatically improve
upon our current data management aspects of childhood immunization,
particularly as it relates to timely and automated registry systems
which follow the child regardless of provider, the need for the
automation of vaccine delivery, including the need for necessary
equipment and technology for bar code reading of vaccine vials in every
physician's office and public health clinic in the country, and most of
all, the need for standardized ``antigen packages'' for combination
vaccines. This latter recommendation relates to the need for some type
of understanding, agreement or regulation which requires manufacturers
to include a core set of antigens in a specified combination vaccine. I
recognize this latter recommendation has many obstacles, including the
current licensure process for vaccines via the Food and Drug
Administration, concern regarding the incentive for industry to develop
new vaccines, antitrust issues related to collaborative industry
efforts, and concern that government begin directing vaccine
development in a procurement manner similar to that currently used by
such agencies as the Department of Defense for other contract items.
However, if we do not address all three of these above areas
immediately, the future for childhood immunization in this country will
be problematic. In addition, I might add less crucial, but helpful
areas we need to address include state flexibility for ordering among
all possible immunization products for VFC and our need for continued
317 grant support for staff to provide technical assistance to
providers and parents.
I believe that this Subcommittee, as part of its ongoing effort to
maintain the highest possible levels of immunizations among our
children can play a role in helping direct us through both the future
opportunities and challenges regarding this problem.
Thank you. I will be happy to answer any other questions you or
other members of the Subcommittee may have.
VACCINE PRODUCT OPTIONS AVAILABLE FOR PRESCHOOL-AGED CHILDREN TO MEET RECOMMENDED IMMUNIZATION SCHEDULE (DTaP, IPV/OPV, HIB, HBV [LOW AND HIGH-RISK],
MMR, VARICELLA)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Fewest injections
-------------------------- Fewest
Age of child Vaccination against Vaccine options Products available HR (HBV) LR (HBV) products
\1\ \2\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Birth Hepatitis B........... HBV (hepatitis B)..... Merck, RECOMBIVAX HB (ped) \3\...... ........... ........... ...........
...................... ...................... Merck, RECOMBIVAX HB (high-risk/ 1 ........... 1
adol) \3\.
...................... ...................... Merck, RECOMBIVAX HB (adult)........ ........... ........... ...........
...................... ...................... SmithKline Beecham (SKB), Engerix-B ........... ........... ...........
(ped) \3\.
1 month Hepatitis B........... HBV................... Merck, RECOMBIVAX HB (ped) \3\...... ........... ........... ...........
...................... ...................... Merck, RECOMBIVAX HB (high-risk/ 1 ........... 1
adol) \3\.
...................... ...................... Merck, RECOMBIVAX HB (adult)........ ........... ........... ...........
...................... ...................... SmithKline Beecham (SKB), Engerix-B ........... ........... ...........
(ped) \3\.
2 to 6 months Hepatitis B........... HBV................... Merck, RECOMBIVAX HB (ped) \3\...... ........... ........... ...........
...................... ...................... Merck, RECOMBIVAX HB (high-risk/ 1 ( 6 mo.) ........... 1
adol) \3\.
Diphtheria............ ...................... Merck, RECOMBIVAX HB (adult)........ ........... ........... ...........
Tetanus, Pertussis.... ...................... SKB, Engerix-B (ped) \3\............ ........... ........... ...........
...................... HBV+Hib............... Merck, COMVAX (2 and 4 months only) ........... 2 ...........
\3\.
H. influenzae type B.. DPT+Hib............... Wyeth-Lederle, TETRAMUNE \3\........ ........... ........... ...........
...................... ...................... Pasteur Merieux Connaught (PMC) DPT/ ........... ........... ...........
ACTHib \3\.
...................... DTP................... PMC,------.......................... ........... ........... ...........
...................... ...................... SKB,------.......................... ........... ........... ...........
...................... ...................... Wyeth-Lederle, TRI-IMMUNOL.......... ........... ........... ...........
...................... DTaP.................. PMC, Tripedia \3\................... ........... ........... 2
...................... ...................... Wyeth-Lederle, ACEL-IMUNE \3\....... 3 3 ...........
...................... ...................... SKB, Infanrix \3\................... ........... ........... ...........
...................... Hib................... Merck, PedvaxHIB \3\ (2 & 4 mos. 2 ........... 3
only).
...................... ...................... PMC, ActHIB \3\..................... ........... ........... ...........
...................... ...................... SKB, OmniHIB........................ ........... ........... ...........
...................... ...................... Wyeth-Lederle, HibTITER \3\......... ........... ........... ...........
Polio................. OPV................... Wyeth-Lederle, ORIMUNE \3\.......... ........... ........... ...........
...................... IPV................... PMC, IPOL \3\....................... 2 2 4
12 to 18 months Hepatitis B........... HBV................... Merck, RECOMBIVAX HB (ped) \3\...... ........... ........... ...........
...................... ...................... Merck, RECOMBIVAX HB (high-risk/ ........... ........... ...........
adol) \3\.
Diphtheria............ ...................... Merck, RECOMBIVAX HB (adult)........ ........... ........... ...........
Tetanus, Pertussis.... ...................... SKB, Engerix-B (ped) \3\............ ........... ........... ...........
...................... HBV+Hib............... Merck, COMVAX \3\................... ........... 1 ...........
H. influenzae type B.. DTP+Hib............... Wyeth-Lederle, TETRAMUNE \3\........ ........... ........... ...........
...................... ...................... PMC, DPT/ActHIB \3\................. ........... ........... ...........
...................... DTP................... PMC,------.......................... ........... ........... ...........
...................... ...................... SKB,------.......................... ........... ........... ...........
...................... ...................... Wyeth-Lederle, TRI-IMMUNOL.......... ........... ........... ...........
...................... DTaP.................. PMC, Tripedia \3\ ( 15 mos.)........ ........... ........... ...........
...................... ...................... Wyeth-Lederle, Acel-Immune \3\ ( 15 ........... 1 2
mos.).
...................... ...................... SKB, Infanrix \3\ ( 15 mos.)........ ........... ........... ...........
...................... DTaP+Hib.............. PMC, TriHIBit \3\ (4th dose only)... 1 ........... ...........
...................... Hib................... Merck, PedvaxHIB \3\................ ........... ........... ...........
...................... ...................... PMC, ActHIB \3\..................... ........... ........... 3
...................... ...................... SKB, OmniHIB........................ ........... ........... ...........
...................... ...................... Wyeth-Lederle, HibTITER \3\......... ........... ........... ...........
...................... ...................... PMC, ProHIBIT ( 15 mos.)............ ........... ........... ...........
Polio................. OPV................... Wyeth-Lederle, ORIMUNE \3\.......... ( \4\ ) ( \4\ ) 5
...................... IPV................... PMC, IPOL \3\....................... ........... ........... ...........
MMR................... MMR................... Merck, MMR II \3\................... 1 1 6
Varicella............. Varicella............. Merck, Varivax \3\.................. 1 1 7
4 to 6 years Diphtheria............ DTP................... PMC,------.......................... ........... ........... ...........
Tetanus, Pertussis.... ...................... SKB,------.......................... ........... ........... ...........
...................... ...................... Wyeth-Lederle, TRI-IMMUNOL.......... ........... ........... ...........
...................... DTaP.................. PMC, Tripedia \3\................... 1 1 2
...................... ...................... Wyeth-Lederle, Acel-Immune \3\...... ........... ........... ...........
...................... ...................... SKB, Infanrix \3\................... ........... ........... ...........
Polio................. OPV................... Wyeth-Lederle, ORIMUNE \3\.......... ( \4\ ) ( \4\ ) 5
...................... IPV................... PMC, IPOL \3\....................... ........... ........... ...........
MMR................... MMR................... Merck, MMR II \3\................... 1 1 6
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ HR, infants at high risk for HBV.
\2\ LR, infants at low risk for HBV.
\3\ Federal contract (n = 17)
\4\ Oral.
Note: Fewest injections: 13 for LR infants and 15 for HR infants, using 9 different products. Total products equal 23. Fewest products: 7, resulting in
16 injections (+2 oral) for both low- and high-risk HBV infants.
recently licensed combination vaccines
DTaP-Hib
Hib-Hep B
potential future vaccines
DTaP-Hep B
DTaP-IPV
DTaP-Pneumococcal
DTaP-Meningococcal
DTaP-Hep B-Hib
DTaP-Hib-IPV
DTaP-Hep B-IPV
DTaP-Hib-Pneumococcal
DTaP-Hib-Pneumococcal-Meningococcal
DTaP-Hib-Hep B-IPV
DTaP-Hib-Pneumococcal-Meningococcal
DTaP-Hib-Hep B-IPV-Hepatitis A
Hib-Pneumococcal
Hib-Meningococcal
Hib-Pneumococcal-Meningococcal
Hib-Hep B-IPV
Hib-IPV-Pneumococcal-Meningococcal
Pneumococcal-IPV
Pneumococcal-Meningococcal
MMR-Varicella
remarks of senator bumpers
Senator Bumpers. Thank you very much, Dr. Osterholm. And
thank all of you.
Let me just open by saying that this is, in all the 22\1/2\
years I have been involved in immunization, this morning is one
of the most gratifying times that Betty and I have experienced.
The explosion, as Dr. Paradiso outlined, the explosion of new
products which are so badly and desperately needed, is an
incredible thing.
But as we all know, all progress carries its own unique set
of problems, too. So here we are with all these magnificent
advances, vaccines for all kinds of new things. Who would have
ever thought about a vaccine for pneumonia or for ear
infections and so on, or rotavirus? Those things even 10 years
ago in my mind would have been absolutely impossible to conjure
up or to think about.
testing efficacy of vaccines
So it seems to me that here we are now with all of these
advances. And one other thing, Dr. Orenstein, I might mention.
You mentioned that it takes 10,000 people participating in a
test, but I think your testimony showed, or maybe Mary Ann's
memo to me showed, that the testing of combinations to make
sure that antigens are compatible only requires 4,000. Is that
correct?
Dr. Orenstein. I am not sure exactly what the numbers are.
The numbers that actually--what we have seen in prelicensure
trials--and Dr. Paradiso may be better able to comment on it--
is generally up to 10,000 and not more than 10,000. Some of the
studies have involved fewer than 10,000 in the initial trials,
but in combinations less than that.
Senator Bumpers. Yes.
Dr. Orenstein. I do not know if it is 4,000.
Senator Bumpers. Dr. Paradiso?
Dr. Paradiso. It obviously depends on the incidence of the
disease, and so for a disease like Haemophilus b, where the
meningitis is fairly rare, we did trials in the 20,000 to
30,000 children range. For acellular pertussis, which is more
common, or pertussis is more common, vaccine trials were in the
8,000 to 10,000 range.
Our combination DTP-Hib vaccine was tested in about 4,000
or 5,000 children, and those were predominantly safety trials.
Those were trials for vaccines that had two components that had
already been very extensively tested for safety and efficacy,
so that was the reason probably that it did not need and does
not need to go as high as the vaccines where you are showing
efficacy against rare disease and vaccines where you are using
products that you have never used before and so you want to get
some more primary data.
antigen compatibility
Senator Bumpers. One of my questions is, does medical
science--I assume that medical science allows the researchers
who develop these things to make a pretty good educated,
calculated guess as to whether certain antigens are going to be
compatible or not. Do they or not? Or does that have to be
determined simply by test or can you--I mean, you have to do
the test, of course, to be sure.
But is there a reasonable certainty that you can reach--can
you reach a decision with a reasonable certainty that two
antigens are going to be compatible?
Dr. Paradiso. Actually, the history of combination vaccines
is that interference is the biggest problem with mixing
antigens. It was seen with MMR.
Senator Bumpers. One interferes with the other?
Dr. Paradiso. One interferes with the other. It was seen
with the oral polio vaccine when they first mixed the three
types. When we developed a vaccine for DTP-Hib combined--by
``we'' I mean our company--we mixed a DTP product with
Haemophilus b and it worked the first time and we thought we
were wonderful and it would always be that easy. What we are
learning now is that it is not that easy.
The recent attempts to combine the Haemophilus b vaccine
with the acellular pertussis--and virtually every group has
seen this--results in interference in the response of the
Haemophilus vaccine. We do not know why that is. It was not
predicted in any of the animal studies that we did or it was
not predicted by anything until you actually got into young
infants and you saw that there was a two, three, five, tenfold
reduction in the response to the Haemophilus b conjugate. We do
not know what that means from a clinical standpoint, but, you
know, from the charts we looked at, you are currently
controlling that disease not only by protecting the individual,
but by protecting the environment and the herd.
So you are very reluctant to make changes that reduce the
responses in children without knowing exactly what effect that
is going to have on long-term disease.
I agree with Mike, Dr. Osterholm, that it would be
wonderful to preset what combinations and what antigens should
go into a vaccine, but what we have learned is that we do not
know that those will be the ones that will actually be
combinable. So we need to be flexible, I think, in what we do.
If I could show a couple of other charts that just
illustrate how we think about this. Obviously, as we work now
on new vaccines we pay attention to combination vaccines
because we know we cannot just keep adding vaccines to the
schedule.
new vaccines and ease of delivery
Senator Bumpers. While he is putting those charts up, Dr.
Paradiso, let me ask you this. I saw a segment on one of the
newscasts the other night about the use of the nasal drop in
infants. That is a flu vaccine, I take it.
Dr. Paradiso. Yes.
Senator Bumpers. My question is when can we expect that to
come on line?
Dr. Paradiso. Well, I read the same articles. I think that
is pretty exciting, from what I have read. That was a flu
vaccine that has been given as a spray in children, I think 1
to 5 years of age.
Senator Bumpers. Yes.
Dr. Paradiso. My reading is that those results were very
positive, and so I think the projections were for within the
next year or two that they would complete the data that they
need for safety and efficacy.
Senator Bumpers. Who is developing that?
Dr. Paradiso. That is a company called Avron in California.
It is exciting also because there are a number of
respiratory viruses that affect young infants, respiratory
syncytial virus, parainfluenza virus, that cause up to 5,000 to
8,000 hospitalizations a year in babies. Those can all
potentially be given by that same method, as an intranasal
spray, and they are being tested. My company, for example, is
working on vaccines for respiratory syncytial virus delivered
the same way to very young infants. If the protection can be
that good, then that is obviously ideal and it does not require
an injection and protects against a difficult disease.
Senator Bumpers. Go to the chart.
Dr. Paradiso. These are looking another way at what Dr.
Orenstein and Dr. Osterholm have already talked about, the
increase in new products from 1980 to 1990 and what we think we
may see in the year 2000. I think first of all we should point
out that most recently the introduction of the acellular
pertussis vaccines, the recommendation now to use IPV in the
infant schedule has caused some increases in the number of
injections, increase in the number of possible combinations,
and clearly some potential confusion.
My opinion is that those are short-term issues because all
of us are working on combinations. If you look at the next
slide, our goal and I think the goal of many groups is to
reduce back down to two immunizations per infant. There are a
couple of different combinations that you could look at that
different companies are working on that would do that. If you
look at the first shot, which is usually referred to as the DTP
or DTaP combination, there are groups working on those various
combinations, some of which have all four of those antigens
that are currently in use in that combination vaccine.
issues related to manufacturing combination vaccines
Senator Bumpers. Let me interrupt just a moment. Something
just occurred to me. Some of those vaccines are made by
different manufacturers. How are we going to let the
manufacturers collaborate and cooperate on developing those?
You have a patent on one, somebody else has a patent on another
one. Yet we are trying to develop combination shots. How do we
do that without violating antitrust laws?
Dr. Paradiso. Mostly that has been done through
collaborations between the companies, through joint ventures
between the companies. Sometimes it is consolidations and
buyouts, and there are a number of ways that that happens.
Senator Bumpers. But each company would have a right to
sell the combination, wouldn't it?
Dr. Paradiso. Some companies have all four of those
combinations or all of the components that go in. So you're
right----
Senator Bumpers. For example, if I had OPV or IPV and you
had Hib and somebody else had DTaP, each one would want to
manufacture its own combination.
Dr. Paradiso. Right.
Senator Bumpers. And would they--that would have to be
agreed to, of course, when you start in on the research of the
combination vaccine?
Dr. Paradiso. Exactly, exactly.
Senator Bumpers. Has that worked reasonably well in the
past?
Dr. Paradiso. Yes.
Senator Bumpers. We have some combination shots now.
Dr. Paradiso. Yes; there are, and those are the result of
companies' own products and also the result of companies who
have gotten together and developed vaccines and provided
antigens together for specific products.
postmarketing surveillance of vaccines
Senator Bumpers. One other question, Dr. Paradiso. It takes
a long time sometimes, does it not, to determine whether or not
this combination has any side effects? I mean, what if 10 years
from now--if all the studies indicate that this combination
shot is fully effective against all of the diseases it is
designed to prevent and in 10 years a child gets measles or a
child gets Haemophilus influenza b, are those possibilities,
that over a 10-, 15-year period, much longer than the
experimental stage of it----
Dr. Paradiso. I guess the question is, will they be more
likely to get the disease as a result of the combination----
Senator Bumpers. No.
Dr. Paradiso [continuing]. As opposed to when they were
getting the----
Senator Bumpers. No; I'm talking about efficacy.
Dr. Paradiso. Right.
Senator Bumpers. To make sure that--we'll say you have a
combination of three vaccines, and what I'm concerned about is
how can we be sure of the efficacy of all of them when these
studies--for example, if there are only 4,000 people and it
takes a long time sometimes to determine efficacy. I mean,
somebody may not be exposed to anything.
Dr. Paradiso. There are two ways, I think, that that can
and is being done. We as part of our licensure approvals agree
to do what are called postmarketing surveillance studies, in
which we actually follow large populations. Usually now we are
talking about populations of 100,000 or 150,000, children who
receive the vaccine and then we follow them for rare adverse
events--hospitalizations, emergency room visits, things that
you would expect to happen in the 1 in 5,000, 1 in 10,000 very
rare occurrences.
The second is, as Dr. Orenstein talked about, surveillance
by the CDC both for adverse events and for disease rates. I
think that those surveillance mechanisms and the support for
those surveillance mechanisms are critical. We have had years
where funding for that has been interrupted and we had gaps in
some of our data. But I think it is critical over the next
years that we continue to follow these vaccine-preventable
diseases, because it is the only way we know whether we are
keeping them under control and whether vaccines that we are
using are effective.
adult immunization
Senator Bumpers. You alluded, I think, did you not, to
adult immunizations? What is the major impediment to adult
immunizations?
Dr. Paradiso. I think adult immunizations are a broad
category and in my mind would include adults of so-called
middle age. There is a separate category that is women,
pregnant women or women of childbearing age who could be
protected against diseases or who could protect their young
infants from diseases by being immunized. And then there is the
elderly, who become more susceptible to quite a number of the
diseases, including some of the ones we use in infants.
I think that the biggest impediment is that, especially
outside the elderly population, either health care is not
sought on a regular basis the way it is in infants or there is
just not a recognition that these are populations that we can
go after. The population has not been educated that these are
diseases that not only affect those populations, but affect
babies and other populations.
So a good example I think is acellular pertussis, where I
think it is becoming clear that the increases in pertussis
around the country are often not in infants, but actually in
adults, and the result is that they can continue to spread that
disease in the population. So they would be a target for
acellular pertussis organizations.
Adults do not like to get immunized. They do not
necessarily like to go to the doctor, and they need to be
educated of the benefits, both to them and to their children.
Potentially pregnant women can be educated that there are
diseases that occur solely in infancy, like respiratory
syncytial virus and group B streptococcus, where if they were
immunized they could pass on that protection to their children.
I think it is important also to make those immunizations
part of reimbursement systems, so that the doctors get
reimbursed for doing that medical care in a preventive way,
rather than therapeutically later on dealing with the
infection.
progress in links of immunization and wic programs
Senator Bumpers. Dr. Orenstein, let me turn to you for a
moment. First of all, let me congratulate you and CDC on these
immunization rates. Really, I think the White House is going to
have something this week or next. Somebody told me this morning
Betty and I had been invited over there for I guess some kind
of an announcement about levels. Certainly CDC--I hope you will
be there, Walt, even if I do not make it; I will let you speak
for me, and I will try to make it. But CDC deserves tremendous
credit, because we have had some rocky times in the last
several years, very difficult times.
The fact that these levels are as low as they are right now
is a real tribute to you and it is a tribute to the State
health offices and a lot of other people. But you are certainly
entitled to a lot of it.
I wanted to ask you about some of the high risk
demonstration projects that we funded last year. What progress,
if any, have we made in linking WIC and immunization services?
Dr. Orenstein. I also would like to thank you for all you
have done in terms of helping us improve our immunization
coverage and bring disease down. For so many years you have
been a champion of this program and kept it going, and
certainly, as the others have said before we will miss you when
you leave. I cannot tell you enough how much I appreciate all
the work that you have done to help us.
Senator Bumpers. You know, Betty slept in another bedroom
for a long time after I introduced that bill to require WIC
recipients to prove that their children had been immunized. She
thought that was the crassest thing she had ever heard of, so I
had to fight her and Hilary and everybody else on that one. But
really, I want to see if I can get back in her good graces with
your answer this morning. [Laughter.]
outreach activities
Dr. Orenstein. Well, Senator, I know she is meeting this
morning with some of our staff to discuss immunization-related
issues.
In terms of the demonstration projects that you directed us
to do, we have awarded grants to four areas, three urban
areas--Detroit, New York City, and San Diego--and one rural
area in Colorado. The urban areas combined serve a population
of about 40,000 children and involve community health networks
of about 43 different sites in these areas.
What they are doing is three things. First is to improve
the immunization practices of their own clinics, which already
serve substantial populations. That is, to try and reduce
missed opportunities for immunization, to implement what we
call a fix or repair the assessment of immunization coverage of
children who attend their clinics and feed back and stimulate
competition to improve immunization coverage, linkage with WIC
and a variety of other things.
The second task that they are undertaking is to reach out
using their stature as academic medical centers leading these
community health networks to involve other health networks
within that catchment area to get them to do the same thing.
The third task is to try innovative strategies with
outreach.
All of them are coming to the conclusion that registries
are extremely important, that it is very difficult to know how
to improve coverage without having a better estimate of the
overall population that needs to be reached. And they are all
looking at trying to build those as well.
But I think we are optimistic. It is early now, but I think
this is a step in the right direction. I think what is
impressive to us is the enthusiasm of public health officials,
academic medical centers, the community health networks, and
others. The brain power that is being brought to this process
is a real step in the right direction.
measles eradication
Senator Bumpers. Let me just say that we have always found
that the providers share a good portion of the blame, have in
the past, for the difficulty we have had in getting the rates
as low as they are right now, because we have found that, as
you know, in other studies people would bring their children
into clinics 10, 15 times, nobody ever mentioned immunizations
to them. So that has been a real problem.
Incidentally, as I look over the various combinations we
are looking at, if I were a provider I would probably just
slash my wrists and forget the whole thing. This is going to be
a nightmare for a while. Presumably and hopefully, this will
all wash out in time. But this is another one of those things
we were talking about. Not only are combinations maddening as a
result of this progress. We have all of these combinations
coming on. But you think, if you are a provider out there and
what shall you keep in your refrigerator? I thought that was a
good chart on the refrigerators.
But in any event, I want an answer to that question on
those pockets of resistance that we had run into over a period
of time. But I also want to ask you--I think you testified or I
have seen some data somewhere that all the measles cases, we
believe that all the measles cases last year, for example, were
not endemic, but they were imported.
No. 1, how do you know that? And No. 2, if that is in fact
true, should we not start on an international eradication of
measles, as we have on polio?
Dr. Orenstein. Thank you very much.
Senator Bumpers. Measles is still the biggest killer of
children in the world, is it not?
Dr. Orenstein. Right about 1 million deaths, even with the
availability of good measles vaccine.
What we can say is since 1993 we have probably eliminated
the indigenous transmission of measles about three times within
the United States. The best evidence is in 1993 and comparing
it to the years before 1993. Virtually all of the measles
viruses isolated during the big epidemic of measles between
1989 and 1991 were of one type. That type has not been isolated
in the United States since 1992. All of the viruses that have
been isolated have been viruses that have been seen elsewhere
in the world, implying that new viruses have come to the United
States. None of these types of viruses were found during this
earlier period.
The second is our surveillance data that show over
prolonged periods in 1993, I believe in 1995, and certainly in
1996 going into 1997, there were very prolonged periods in
which no cases at all were reported in the United States. So
this is the reason why we think it has been interrupted.
I think that there is substantial progress with measles
control abroad, which gives us also some feeling that measles
can be eradicated. During our big epidemic of measles during
1990, almost 250 importations from Latin America were detected
in the United States, many of them in U.S. citizens who had
gone to Latin America and returned. In 1996 there were zero
importations detected, even though we detected almost 50
importations from elsewhere in the world. So that we believe
measles can be eradicated.
In July 1996 we convened, in cosponsorship with the Pan
American Health Organization and the World Health Organization,
a meeting to discuss the feasibility of eradication with some
experts, and they said it could be eradicated, and actually
recommended setting a goal for some time between 2005 and 2010.
One of the big issues to overcome in order to move forward
is to get the political will, particularly in the developed
world. Most of measles detected now is being exported from
countries like Japan, Germany, Italy, and the like, and that is
where I think we need to place more effort.
state carryover balances from prior years
Senator Bumpers. Let me ask you an additional question,
Walt, about cost. The 317 program has had carryovers for the
last several years, and I think the VFC program is up to close
to one-half billion dollars a year, is it not?
Dr. Orenstein. The actual appropriation had been that. The
actual spending has been substantially below the appropriation.
Senator Bumpers. Has it?
Dr. Orenstein. Yes.
Senator Bumpers. Well, that is an entitlement program.
Dr. Orenstein. Right.
Senator Bumpers. So we do not appropriate money for it.
Dr. Orenstein. Right.
Senator Bumpers. We give you whatever you need and there is
no problem with the carryover there.
Dr. Orenstein. Right.
Senator Bumpers. But with the 317 program, these
carryovers, of course, can be used presumably to cover some of
the increased costs that we are facing here. But we are going
to have to depend on you to tell us. I do not want us to wind
up here putting these new vaccines, and some of them very
costly--Varicella is what, $34 a dose?
Dr. Orenstein. Correct.
Senator Bumpers. That is twice as high as any other vaccine
that I know of.
Obviously, the cost is going to escalate for the 317 funds,
for these 317 programs. We are going to have to depend on you
to give us a little advance guidance on this, so that we do not
wind up in the middle of the year out of money, because, as I
say, we are adding a lot of new vaccines and combinations and
the cost is going to grow. There will be no problem getting the
money appropriated here. All we need to know is what is the
right amount to deal with this.
I have more questions here that I would ask. Dr. Osterholm,
let me turn to you. You mentioned bar codes. I was intrigued by
that, but I did not understand it.
confusion caused by number of vaccines on the market
Dr. Osterholm. Mr. Chairman, today what we are seeing
happening in many of our clinics out there, both in terms of
the private practice and public health clinics, is we have
people such as certified medical assistants who really have
minimal understanding of all this combinations, and they are
basically trying to do medical ordering much as we would do
today out of a hospital pharmacy, where we would require a
pharmacist to actually draw the meds and you would require that
there be double or triple checks before those meds are
delivered in the hospital setting.
In our clinics today we are finding that, with all the
confusion and not understanding what these different vaccines
mean--it was very easy when there was an MMR or there was a DPT
or there was a polio to do it. So that what this would allow
you to do actually is take some of the confusion out of which
vaccines are you using and in fact which vaccines do you need.
The ideal system would be if you had a child's total
immunization history to that point electronically there, and
that it could then print out for you in a program what are the
appropriate immunizations you need to either minimize the
number of injections or minimize the number of different types
of products, and that that could then be reliably verified by
what is on the vaccine and what is on the medical charts. In
other words, it matches it up and it spits out for you what you
need.
We do this in blood banking. We do this in a lot of other
areas, where the reliability then is assured through that
process, as opposed to having some certified medical assistant
make a decision about these are the vaccines we really need
here.
bar coding of vaccines
Senator Bumpers. Dr. Paradiso, what do you think about
that?
Dr. Paradiso. I think it is a great idea. We use bar coding
to do all of our clinical trials, so that each vaccine vial is
bar coded and when the child is immunized the bar codes gets
put on his record and it gets on the vial and it goes into the
computer. The samples from the child get sent with a bar code.
You do not write anything.
Senator Bumpers. You eliminate a lot of human error and get
a lot of human information.
Dr. Paradiso. The computer reads all the information and
spits it back.
Senator Bumpers. That sounds pretty fascinating to me. Of
course, that is up to you all, I assume, to do that. I do not
think we are going to take that upon ourselves here, to order
you to do it. It seems to me that that is just something that
ought to be done by the pharmaceutical companies.
immunization registries
Dr. Paradiso. Well, yes, but in terms of the registries
that allow the tracking, these are systems that need to be
developed.
Senator Bumpers. Yes.
Dr. Paradiso. We can put the bar codes on, but it needs to
be fit within a system.
Senator Bumpers. Dr. Osterholm, you talked about the
automatic tracking system. Several years ago you did not much
endorse this notion before this committee. Have you changed
your mind?
Dr. Osterholm. Mr. Chairman, I think that may be a slight
misinterpretation.
Senator Bumpers. It probably is.
Dr. Osterholm. What I was trying to do is predict history
for you, and in fact I can tell you that one of the more
memorable meetings I have had in my career was with your wife,
who in 1991 or 1992 was in a meeting with me at the Carter
Center. Obviously, I have the same respect for Mrs. Bumpers as
I do you, and I was trying to share with her that I did not
believe that the climate was right in the United States for
mass proliferation of a smart card with everybody's record on
it, as has been promoted by many people.
She I think misinterpreted that, as maybe this committee
did, that I was speaking against it. I was merely trying to say
the reality is this is not going to happen. Well, here we are 5
years later and it has not happened.
Senator Bumpers. You are right.
Dr. Osterholm. And I have run into that same problem in my
own State legislature trying to get registry efforts through,
in which there is a segment of society that says: Stay out of
my life, I do not want you in there. So we continue to struggle
with that.
Do I think registries are the right thing and the best
thing for public health? Absolutely. So what I am trying to do
is kind of, I think you might say, bridge the gap between
reality and what is ideal and what can we find. So I very
strongly support the registry approach. I think that, given a
State like ours, where I mentioned 25 percent of the children
in managed care each year are changing health plans, moving
that data with them has been very difficult. This would be
ideal.
So we very much promote the idea and we believe it has to
start at a State and local level, and that has been very
difficult. I think Mrs. Bumpers, who has probably shared with
you that, if you look at the Robert Wood Johnson effort, that I
am on the executive committee of the All Kids Count Program
and, as much as I think that there have been some real pluses,
I am still disappointed that 5 years into that effort we still
do not have a major national initiative and a real groundswell
of support to put these into place.
What we have had are local providers, which have been
great. But we need to do much more in this area.
tracking immunizations of children
Senator Bumpers. Well, I agree with that. Tracking is
working to some extent in some areas. You know, I do not know
that we will ever be able to develop a total tracking system.
It obviously will never work perfectly. But every time you get
a child in the tracking system so that you know exactly where
that child is in the immunization schedule and everything, you
are just that much better off, because there are so many people
who are changing providers all the time and it is just
impossible to keep up with what the child has been immunized
against and what he has not been immunized against.
I always thought Betty was kind of a Johnny One Note on
that. She just talked about that incessantly for years. And she
is still enamored of this fellow down in Mississippi, I guess,
who started the first tracking system. It has much to be said
for it, but it has not--we just have not committed to it is the
reason it has not worked, and maybe we never will.
But as I say, for everybody that goes into the tracking
system, that is a big plus.
I think that just about covers most of the questions I had
except some that I do want to--oh. For all of you, let me ask
this question. The role of the advisory committee is changing
as the vaccine market changes and recently the advisory
committee decided to request and review a new cost-benefit
analysis on Varicella vaccine, which was approved by the
committee last year.
cost benefit of vaccines
Is it appropriate for the advisory committee, which is an
independent panel of scientists, to make economic decisions
related to cost-benefits? And should the committee confine its
advisory role to safety, efficacy, and public health criteria?
Shall I repeat that question? Do you understand what I am
saying? Dr. Paradiso, are you familiar with that committee? I
used to hear about it every night when Betty went, but I do not
hear much about it any more.
Dr. Paradiso. Yes; I am. I think it is fair to say that
that is a committee of public health experts and medical
experts, and their job has traditionally been to make
recommendations on vaccines on the basis of medical need. Cost
effectiveness or cost-benefit has been part of that analysis
and obviously it is related to the need and to the requirement
for a vaccine and on the basis of the disease.
I think the difficulty that the group is--the difficult
position they are put in is when, once they have decided that
there is a public health need and that the vaccine should be
recommended, if they have to then go back and redecide on the
basis of the dollars that are going to be spent, then that puts
them in a difficult situation where potentially they could be
preventing coverage for certain portions of the population,
either while they are making that decision or forever if the
recommendation is not made.
So it seems to me that the goal for that committee and what
Congress' intent was for them to make that decision once, to
decide whether a vaccine should be recommended universally, and
if it is then that becomes part of the entitlement program you
mentioned. I think that creates a situation that the committee
can deal with, and it allows them to act on the basis of their
expertise.
Senator Bumpers. You want to comment on that, Dr.
Osterholm?
Dr. Osterholm. Well, I think from the standpoint of cost
benefit I guess the issue really becomes one of what we mean
just by cost benefit, if we are talking about dollars as the
meaning here. I think that----
Senator Bumpers. Well now, let me interrupt you just a
moment to make this question a little more interesting. You
know, it was the committee that decided how we ought to mix
OPV's and IPV's, and so far as I know that is the regimen we
are now following. Is it not, Walt?
Dr. Orenstein. That is correct.
Senator Bumpers. In the country on how we give oral and
intravenous polio vaccines. And I thought that was an
appropriate role for them. They are scientists. I never
understood why Betty was on that committee. She just really had
no business being on it. In a way, she learned a lot. But that
is a scientific committee who makes really important
recommendations, as they did in that case.
I am not saying that they should not be precluded from
doing cost studies, because in these combinations the
combination we pick is going to have everything to do with the
cost of this program. If you can eliminate the doctor--if you
can make one doctor visit and get five antigens, as opposed to
making three visits, you save a lot of money.
So it seems to me that it is hard to extricate the two, but
I just wanted to know whether you thought this group of
scientists really had any business working on anything except
safety and efficacy and should add cost-benefit analyses to
their studies?
Dr. Osterholm. Actually, I appreciate that additional
information, because actually I was going to try to take the
question in that very direction.
Senator Bumpers. Well, feel free to go any direction you
want.
problems related to vaccine delivery
Dr. Osterholm. And again, I do not mean to presume here,
but I will there to help provide why I think Mrs. Bumpers
played a key role on that committee as a group of scientists.
Imagine today if you had a petroleum company that could make
the world's best gas, that had the most clean kind of burning
gas, that had the most power, they had the engineers that could
build the best gas stations, et cetera, et cetera, but they
really screwed up on the pumps and nobody knew how to use them.
So when it came time to put your gas in the car nobody went
there because they could not figure out how the devil to make
the pump work. Sometimes that is just kind of Joe Citizen that
helps them with that.
I think what this committee actually needs to do is have
more Joe Citizen approaches to the world to help people
understand that you can have the best vaccine in the world, you
can have the most elaborate delivery system, but in fact the
people are not going to use it or they are going to be so
confused as to how to use it that they do not use it. That is
where the problem is.
advisory committee on immunization practices [acip]
I think ACIP, if I had to say one observational kind of
statement about ACIP is I think we need to look much more at
combination vaccines. This should not be a government versus
industry or public health versus private sector or consumer
versus whatever. This is about in the end how do we get the
most vaccine in the most kids, which satisfies everybody's
outcome.
I think the combination vaccines, as I said in my testimony
this morning, is a major problem. I think what Mrs. Bumpers
does is bring a reality to that very point that says: ``Do not
give me the best and most number of antigens there if I cannot
get it into kids; I have got to get it into kids.'' So I think
that that committee needs to do much more in looking at that
very prospect.
Senator Bumpers. Well, my crack ace aide Mary Ann Chaffee
agrees with you on that, too.
Dr. Osterholm. Then it must be right.
members of acip
Dr. Orenstein. I just wanted to clarify. Who are the
members of ACIP and whether they are scientists versus other
kinds of people? The ACIP presently consists of 10 people. Of
that group, four of them are public health officials, two State
epidemiologists, one State health officer, and a local health
officer who administers an immunization program.
vaccine delivery issues
It has people on it who are university scientists, who are
involved with actual vaccine-related research. And it has plans
to increase its membership from 10 to 12 to include more people
who have expertise in immunization delivery in the private
sector.
I think it is extremely important that they take cost-
benefit and cost-effectiveness issues into account in their
recommendations because these issues are independent--their
recommendations go beyond what the Government purchases. These
are recommendations that basically affect public health
practice and even practice in private medicine. So I think they
need to understand when they make a recommendation whether this
is something that will be acceptable.
In terms of whether their recommendations should
automatically be funded, it is a very controversial one, I
think, as you point to, because one of the things that they do
not take into account is what else in the budget might suffer
in promoting the vaccine side of it. The advantage for us in
the immunization program is that we can more rapidly, even with
the two-step process, more rapidly implement and have more
assurance that we can implement it when they make their
decisions.
So these are the two balancing factors that need to be
considered in their decisions.
acip recommendations
Senator Bumpers. A final question: Are we going to be
looking to the advisory committee to determine which
combinations would be most viable?
Dr. Orenstein. I think what the advisory committee is doing
is trying to work with a whole group of people to develop a set
of recommendations for combination vaccines. Industry is
participating in that discussion.
Senator Bumpers. Of course.
Dr. Orenstein. These are complicated kinds of things.
Whether the committee will say, we will take only this five-
combination vaccine, I doubt this will happen. If there are
certain data that show the merits of that far exceed the merits
of any other combination available, I think the committee would
recommend it.
But I think what I see happening is a much more murky
process, where it will not be crystal-clear which combinations
are better than others. I think what the committee is
attempting to do is to settle on some basic principles, the
principles being: One, the preference, whenever feasible, for
combination vaccines to avoid extra injections and potential
extra visits; second, they are addressing issues of
interchangeability so that the physicians have guidance on
that. The third issue they are talking about is giving
permission to limit the inventory or formulay if necessary,
such as in refrigerator 1, which was the simplest one in my
example.
advantages of tracking immunizations of children
Another issue they are saying is, at times, for
simplicity's sake, it may be necessary, it may be acceptable to
administer extra antigens, such as would occur using the two
Hib combinations discussed earlier. Also the ACIP will push for
getting better data systems to determine what the child
previously received and, therefore, put the doctor in a better
position to determine what the child needs. And we have been
talking with industry about bar coding, but, as Dr. Paradiso
points out, far more is needed to try and determine what a
child has actually had.
One of the things and one of the advantages of potential
registries in the future is that we can build in algorithms so
that, given what a child has, it can automatically tell a
doctor or a nurse, this is what you should be giving. Right now
it can be, as Dr. Osterholm, I think, pointed out beautifully,
it can be extremely confusing. If we can automate through an
electronic system, that would be of help.
That is what I think the committee will do. I think there
is another committee----
Senator Bumpers. Well, FDA has to do this first, do they
not?
Dr. Orenstein. Correct.
Senator Bumpers. FDA is going to have to approve the
combination first.
Dr. Orenstein. Correct.
Senator Bumpers. Based on the tests submitted by the
pharmaceutical company.
Dr. Orenstein. Correct. And then what one will have to look
at is what the other issues are in terms of recommendations
versus use. What I think the committee in the past has done,
and which I think they will continue to do is, if there are
clear indications one is better than another, the committee
will recommend the better vaccine. If it is not, the committee
will allow choice. But even in choice, I think we, at CDC, have
an obligation to begin helping States figure out what they
should purchase.
One of the things that we are working on at CDC is to
develop economic models that will help States. They can plug in
things to figure out which vaccines to purchase. For example,
there was a lot of controversy when the first DTP-Hib vaccines
came out. One of them was premixed, one of them you had to mix.
The one that was premixed was a little bit more expensive. We
made a decision that, since they both protected against the
same diseases, go ahead and get the cheaper version. I think
many States were upset by that.
We are working with the States to allow some flexibility in
choice such that, if, in fact, it takes more nurse time to mix
then they actually save with the unmixed version, they can buy
the premixed product. Those are the kinds of things I think we
will need to do in the future.
new applications for fda approval
Senator Bumpers. Dr. Paradiso, does Wyeth-Lederle have any
applications before FDA right now on new applications?
Dr. Paradiso. Yes; we have an application for a DTaP-
Haemophilus b combination, also for use in toddlers. We are the
premixed group for that combination as well as the first one.
the efficacy of combination vaccines
Senator Bumpers. I must say, I think I would opt for the
premixed.
Dr. Paradiso. I guess what we feel that we need to see is
that those providers are able to choose the vaccine on that
basis. We took the extra effort to make it premixed because it
would be more user-friendly and it would give us an edge over
the competition. And if the Government is going to be the major
purchaser of vaccines and we lose that edge, then it takes the
incentive out of doing that extra step and trying different
combinations.
For the list, we will be working on a lot of those. We
cannot work on all of them. But we cannot predict which ones
are going to work. So it is a gamble for us. The fact that
there are so many groups working on it sort of spreads out the
gamble.
We, as the other companies, are global vaccine groups and
so we are thinking of other markets. Other markets do not use
hepatitis B, other markets do not use IPV, have different--some
do not use acellular pertussis. So there will be an array of
combinations that will be developed for various populations and
that will be available for use in the United States. I think it
is my feeling that if the committee is going to make kind of
recommendations, it should be predominantly what antigens that
they would like to see in those mixtures or in the total sum of
the mixtures, what antigens would they like to see for kids at
2 months of age; and second, how many shots do they think they
can tolerate. And if the answer is two, then it is our job to
fit all of them into two shots. If it is three and we can get
provider acceptance of that, then that is a different scenario.
I think the goal should be to reduce the number of shots,
as everybody does, and to set a standard in that way.
Senator Bumpers. Do any of you have answers to questions
you wish I had asked?
Dr. Osterholm. Well, maybe if I could elaborate on this
point that was just made. I think that one of the concerns that
we still have in Minnesota, a State with a very expanded VFC
program--offering all three of the DTaP's, for example--is that
we still have to interface with the private sector, where kids
will come from. So if a particular pharmaceutical company
aggressively markets a particular combination vaccine which may
not in the wisdom of everyone else be the most compatible or
the most schedule-friendly vaccine and a child comes from a
practice where that vaccine was administered because of a cost
advantage initially to that private practitioner and now comes
back into another system that is primarily VFC, we now still
have to respond to that. In other words, we still have to be
sensitive.
So we cannot set our VFC program, for example, in isolation
because we are mixing and matching clients all the time. I
think this is a very important consideration, and what we see
today is one pharmaceutical company or two pharmaceutical
companies aggressively marketing one or two of the
combinations, which then makes it inconsistent with all the
rest.
We need to help standardize that because that is what is
causing the confusion. And I think the pharmaceutical industry
is underestimating the backlash that is going to occur in the
next 2 to 3 years around this. I can tell you right now in
pediatric meetings, meetings of family practitioners, this is
the highest frustration level issue we have. It is not even in
Minnesota how much they are being reimbursed in managed care in
general. It is around immunizations and the confusion.
What we are afraid we are going to see in the very near
future is people saying, this is just so difficult for us, so
confusing, we are going to send all of them to you guys; you
all in the public sector, just take this. We have worked hard
in Minnesota for years to keep our children in their clinic
homes and to try to keep them in the private sector and support
that ongoing relationship, and they have about had it.
standardization of vaccine delivery
So I think that somebody has to provide the national
leadership to say that we have to come together somehow and
start to understand how we can standardize around this, and
that cannot be automatically knee-jerk interpreted by the
industry as meaning we are going to regulate it to say you have
to have this. That cannot be at the Government level saying
that we cannot do anything about it.
Somewhere somebody has to come together, or the consumers
will do it for us and we will be back here talking about lots
of cases of disease, because we will have watched the ebb and
flow of immunization levels.
Senator Bumpers. Dr. Osterholm, when I send each of you
written questions I would like for you to put what you said in
writing and any elaboration on that in writing to me.
Dr. Osterholm. I would be happy to.
conclusion of hearing
Senator Bumpers. It is a very interesting point you just
made and it makes a lot of sense.
Gentlemen, I thank you all very much for your time and fine
eloquent statements this morning. I think this is extremely
helpful to me and it will be to the committee and the Congress.
Thank you again for being here, the subcommittee will stand
in recess subject to the call of the Chair.
[Whereupon, at 12:08 p.m., Wednesday, July 16, the hearing
was concluded, and the subcommittee was recessed, to reconvene
subject to the call of the Chair.]
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