[Senate Hearing 105-660]
[From the U.S. Government Publishing Office]


                                                        S. Hrg. 105-660

 
                     NATIONAL IMMUNIZATION PROGRAM

=======================================================================

                                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

                                 ______


                     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
                                 ------                                

 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

                              ----------                              
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

                              ----------                              


                        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.
---------------------------------------------------------------------------
    \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.
---------------------------------------------------------------------------
    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\
---------------------------------------------------------------------------
    \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.
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
    \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.
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
    \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).
---------------------------------------------------------------------------
      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).
---------------------------------------------------------------------------
    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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