Childhood Vaccines
Ensuring an Adequate Supply Poses Continuing Challenges
Gao ID: GAO-02-987 September 13, 2002
Immunizations are considered one of the leading public health achievements of the 20th century. Mandatory immunization programs have eradicated polio and smallpox in the United States and reduced the number of deaths from several childhood diseases, such as measles, to near zero. A consistent supply of many different vaccines is needed to support this effort. Recent childhood vaccine shortages have prompted federal authorities to recommend deferring some immunizations and have caused states to reduce immunization requirements. At the state and local levels, 49 state immunization programs reported rationing one or more vaccines. Shortages have also prompted most states to waive or change immunization requirements for school and day care programs so that children who have not received all mandatory immunizations could enroll. Many factors contributed to recent vaccine shortages, and while these have largely been resolved, the potential exists for future shortages. On the supply side, some manufacturers had production problems, causing them to fall below their expected output, while others discontinued making some vaccines altogether. On the demand side, one manufacturer could not keep pace with the greater-than-expected demand for a new recommended vaccine. Federal agencies and advisory committees are exploring ways to help stabilize the nation's vaccine supply, but few long-term solutions have emerged. One option--expanding vaccine stockpiles--is being widely considered as a short-term strategy to help cushion disruptions in vaccine supply. Stockpiles have been used successfully to help mitigate supply disruptions in the past.
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GAO-02-987, Childhood Vaccines: Ensuring an Adequate Supply Poses Continuing Challenges
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United States General Accounting Office:
GAO:
Report to Congressional Requesters:
September 2002:
Childhood Vaccines:
Ensuring an Adequate Supply Poses Continuing Challenges:
GAO-02-987:
Contents:
Letter:
Results in Brief:
Background:
Shortages Prompt Actions to Reduce Immunization Requirements:
Problems Causing Shortages Largely Resolved, but Shortages Could Recur:
No Clear Path Yet to Resolve Ongoing Supply Issues:
Conclusions:
Matter for Congressional Consideration:
Recommendations for Executive Action:
Agency Comments and Our Evaluation:
List of Requesters:
Appendix I: Comments from the Department of Health & Human Services:
Appendix II: GAO Contacts and Staff Acknowledgments:
Tables:
Table 1: Functions of Federal Agencies and Committees to Address
Vaccine Shortages:
Table 2: Duration of CDC-Reported Childhood Vaccine Shortages:
Table 3: Modification of Immunization Schedule during Vaccine
Shortages:
Table 4: Extent of Vaccine Shortages in State Immunization Programs:
Table 5: Number of Manufacturers Producing Routine Childhood Vaccines
in the United States:
Abbreviations:
AAP: American Academy of Pediatrics:
ACIP: Advisory Committee on Immunization Practices:
ASTHO: Association of State and Territorial Health Officials:
ATSDR: Agency for Toxic Substances and Disease Registry:
BLA: biologics license application:
CDC: Centers for Disease Control and Prevention:
DTaP: diphtheria, tetanus, and acellular pertussis:
EPA: Environmental Protection Agency:
FDA: Food and Drug Administration:
Hep B: hepatitis B:
Hib: haemophilus influenzae type b:
HHS: Department of Health and Human Services:
ICH: International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use:
IPV: inactivated polio vaccine:
MMR: measles, mumps, and rubella:
NIH: National Institutes of Health:
NIS: National Immunization Survey:
NVAC: National Vaccine Advisory Committee:
NVP: National Vaccine Plan:
NVPO: National Vaccine Program Office:
PCV: pneumococcal conjugate vaccine:
PHS: U.S. Public Health Service:
Td: tetanus and diphtheria booster:
VFC: Vaccines for Children:
VICP: Vaccine Injury Compensation Program:
[End of section]
United States General Accounting Office:
Washington, DC 20548:
September 13, 2002:
Congressional Requesters:
Immunizations are widely considered one of the leading public health
achievements of the 20th century. Mandatory immunization programs have
eradicated polio and smallpox in the United States and reduced the
number of deaths from several childhood diseases, such as measles, to
near zero. A consistent supply of many different vaccines is needed to
support this effort. By 18 months of age, it is recommended that each of
the 11,000 babies born each day in the United States receive up to 20
doses of vaccine to protect against 11 diseases.
The federal government plays a variety of roles in immunization
programs. Although vaccines are made by private companies and
immunization policies are set at the state level, various agencies of
the Department of Health and Human Services (HHS) have roles in
regulating vaccine production, purchasing vaccines and making them
available to states, and making recommendations for states to consider
in setting immunization policies, such as those for school and day care
enrollment. The federal government also plays a central role in
ensuring the adequacy of the nation‘s vaccine supply”a matter of
increasing concern in recent years. Although sporadic interruptions in
the supply of vaccines have occurred in the past, these interruptions
have become much more pronounced in the past 2 years. In late 2001, the
Centers for Disease Control and Prevention (CDC) reported shortages in
five of the eight recommended childhood vaccines. Concerned about the
increasing frequency of these shortages, you asked that we answer the
following questions:
1. To what extent have recent childhood vaccine shortages affected
immunization policies and programs?
2. What factors have contributed to the recent shortages, and have they
been resolved?
3. What strategies are federal agencies considering to help mitigate
disruptions in the vaccine supply?
To assess the effect of vaccine shortages on immunization policies and
programs, we surveyed 64 state, territorial, and local immunization
programs supported by CDC, [Footnote 1] examined recent changes in
recommended immunization schedules, and reviewed studies of past
outbreaks. To identify the factors that contributed to shortages and
determine if they are being resolved, we visited the four primary
vaccine manufacturers, determined how federal regulatory procedures
affect vaccine production, and reviewed various analyses of vaccine
supply problems by HHS agencies and other entities. To identify
strategies being considered by federal authorities to help prevent or
mitigate vaccine shortages, we reviewed studies and recommendations to
strengthen the vaccine supply, attended advisory panel meetings
examining vaccine shortages, and interviewed agency officials and other
vaccine experts. We conducted our work from November 2001 through July
2002 in accordance with generally accepted government auditing
standards.
Results in Brief:
Recent childhood vaccine shortages have prompted federal authorities to
recommend deferring some immunizations and have caused states to
reduce immunization requirements. The federal Advisory Committee on
Immunization Practices (ACIP) and CDC, which recommend immunization
standards for the nation, have recommended that physicians defer
immunizations for vaccines in short supply, so that the vaccines will
continue to be available to those at highest risk. At the state and
local levels, 49 state immunization programs reported rationing one or
more vaccines. Shortages have also prompted the majority of states to
waive or change immunization requirements for school and day care
programs so that children who had received fewer than the mandatory
immunizations could enroll. States reported that vaccine shortages and
missed make-up vaccinations may reduce coverage and increase the
potential for disease to spread; however, data are not currently
available to measure these effects.
Multiple factors contributed to recent vaccine shortages, and while
these have largely been resolved, the potential exists for shortages to
recur. The shortages stemmed from a number of factors that affected
both supply and demand. On the supply side, for example, some
manufacturers had production problems that caused them to fall below
their expected output, while others discontinued making some vaccines
altogether. On the demand side, one manufacturer could not keep pace
with the greater-than-expected demand for a new recommended vaccine.
CDC reported supplies for all but one vaccine were beginning to return
to normal by July 2002. However, the potential for recurring shortages
will remain because the complex nature and often year-long production
schedule of vaccine manufacturing will continue to make it difficult
for the supply system to respond rapidly to sudden changes in supply or
demand. Additionally, with so few firms making each vaccine (five of
the eight recommended childhood vaccines have only one manufacturer
each), production problems or a manufacturer‘s decision to withdraw may
leave few or no alternative sources of vaccine. One development that
may help add greater capacity in meeting future needs is that a number
of new vaccine products that could be used to meet the existing
childhood immunization schedule are in varying stages of development,
ranging from clinical testing to review by the Food and Drug
Administration (FDA). However, the process to complete clinical trials
and undergo FDA review likely will take several years, and these
products generally do not qualify for expedited review
under FDA policies.
Federal agencies and advisory committees are exploring options to help
stabilize the nation‘s vaccine supply, but few long-term solutions have
emerged. One option, expanding vaccine stockpiles, is receiving wide
consideration as a short-term strategy that could help cushion
disruptions in vaccine supply. Stockpiles have been used successfully
to help mitigate supply disruptions in the past. While CDC is required
by law to stockpile a 6-month supply of recommended childhood vaccines
and has the necessary funding, it currently has established partial
stockpiles for only two”one for measles, mumps, and rubella and one for
polio. In light of the recent shortages, CDC is now considering plans
to expand the stockpile to include additional vaccines. Stockpiling
vaccines, however, has its limitations. While stockpiling can provide a
cushion in the event of a supply disruption, limited supply and
manufacturing capacity will restrict CDC‘s ability to build certain
stockpiles in the near term. In addition, it is unclear whether the
authority that CDC is using to establish these stockpiles provides for
their use for all children. Another problem in expanding stockpiles is
that CDC lacks a strategy for determining such things as how much
vaccine to stockpile, where it should be stored, and how to ensure that
the stockpile is additional to a manufacturer‘s normal inventory. CDC
also lacks important information from FDA, manufacturers, and states
needed to anticipate and manage supply disruptions.
We are making several recommendations to the Secretary of HHS to help
promote the availability of vaccine products. These recommendations
include adding vaccines to the types of products that can be considered
under FDA‘s authority to expedite the approval of products in
development trials and directing CDC to address several operational and
strategic issues in expanding childhood vaccine stockpiles. In its
general comments on a draft of this report, HHS stated that it agrees
with the report‘s findings and has initiated actions to implement the
recommendations. The report also contains a matter for congressional
consideration to address the extent to which currently stockpiled
vaccines are available for use by all children in the event of a
shortage.
Background:
CDC currently recommends routine immunizations against 11 childhood
diseases: diphtheria, tetanus, pertussis (whooping cough), haemophilus
influenzae type b (most commonly meningitis), hepatitis B, measles,
mumps, rubella (German measles), invasive pneumococcal disease, polio,
and varicella (chicken pox). [Footnote 2] Some vaccines protect against
multiple diseases. By combining antigens (the component of a vaccine
that triggers an immune response), a single injection of a combination
vaccine can protect against multiple diseases. Examples include the MMR
vaccine (for measles, mumps, and rubella) and the DTaP vaccine (for
diphtheria, tetanus, and pertussis). As a result of these combinations,
eight vaccines are normally used to provide protection against the 11
childhood diseases. To build and maintain sufficient immunity, multiple
doses of each of these vaccines are usually needed through infancy and
early childhood. CDC‘s suggested vaccine timetable calls for children
to receive up to 23 doses of these vaccines through the first 6 years
of life. An additional tetanusdiphtheria booster is recommended during
adolescence. When very large shares of the general population are
immunized, vaccines are successful at preventing major outbreaks of
disease. Vaccines also offer some degree of protection to individuals
not immunized, because a high immunization rate in a population gives a
disease less opportunity to take hold and spread”a concept known as
’herd immunity.“ Development of vaccines and establishment of large-
scale immunization programs have virtually eliminated some diseases and
drastically reduced the impact of others. Finally, with the ease of
international travel, wide-scale vaccination programs help protect
against infected travelers transmitting diseases, such as measles, from
foreign countries where the diseases are still common.
Consolidation Resulted in Four Companies Engaged in Vaccine
Manufacturing:
Making vaccines is a complicated and time-consuming process. In contrast
to drug manufacturing, vaccine manufacturing entails the use of
biological organisms, including viruses and bacteria, which requires
adherence to strict and complex manufacturing controls to ensure that
they grow and react during processing as expected. Under current
technology, vaccines typically require long production times.
Manufacturers report that a typical production schedule, including
growing the antigen, purifying, testing, packaging, and performing
final quality checks, can exceed a full year for some vaccines.
Virtually all routine childhood vaccines are made by commercial
manufacturers. [Footnote 3] Reflecting the challenges of vaccine
production, the vaccine-manufacturing base in the United States has
been marked by substantial consolidation over the past three decades.
According to HHS, there were 26 manufacturers licensed to distribute
vaccines in 1967. Due in part to acquisitions and mergers, at present
there are 12 manufacturing entities that hold U.S. licenses, four of
which produce almost all of the routine childhood vaccines on the U.S.
market. Two of these companies”Merck & Company and Wyeth”are
headquartered in the United States, and two”Aventis Pasteur and
GlaxoSmithKline”are headquartered in Europe.
Federal and State Governments Play Key Roles:
The federal government has a role both as a purchaser of vaccines and
as a regulator of the industry. The federal government is the largest
purchaser of vaccines in the country. CDC negotiates large purchase
contracts with manufacturers and makes the vaccines available to public
immunization programs under the Vaccines for Children (VFC) program.
Under VFC, vaccines are provided for certain children”Native
Americans/Alaska Natives, those eligible for Medicaid, those who are
uninsured, and, when vaccinated in federally qualified health centers
or rural health clinics, those who are not insured with respect to the
vaccine. Participating public and private health care providers obtain
vaccines through VFC at no charge. Under a second program, known as the
section 317 grant program because it was established under section 317
of the Public Health Service Act, [Footnote 4] project grants are
provided for preventive health services including immunization
programs. Currently, participants include 64 state, local, and
territorial immunization programs. These grants are intended to help
states maintain immunization infrastructures or purchase vaccines not
covered by private insurance or not available through VFC. In addition,
state immunization programs can use their own funds to buy vaccines
through CDC contracts. In total, about 50 percent of all the childhood
vaccines administered in the United States each year are obtained by
public immunization programs through CDC contracts.
The cost of the full schedule of recommended vaccines under the CDC
contracts has increased substantially in recent years, with a large
share attributable to new higher-cost vaccines that have been added to
the childhood immunization schedule. [Footnote 5] For example, as of
May 2002, the CDC contract price for vaccine doses needed to complete
the immunization schedule was about $413. [Footnote 6] Over half of
this amount is attributable to the most recent ACIP-recommended
vaccines”varicella (recommended in 1996) and pneumococcal conjugate
vaccine (recommended in 2001).
In addition to purchasing vaccines, the federal government is
responsible for ensuring the safety of the nation‘s vaccine supply.
FDA, an agency within HHS, regulates the production of vaccines. It
licenses all vaccines sold in the United States, requiring clinical
trials to demonstrate that a vaccine is safe and effective, and
thoroughly reviews the manufacturing process to ensure that vaccines
are made consistently in compliance with current good manufacturing
practices. Once vaccines are licensed, FDA also conducts periodic
inspections of production facilities to ensure that manufacturers
maintain compliance with FDA manufacturing requirements.
Other HHS agencies and programs also provide support for national,
state, and local immunization efforts nationwide. The National Vaccine
Program Office (NVPO), within the Assistant Secretary for Health‘s
office, is responsible for coordinating the efforts of all federal
agencies, states, providers, industry, and other stakeholders involved
in immunization activities. CDC‘s National Immunization Program, in
addition to purchasing vaccines for VFC, conducts a number of
activities to strengthen the nation‘s immunization infrastructure, such
as monitoring the delivery of vaccines to state immunization programs
and providing technical assistance to help health departments implement
immunization programs. In times of vaccine shortages, several federal
agencies and advisory committees play key roles (see table 1).
Table 1: Functions of Federal Agencies and Committees to Address Vaccine
Shortages:
Agency/committee: ACIP;
Functions that help avert or mitigate vaccine shortages: Evaluate and
recommend changes in the immunization schedule to accommodate reduced
supplies.
Agency/committee: CDC;
Functions that help avert or mitigate vaccine shortages: Monitor
production, monitor inventories of state immunization programs, manage
distribution of public supplies, administer stockpiles, track back
orders, and work with ACIP to modify immunization schedules in order to
respond to vaccine shortages.
Agency/committee: FDA;
Functions that help avert or mitigate vaccine shortages: Accelerate
review of revisions to existing licenses and vaccine lots submitted for
release. Work with manufacturers to correct violations of good
manufacturing practices that could disrupt production.
Agency/committee: NVPO;
Functions that help avert or mitigate vaccine shortages: Facilitate
development of contingency plans, identify the reasons for shortages
and options to address them, and identify strategies to prevent future
shortages.
Agency/committee: National Vaccine Advisory Committee (NVAC);
Functions that help avert or mitigate vaccine shortages: Study and make
recommendations to the HHS Assistant Secretary for Health on ways to
achieve an adequate supply of safe and effective vaccines.
Source: ACIP, CDC, FDA, NVPO, and NVAC.
[End of table]
States also have an important role in setting immunization policy and
establishing an immunization infrastructure. Policies for immunization
requirements, including minimum school and day care entry requirements,
are made almost exclusively at the state level, although cities
occasionally impose additional requirements. For example, the state of
New York requires students to have three doses of DTaP upon entering
day care or school, while New York City requires an additional fourth
dose. Each state also establishes an immunization infrastructure to
monitor infectious disease outbreaks, administer federal immunization
grants, manage centralized supplies of vaccine, direct professional and
public education efforts, and otherwise promote immunization policies.
Vaccine Shortages Have Peaked and Most Supplies Are Returning to
Normal:
The recent incidents of vaccine shortages began in fall 2000 when
supplies of the tetanus and diphtheria booster (Td) fell short. Over
the course of a year, supplies of other vaccines also declined and by
fall 2001, CDC reported shortages of five vaccines that, because some
are combination vaccines, protect against eight childhood diseases (see
table 2). In July 2002, updated CDC data indicated supplies were
returning to normal for most vaccines. The shortage of pneumococcal
conjugate vaccine (PCV), however, was expected to continue through at
least late 2002.
Table 2: Duration of CDC-Reported Childhood Vaccine Shortages:
Vaccine, in short supply: Tetanus and diphtheria booster (Td);
Approximate start of shortage: November 2000;
Actual or projected end of shortage: Ended June 2002.
Vaccine, in short supply: Diphtheria, tetanus, and acellular pertussis
(DTaP);
Approximate start of shortage: January 2001;
Actual or projected end of shortage: Ended June 2002[A].
Vaccine, in short supply: Pneumococcal conjugate vaccine (PCV);
Approximate start of shortage: September 2001[B];
Actual or projected end of shortage: Continue through at least late
2002.
Vaccine, in short supply: Measles, mumps, and rubella (MMR);
Approximate start of shortage: October 2001;
Actual or projected end of shortage: Ended June 2002[A].
Vaccine, in short supply: Varicella;
Approximate start of shortage: October 2001;
Actual or projected end of shortage: Ended July 2002.
Vaccine, Adequate supply:
Hepatitis B (Hep B);
Haemophilus influenzae type b (Hib)[C];
Inactivated polio vaccine (IPV).
[A] Supplies of DTaP and MMR are sufficient to meet demand for routine
use, but not yet sufficient for extensive make-up initiatives.
[B] CDC reported shortages of PCV existed throughout most of 2001, but
intensified in September 2001.
[C] Not considered a shortage by CDC; however, two of three
manufacturers reported shipment delays up to 60 days. A third
manufacturer had product available.
Source: CDC vaccine shortage reports, July 2002.
[End of table]
Shortages Prompt Actions to Reduce Immunization Requirements:
Recent vaccine shortages have necessitated temporary modifications to
the recommended immunization schedule and have caused states to scale
back immunization requirements. Federal health officials and experts
responsible for the development of immunization guidelines have
temporarily scaled back their recommendations regarding the timing of
immunizations for vaccines in short supply. At the state level,
immunization programs are rationing the amount of vaccines distributed
to providers. Many states have also suspended existing immunization
requirements, allowing children who have received fewer than the
previously recommended number of vaccinations to attend day care or
school. Data to capture the full impact of the shortages on vaccination
coverage are not yet available; however, public health officials are
concerned that shortages raise the potential for disease outbreaks.
Federal Immunization Recommendations Scaled Back:
In response to recent vaccine shortages, ACIP and CDC issued temporary
recommendations to defer immunizations for some groups of children, so
that the available supply can be directed to those considered at higher
risk for contracting vaccine-preventable diseases. [Footnote 7] Five
vaccines are included: Td, DTaP, PCV, MMR, and varicella (see table 3).
The revisions give guidance to providers that are facing shortages and
are intended to help ensure vaccine availability for priority needs.
For example, the shortage of PCV, which began in 2001, prompted ACIP to
recommend that the full series of doses be given only to high-risk
children, such as those with chronic diseases, and that fewer doses be
given to healthy children. In the case of varicella immunizations,
where only one dose is generally needed to confer long-term immunity,
ACIP has recommended that doses be delayed.
Table 3: Modification of Immunization Schedule during Vaccine
Shortages:
Vaccine: Td;
Recommended schedule: Routine booster every 10 years;
Age at vaccination: 11–15 years and every 10 years thereafter;
Revised recommendations: Defer routine boosters; prioritize vaccine from
highest to lowest risk groups[A];
Date of revision: November 2000.
Vaccine: DTaP;
Recommended schedule: 5 doses;
Age at vaccination: 2 months; 4 months; 6 months; 15–18 months; 4–6
years;
Revised recommendations: Defer fourth dose; also defer fifth dose, if
necessary;
Date of revision: March 2001.
Vaccine: PCV;
Recommended schedule: 4 doses; a fifth dose is recommended for certain
high-risk groups[B];
Age at vaccination: 2 months; 4 months; 6 months; 12–15 months; 24–59
months;
Revised recommendations: Recommendations vary according to severity of
shortage[C];
Date of revision: December 2001.
Vaccine: MMR;
Recommended schedule: 2 doses;
Age at vaccination: 12–15 months; 4–6 years;
Revised recommendations: Defer second dose;
Date of revision: March 2002.
Vaccine: Varicella;
Recommended schedule: 1 dose; 2 doses are recommended for high-risk
groups[D];
Age at vaccination: 12–18 months; 13 years or older;
Revised recommendations: Delay until 18–24 months: prioritize to high-
risk groups if shortage persists[E];
Date of revision: March 2002.
[A] Recommendations for use (highest to lowest priority) of Td are
those traveling to countries where the risk for diphtheria is high,
those requiring tetanus vaccination for wound management, those who
have received fewer than three doses of vaccine containing Td, pregnant
women, those at occupational risk for tetanus-prone injuries, and those
who have not been vaccinated within the preceding 10 years.
[B] High-risk children include those with sickle-cell disease, human
immunodeficiency virus infection, and other immunocompromising or
chronic medical conditions.
[C] In December 2001, ACIP issued updated recommendations for PCV use
for healthy children during moderate and severe shortages. For infants
who receive their first dose before age 6 months, vaccination with a
maximum of three doses is recommended during a moderate shortage, and
two doses are recommended during a severe shortage. All health care
providers have been asked to reduce the number of doses used and
ordered, regardless of their current supply, so that vaccine is
more widely available until supplies are adequate.
[D] Susceptible individuals aged 13 years or older should receive two
doses spaced at least 4 weeks apart.
[E] Recommendations for use (highest to lowest priority) of varicella
vaccine are health care workers, family contacts of immunocompromised
persons, individuals aged 13 years or older, and adults with high-risk
children (for example, children infected with human immunodeficiency
virus and children with asthma or eczema).
Source: ACIP and CDC recommendations.
[End of table]
States Reduce Immunization Requirements:
The shortages that prompted federal officials to scale back their
immunization recommendations have also affected programs at the state
level. In our survey of 64 state immunization programs, administered
through the Association for State and Territorial Health Officials
(ASTHO), all 52 responding programs indicated that they had experienced
shortages of two or more vaccines and had taken some form of action to
deal with the shortages (see table 4). [Footnote 8] Officials from 31
of these 52 programs indicated that they had experienced shortages of
five or more of the vaccines routinely recommended for children. The
most frequently cited vaccines in short supply”DTaP, Td, varicella,
MMR, and PCV”protect against eight diseases: diphtheria, tetanus,
pertussis, varicella, measles, mumps, rubella, and pneumococcal
disease.
Table 4: Extent of Vaccine Shortages in State Immunization Programs:
Extent of vaccine shortages: Shortages of two or more vaccines;
Number of state immunization programs reporting: 52.
Extent of vaccine shortages: Shortages of five or more vaccines;
Number of state immunization programs reporting: 31.
Extent of vaccine shortages: Shortages of one or more vaccines for 12
months or longer;
Number of state immunization programs reporting: 9.
Extent of vaccine shortages: Ration vaccines to providers;
Number of state immunization programs reporting: 49.
Extent of vaccine shortages: Allow children to attend school with fewer
than recommended number of vaccinations[A];
Number of state immunization programs reporting: 35.
Note: Information is based on responses from 52 state immunization
programs.
[A] While states set the minimum immunization requirements for school
and day care entry, local immunization programs have the option to
establish additional requirements according to local needs.
Source: GAO survey of 64 state immunization programs.
[End of table]
Forty-nine state immunization programs reported taking steps to ration
the vaccines they distribute to providers due to the shortages. Under
normal supply conditions, states maintain vaccine inventories that allow
providers to keep at least a 1-month supply on hand. With a limited
supply of vaccine available, states reported not receiving enough
vaccine to maintain ideal inventories, and filling only partial orders
to ship to providers. For example, in March 2002 officials from the
immunization program in Arkansas reported that they planned to cut the
size of vaccine shipments to public and private providers by 50 to 80
percent, with the percentage reduction depending on the supply of
vaccine in the state depot. The cuts are made to ensure an even
distribution of vaccine among providers throughout the state. Officials
from nine states reported being short of vaccines for 12 months or
longer, and in some cases states reported having been completely out of
certain vaccines for months at a time. For example, the immunization
program in Philadelphia reported it had been unable to supply its
health care providers with varicella and PCV for a 3-month period, and
the program in Illinois reported that it had ordered over 70,000 doses
of PCV since January 2002 but had received no doses as of the end of
May 2002.
Vaccine shortages experienced at the state level have, in turn, prompted
cutbacks in immunization requirements for admission to day care or
school. Thirty-five states reported putting into effect new, less
stringent immunization requirements that allow children who have
received fewer than the recommended number of vaccinations to attend
school. [Footnote 9] In general, these states have reduced the
immunization requirements for day care and/or school entry or have
temporarily suspended enforcement of those requirements until vaccine
supplies are replenished. For example, the Minnesota Department of
Health suspended the school and postsecondary immunization laws for Td
vaccine for the second year in a row, with the suspension extending
through the 2002-2003 school year. Other states, including Washington
and South Carolina, reported allowing children to attend day care or
school even if they were not immunized in compliance with immunization
requirements, under the condition that they be recalled for
vaccinations when supplies became available.
Deferred Immunizations Likely to Lower Vaccination Coverage and May
Increase the Risk of Outbreaks:
While it is too early to measure the effect of deferred vaccinations on
immunization rates, a number of states reported that vaccine shortages
and missed make-up vaccinations may take a toll on coverage and, as
such, increase the potential for infectious disease outbreaks. The full
impact of vaccine shortages is difficult to measure, for several
reasons. First, none of the surveys that estimate immunization coverage
at the national level measures the rate of age-recommended immunizations
among children under the age of 18 months”the age cohort receiving the
majority of vaccinations. Second, although the National Immunization
Survey (NIS) [Footnote 10] measures vaccination coverage among children
aged 19 to 35 months, it does not inquire why children are not
immunized. A reported decrease in coverage for any given year may be
due to a number of factors, such as parental concerns about vaccine
safety. Third, it would take some time after the shortages have ended
to determine how many children were not recalled for missed
vaccinations, a measure that could be useful in evaluating the impact
of the shortages. [Footnote 11]
High vaccination rates from recent years could delay the immediate
effects of deferred immunizations, but underimmunization destabilizes
population immunity and may lead to outbreaks. Immunization rates for
children receiving the series of all recommended vaccinations have been
rising steadily since the inception of the NIS in 1994”from 55 percent
in 1995 to 74 percent in 2001 for children aged 19 to 35 months.
[Footnote 12] Coverage with three or more doses of DTaP alone was
approximately 94 percent in the most recent survey. Immunization
experts generally agree that the residual effects of such high levels
of population immunity may afford temporary protection for
underimmunized children against communicable, vaccine-preventable
diseases; however, the more numerous the population of susceptible
individuals becomes, the greater the probability that those who are
susceptible will come into contact with an infected person. Past
outbreaks demonstrated this concept and highlight the importance of
giving all recommended doses according to schedule. For example, a CDC
analysis of a 1998 outbreak of measles in an Anchorage, Alaska, school
showed that only 51 percent of the 2,186 children exposed had received
the requisite two doses of measles-containing vaccine. This and other
studies of measles outbreaks cited by CDC underscore the potential
ramifications of deferring the second dose of MMR vaccine.
In addition to the potential for vaccine shortages to reduce coverage,
public health officials are concerned that the deferment of
immunizations undermines years of efforts to educate parents and
physicians about the importance of vaccinating children as recommended.
Although providers are being asked to set up recall systems for
children who have been turned away for needed vaccinations,
immunization officials are concerned that some children will not be
recalled and therefore will remain underimmunized.
Problems Causing Shortages Largely Resolved, but Shortages Could Recur:
The problems causing most of the recent vaccine shortages have largely
been resolved, but the potential exists for other, similar problems to
bring about a recurrence of shortages. The recent shortages stemmed
from a number of largely unforeseen factors that affected both supply
and demand. By July 2002, the supplies for many vaccines were becoming
sufficient to return to the recommended immunization schedule, but the
complex nature of vaccine manufacturing and the limited vaccine
manufacturing base make it difficult to respond rapidly if similar
problems should occur in the future. Thus, any of the variety of
technical difficulties that can occur with vaccine production”including
those that contributed to recent shortages or other problems, such as a
major product recall or catastrophic event like a vaccine plant
fire”could trigger shortages again. One prospect that may help
alleviate the potential for shortages is that several new vaccines
under development could possibly add to the supply of existing
childhood vaccines. However, clinical trials and FDA review of these
products still need to be completed. These steps usually take several
years, and under FDA policies, these products generally do not qualify
for expedited review.
Many Factors Affected Supply of and Demand for Vaccine:
No single reason explains the rash of recent vaccine shortages; rather,
multiple factors coincided that affected both the supply of and demand
for vaccines. We identified four key factors: production problems,
calls by immunization policy-making bodies to remove a preservative from
vaccines as a precautionary measure, a manufacturer‘s decision to cease
production of some vaccines, and greater-than-expected demand for a
vaccine that had recently been added to the immunization schedule.
Production Problems:
Manufacturing production problems contributed to reductions in the
supply of certain vaccines. In some cases, production slowdowns or
interruptions occurred as manufacturers addressed problems identified in
FDA inspections; in other cases, production was affected when planned
maintenance activities took longer than expected. For example, the
shortages of MMR and varicella vaccines (which are produced by the same
manufacturer) were brought about by two voluntary interruptions to
production. In August 2001, the manufacturer temporarily suspended
operations in one of its manufacturing facilities to address issues
raised by FDA inspectors during a routine plant inspection. The
production halt continued while the manufacturer made scheduled
modifications to its facility. These modifications took longer than
anticipated and had a substantial impact on production. In the months
immediately following the interruptions, supply levels of MMR and
varicella vaccines dropped by about 45 percent. Supplies remained low
for the next several months, then significantly improved in the spring.
In late June, CDC announced that the supply of MMR was sufficient to
return to the recommended immunization schedule, although enough
vaccine was not available for aggressive efforts to recall children for
missed vaccinations. In July 2002, CDC announced that supplies of
varicella were sufficient to return to the recommended immunization
schedule. Difficulties meeting FDA manufacturing requirements also
contributed to supply problems with DTaP, Td, and PCV.
Changes in FDA inspection practices may have resulted in the
identification of more or different instances of manufacturers‘
noncompliance with FDA manufacturing requirements. In 1997, FDA
implemented a new program for inspecting the biologics industry
(including vaccines), called Team Biologics. This new approach
emphasizes a more complete assessment of manufacturers‘ compliance
with current good manufacturing practices, which are the agency‘s
regulatory requirements for ensuring that biological products remain
safe, pure, and potent through the entire manufacturing process. These
requirements address a broad range of issues, such as quality assurance,
recordkeeping, personnel qualifications, equipment cleaning, and
laboratory controls. Team Biologics was phased in starting with plasma
fractionation products and moved to vaccines in October 1999. Prior to
this change, biologics inspections were generally shorter and involved
smaller inspection teams, according to FDA officials. The inspections
also tended to focus primarily on scientific or technical issues and
less on compliance with good manufacturing practices and documentation
issues. Several manufacturers confirmed that under this new approach,
inspections have intensified and the emphasis on compliance has
increased, making it more difficult for manufacturers to be considered
in compliance.
FDA did take some steps to inform manufacturers about the program
changes; however, some manufacturers reported problems related to how
well the changes were communicated. An official at one company said the
manufacturer was not well informed of the new expectations and officials
at another company said the change in FDA‘s inspection approach created
a gap in perception of what was needed to be considered in compliance.
Manufacturers underscored the importance of clear guidance from FDA to
help them understand evolving expectations. FDA‘s efforts to inform
manufacturers about the new inspection approach did include numerous
presentations made by agency personnel at a variety of meetings and
conferences since 1997. In addition, in October 1999, when FDA was
beginning to apply Team Biologics to vaccines, FDA issued a compliance
program guidance manual detailing the new protocol for conducting
inspections. Although this manual is intended for FDA‘s staff, the
information in it could have provided manufacturers a better
understanding of the scope of the inspections. However, the manual was
not made widely available”only upon request. FDA has made compliance
manuals for other biologic areas available on the Internet, but the
manual for licensed vaccines is still not available on line, well over
2 years after its issuance, nor is it included in FDA‘s annual
comprehensive list of guidance documents published in the Federal
Register.
Removal of Thimerosal:
Calls for the removal of the preservative thimerosal from childhood
vaccines illustrate the effect that policy changes can have on the
supply of vaccine. Efforts to remove thimerosal affected the production
of several vaccines and contributed in particular to the shortage of
DTaP. Thimerosal is a mercury-containing preservative that has been
used as an additive in vaccines for over 60 years. Its presence in
vaccines reduces the risk of bacterial contamination when providers
draw individual doses from multidose vials. Few data are available on
the effects of exposure to ethyl mercury (the form of mercury in
thimerosal) at the levels introduced by vaccines. However, exposure to
mercury-containing compounds, including ethyl and methyl mercury, at
sufficiently high doses has the potential to produce adverse health
effects, including effects on the nervous system. [Footnote 13] The
Food and Drug Administration Modernization Act of 1997 required FDA to
identify and provide an analysis of foods and drugs containing
intentionally introduced mercury compounds. As a result of its review,
in 1999, FDA determined that under the existing recommended immunization
schedule, some children over the first 6 months of life could be
exposed to a cumulative level of mercury from vaccines exceeding one of
the three existing federal guidelines for safe exposure to methyl
mercury. [Footnote 14] As a precautionary measure, in July 1999, the
American Academy of Pediatrics (AAP) and the U.S. Public Health Service
(PHS) issued a joint statement advising that thimerosal in vaccines be
eliminated or reduced as soon as possible. [Footnote 15]
While thimerosal was present in several vaccines, removing it from some
vaccines was more complex than for others. Thimerosal was introduced in
the latter stages of production in one manufacturer‘s hepatitis B
vaccine, and removing it was fairly straightforward. In contrast,
thimerosal was used to help stabilize one company‘s formulation of
DTaP, and the manufacturer said it was not able to completely eliminate
it. This contributed to the manufacturer‘s decision to cease production
of the vaccine, initiating the shortage of DTaP. The shortage was
exacerbated when one of the remaining manufacturers of DTaP had to
switch its packaging from multidose to single-dose vials due to the
removal of the preservative, reducing its output of vaccine by 25
percent, according to the manufacturer.
For manufacturers, reformulating existing vaccines without the
preservative required taking the product through the regulatory approval
process, with the attendant establishment of new procedures, validation,
testing, and labeling. Manufacturers acknowledged that FDA worked hard
to get thimerosal-free vaccines approved, but the process, involving
both FDA and manufacturers, of getting these products onto the market
still took about 10 months for one formulation of hepatitis B vaccine
and approximately 2 years for one manufacturer‘s formulation of DTaP.
Manufacturer‘s Decision to Discontinue Production:
Another major factor in the shortage of DTaP, and also Td, was the
decision of one manufacturer to discontinue production of all products
containing tetanus toxoid. With little advance warning, the company
announced in January 2001 that it had ceased production of these
vaccines. According to the manufacturer, prior to its decision, it
produced approximately one-quarter of all Td and 25 to 30 percent of
all DTaP distributed in the United States, so the company‘s departure
from these markets was significant. In the previous year, another
manufacturer that supplied a relatively small portion of DTaP also had
stopped producing this vaccine. Together, these decisions decreased the
number of major manufacturers of DTaP from four to two and of Td from
two to one. [Footnote 16]
For the manufacturer involved in the most recent departure, a number of
factors were involved in its decision. According to company officials,
the manufacturer was already planning to discontinue its DTaP vaccine
in a few years because it did not think it would be able to compete with
companies developing new DTaP combination vaccines. The company‘s
decision was accelerated when it experienced difficulties eliminating
thimerosal from its vaccine, as noted earlier. Company officials said
the timing of its decision was also triggered by the need to respond to
requirements set forth in a consent decree with the federal government.
[Footnote 17] To comply with these requirements, the company faced
making significant upgrades to its facilities where tetanus-toxoid was
manufactured. For these reasons, the manufacturer had already stopped
releasing vaccine prior to announcing its decision. The manufacturer
added that had the company decided to stay in the DTaP and Td market,
it would have been several years before it could produce vaccines
meeting FDA requirements.
Unanticipated Demand:
The addition of new vaccines to the recommended immunization schedule
can also result in shortages if the demand for vaccine outstrips the
predicted need and production levels. This was the case with a newly
licensed vaccine, PCV, which protects against invasive pneumococcal
diseases in young children. PCV was licensed by FDA in February 2000
and formally added to the recommended schedule in January 2001. CDC
estimates the monthly national need for this vaccine to be 1.3 million
doses, but the manufacturer was only able to provide about half the
needed doses during the first 5 months of 2002. Company officials said
an extensive preeducation campaign resulted in record-breaking adoption
of the vaccine. The company‘s production of vaccine was also hampered by
ongoing manufacturing problems. Changes made in the company‘s quality
assurance procedures, partly to comply with the terms of a consent
decree with the federal government, resulted in delays in the release
of vaccine. Manufacturing equipment problems also affected the
manufacturer‘s ability to meet demand. As of July 2002, both of these
conditions continued to affect the supply of this vaccine.
Underlying Factors Could Allow Shortages to Recur:
While the recent shortages have been largely resolved, the vaccine
supply remains vulnerable to any number of disruptions that could occur
in the future”including those that contributed to recent shortages and
other potential problems, such as a catastrophic plant fire. One key
reason is that the nature of vaccine manufacturing prevents the quick
production of more vaccine when disruptions occur. Manufacturing a
vaccine is a complex, highly controlled process that can take several
months to over a year. Unlike pharmaceuticals, which are usually
synthesized from chemicals, most vaccines are produced from or use
living biological organisms. Strict control is needed over the entire
manufacturing process, and each lot of vaccine is carefully tested for
its purity and potency. To illustrate the lengthy production times that
can be involved, one manufacturer said it takes about 11 months to
produce Td, including almost 7 to 8 months to produce purified vaccine,
followed by 8 to 10 weeks of testing, and another 4 to 6 weeks of
filling, packaging, and final approvals. With such long production
times, it is difficult for the industry to provide a quick response to
major disruptions. Some manufacturing plants are dedicated facilities,
built and maintained to produce a specific vaccine, and cannot be
easily expanded or switched to produce other vaccines. For example,
when one of the two major producers of Td ceased production last year,
both the long production time and fixed capacity left the remaining
manufacturer unable to meet the unexpected drop in supply. The supply
of Td only recently returned to levels sufficient to resume routine
administration, over a year and a half after the shortage began.
The Td vaccine example illustrates another underlying problem: routine
childhood vaccines are available from a limited number of manufacturers.
Of the eight recommended routine childhood vaccines, five are made by a
single major manufacturer; the remainder are made by two, or in one
case, three manufacturers (see table 5). Consequently, if there are
interruptions in supply or if a manufacturer ceases production, there
may be few or no alternative sources of vaccine.
Table 5: Number of Manufacturers Producing Routine Childhood Vaccines
in the United States:
Vaccine[A]: Hib;
Number of manufacturers: 3.
Vaccine[A]: DTaP;
Number of manufacturers: 2[B].
Vaccine[A]: Hep B;
Number of manufacturers: 2.
Vaccine[A]: IPV;
Number of manufacturers: 1.
Vaccine[A]: MMR;
Number of manufacturers: 1.
Vaccine[A]: PCV;
Number of manufacturers: 1.
Vaccine[A]: Td;
Number of manufacturers: 1[C].
Vaccine[A]: Varicella;
Number of manufacturers: 1.
[A] Not shown are two combination vaccines, which can be used to meet
the recommended immunization schedule but are generally used much less
often. DTaP-Hib can be used for booster doses but is not recommended
for primary immunization in infants; this vaccine is made by one
company. Hep B-Hib can be used for all but the birth dose of Hep B and
is made by one company.
[B] One manufacturer has licenses for two different formulations of
DTaP vaccine (produced in geographically separate facilities), so there
are actually three DTaP vaccines currently available on the U.S.
market.
[C] In addition to the one major nationwide manufacturer of Td, the
University of Massachusetts produces a small amount of Td vaccine and
makes some available for nationwide distribution.
[End of table]
Vaccines on Horizon May Increase Supply:
New vaccines in development could potentially add to the supply of
existing vaccines. An example is a new formulation of DTaP that recently
received FDA approval and has helped ease the shortage of DTaP. We
identified 11 routine vaccines in development that could help meet the
current recommended immunization schedule. These vaccines are in
varying stages of development, ranging from clinical testing to FDA
review. Included are the following types of products:
New brands of existing vaccines: About half of the vaccines in the
pipeline represent new sources of existing vaccines. If approved,
several of these vaccines would expand the number of suppliers for
these products.
New combinations of existing vaccines: Some of the vaccines under
development represent new combinations of existing vaccines; for
example, one company is developing a DTaP-IPV-Hib vaccine that protects
against diphtheria, tetanus, pertussis, polio, and haemophilus
influenzae type b. If approved, how these new combination vaccines will
be used and whether they will expand supply or simply replace existing
vaccines depends on several factors. The first determinant will be the
use for which the company seeks licensure. New vaccines could be
licensed for use in all doses or just in some doses in an immunization
series. For example, when one acellular version of diphtheria, tetanus,
pertussis vaccine was first licensed, the company conducted studies and
sought licensure for only the fourth and fifth doses of the five-dose
series. It was eventually licensed for use in all five doses. ACIP has
encouraged the use of combination vaccines over equivalent component
vaccines when possible in order to minimize the number of injections
children receive. In some cases, however, individual vaccines are used
more often than related combination vaccines. [Footnote 18] Combination
vaccines also tend to sell at a premium price compared to the
individual component vaccines, which may affect their market
acceptance. Provider and parental preferences for vaccines can
also come into play.
New vaccines for certain age groups: Some vaccines in the pipeline are
vaccines formulated for new age groups. According to a manufacturer, one
vaccine includes a pertussis component for adolescents and adults, which
is not currently available or included in the recommended schedule.
FDA Policies Restrict Use of Expedited Approval Processes:
Completing clinical testing and FDA review of these new vaccines can be
a lengthy process, but FDA has a number of procedures for facilitating
the development and expediting the review of new pharmaceutical and
biologic products. Clinical testing of a vaccine in humans is typically
done in three phases to establish the product‘s safety and efficacy and
to determine dosing. Once clinical trials are completed, the
manufacturer may submit a biologics license application (BLA) to FDA
that assembles evidence on the vaccine‘s safety, purity, and potency
and whether the manufacturing process can ensure its quality. Based on
its review of the information in the application and any supplemental
information it requests, FDA makes a decision on whether to license the
vaccine. In total, completing clinical trials and FDA review for
vaccines generally takes over 5 years. However, FDA has a number of
mechanisms available to help expedite this process for certain
products, including the following two:
Fast Track: A manufacturer can request fast track designation if the
product is intended for the treatment of a serious or life-threatening
condition and it demonstrates the potential to address unmet medical
needs. As clinical testing nears completion, and preliminary data
support a determination that a fast track product may be effective, FDA
may begin accepting portions of the BLA for review before a complete
application is submitted. [Footnote 19]
Priority Review: A product may be eligible for priority review status
if the product is a significant improvement in the safety or
effectiveness of the treatment, diagnosis, or prevention of a serious
or life-threatening disease. [Footnote 20] FDA‘s goals are to review
and take action on priority submissions in 6 months, compared to 10
months for standard reviews. [Footnote 21]
These mechanisms are not available for use with many vaccines in the
pipeline because FDA policies preclude their application to products
that are essentially new forms of existing vaccines. The Food and Drug
Administration Modernization Act of 1997 requires that fast track
products demonstrate the potential to address unmet medical needs.
While the statute did not define ’unmet medical need“ or provide
criteria for analyzing the need, FDA has established criteria stating
that an unmet medical need is one that is not adequately addressed by
existing therapies. FDA officials pointed out that a temporary vaccine
shortage would not meet the criterion of an unmet medical need, because
by the time a new source of vaccine was approved (even under expedited
procedures), the shortage would be expected to be over and the
condition of unmet need would no longer exist. In addition, because
many of the products in development are either new brands or new
combinations of existing vaccines, an FDA official said that under
current policy they would not meet the agency‘s criteria for fast track
(products address an unmet medical need) or priority review (products
represent a significant improvement). These expedited processes are
applicable mainly to vaccines that offer protection against diseases
for which there are no existing vaccines. This was the case with PCV.
At the time, no vaccines that protected against invasive pneumococcal
disease were licensed for use in children under 2 years of age, so PCV
was eligible to be designated as a fast track product and to receive
priority review. As a result, the review and approval of PCV took about
8.5 months, compared with the median time of 18.5 months for vaccines.
Product Approval Requirements Are Not Standardized among Countries:
Some of the vaccines in the pipeline are already licensed products in
other countries, including Canada and various countries in Europe. FDA
accepts foreign clinical studies in support of U.S. licensure; however,
agency officials stated that if foreign data are used to support the
safety, purity, or potency of a vaccine, FDA would need to
independently assess the information and would usually require
additional data. For example, the manufacturer might be required to
provide evidence demonstrating that the product elicits a comparable
immune response in a U.S. population. These studies can take additional
time to complete. Part of the problem is that regulatory requirements
for product registration often differ among countries. Standardizing
these requirements, a process referred to as ’harmonization,“ is being
discussed, but does not appear to be a near-term solution for vaccines.
Harmonization efforts through the International Conference on
Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH) involve Europe, Japan, and the
United States. According to FDA, at the outset of the harmonization
initiative, all ICH parties agreed to exclude from its scope certain
biological products, including conventional vaccines, in part because
of the complex nature of vaccines. [Footnote 22]
No Clear Path Yet to Resolve Ongoing Supply Issues:
Federal agencies and advisory committees are exploring options to help
stabilize the nation‘s vaccine supply, but few long-term solutions have
emerged. Earlier this year, the National Vaccine Advisory Committee
(NVAC) convened a meeting of vaccine experts to discuss supply problems
and develop formal recommendations for further HHS consideration. The
preliminary conclusion of the NVAC work group was that further study
was needed of strategies, such as additional financial incentives for
manufacturers and streamlining the regulatory process. CDC vaccine
stockpiles have been used successfully to help mitigate temporary
supply disruptions in the past and were considered a priority strategy
by workshop participants. While CDC is required by law to stockpile a 6-
month supply of recommended childhood vaccines and has the necessary
funding to do so, it currently maintains partial stockpiles for only
two. In light of the recent shortages, CDC is considering expanding the
stockpiles to include additional vaccines. While stockpiling vaccines
can provide a cushion in the event of a supply disruption, limited
supply and manufacturing capacity will restrict CDC‘s ability to build
certain stockpiles in the near term. In addition, CDC lacks a
comprehensive strategy and important information needed to effectively
plan and manage the stockpile.
NVAC Studying Strategies to Strengthen Vaccine Supply:
Federal efforts to strengthen the nation‘s vaccine supply have taken on
greater urgency with the recent incidents of shortages. A major effort
by NVAC has been under way since mid-2001. As part of its mandate to
study and recommend ways to encourage the availability of safe and
effective vaccines, NVAC formed a Vaccine Supply Work Group to explore
the issues surrounding vaccine shortages and identify strategies for
further consideration by HHS. In February 2002, the work group convened
a meeting of principal stakeholders”federal and state governments,
vaccine manufacturers, health care providers, legislators, and academic
researchers”to determine the scope and identify contributing causes of
vaccine shortages and develop strategies to strengthen the vaccine
supply. The work group presented its preliminary findings and
recommendations in June 2002.
In its preliminary report, work group members identified several
strategies that hold promise, such as providing financial incentives
for vaccine development, strengthening manufacturers‘ liability
protection, and streamlining the regulatory process, but they concluded
that these strategies needed further study. In regard to liability
protections, the work group did make recommendations to strengthen the
Vaccine Injury Compensation Program (VICP). VICP is a federal program
authorized in 1986 to reduce vaccine manufacturers‘ liability by
directly compensating individuals for childhood-vaccine-related
injuries from a VICP trust fund. It was established, in part, to help
stem the exodus of manufacturers from the vaccine business due to
liability concerns. Manufacturers, however, reported a recent
resurgence of childhood-vaccine-related lawsuits”including class action
lawsuits related to past use of thimerosal”which allege that they are
not subject to VICP. In the manufacturers‘ view, these lawsuits once
again threaten the stability of the industry by creating disincentives
to produce vaccines. While the work group acknowledged that recent
vaccine shortages do not appear to be related to liability issues, it
indicated that strengthening VICP would encourage manufacturers to
enter, or remain in, the vaccine production business. Legislation has
been introduced for the purpose of clarifying and modifying the VICP
program. [Footnote 23] In response to the work group‘s finding that
streamlining the regulatory process needed further study, FDA recently
announced that it is examining regulations governing manufacturing
processes in both drugs and vaccine products to determine if reform is
needed. However, FDA officials told us it is too early to define the
scope and time frame for this reexamination.
The NVAC work group expressed little support for constructing
government-owned production facilities to produce routine childhood
vaccines. One concern raised by the work group was that vaccine
manufacturers might not be able to compete with a government-subsidized
program”potentially causing private manufacturers to withdraw from the
U.S. market, further shrinking the number of manufacturers, and reducing
the level of innovation and introduction of new products. In addition,
government-owned facilities would be subject to many of the same
limitations”such as long production times and stringent quality control
standards”that private manufacturers face. NVAC work group members
concluded that stockpiling vaccines, while having some limitations,
should receive priority consideration to provide temporary relief during
shortages.
Expansion of Stockpiles Is under Consideration:
CDC is considering whether additional vaccine stockpiles will help
stabilize the nation‘s vaccine supply. CDC vaccine stockpiles have been
used to mitigate supply disruptions on at least seven occasions since
they were first established nearly 20 years ago. In 1993, with the
establishment of the VFC program, CDC was required to purchase
sufficient quantities of pediatric vaccines not only to meet normal
usage, but also to provide an additional 6-month supply to meet
unanticipated needs. Further, to ensure funding, CDC was authorized to
make such purchases in advance of appropriations. Despite this
requirement, to date, CDC has established partial stockpiles for only
two”MMR and IPV”of the eight routinely recommended pediatric vaccines.
[Footnote 24]
CDC‘s past decisions to stockpile these two vaccines were based on a
number of factors. First, CDC considered the number of suppliers of each
vaccine”vaccines from a single source were considered at greater risk
and were the highest priority for stockpiling. Second, CDC assessed the
likelihood that changing technology or immunization schedules could
make stockpiled vaccines obsolete”new combination vaccines or revised
ACIP recommendations reduce the priority of stockpiling older vaccines.
CDC officials noted the importance of balancing the cost of
establishing a stockpile versus the risk that the stockpiled vaccine
might soon become obsolete. Third, CDC officials stated that because
the demand for newer vaccines is unknown, manufacturers might not have
excess capacity to create stockpile inventory. In light of recent
shortages, CDC is reevaluating its criteria for setting priorities for
which vaccines to stockpile. For example, limiting stockpiles to
vaccines produced by sole manufacturers may no longer be appropriate.
Even if CDC decides to stockpile additional vaccines, the currently
limited supply of several vaccines will restrict CDC‘s ability to build
certain stockpiles in the near term. CDC estimates it could take 4 to 5
years to build stockpiles for all the currently recommend childhood
vaccines”at a cost of $705 million. Past experience also demonstrates
the difficulty of rapidly building stockpiles. Neither the current IPV
nor MMR stockpiles have ever achieved target levels because of limited
manufacturing capacity. As of July 2002, the IPV stockpile stood at 3.7
million doses, less than half of the 8 million doses on order.
Similarly, the MMR stockpile has never reached its target of 4
million”coming as close as 3.1 million doses in late 2001.
Another issue that will need to be addressed is the extent to which
stockpiled vaccines purchased with VFC funds can be used for non-VFC-
eligible children. In 1993, the Congress passed legislation requiring
the Secretary of HHS to negotiate for a 6-month supply of vaccines to
meet unanticipated needs in connection with the VFC program. The
legislation directed the Secretary to consider the potential for
outbreaks of vaccine-preventable diseases in carrying out this
stockpile requirement. [Footnote 25] CDC bases the target levels of its
current stockpiles on the number of children in the general population
and has allowed manufacturers to borrow from stockpiled vaccines for
releases to this population. We note that the legislation does not
state that the supply of stockpiled vaccines may be made available for
children not otherwise eligible through the VFC program. CDC officials
said that the VFC legislation is unclear as to whether stockpiled
vaccines can be used for these children.
There are other authorities under which CDC could procure stockpiles of
vaccines for children. CDC may develop vaccine stockpiles under its
authority to respond to public health emergencies and is required to
maintain vaccine stockpiles under the National Vaccine Program (NVP).
NVP is not limited to childhood vaccines, but appropriations were
authorized only through 1995. CDC has identified several other
provisions of the Public Health Service Act that would authorize
expenditures for vaccine stockpiles. For example, section 352
authorizes HHS to produce products for use by the public and private
sectors when they are unavailable from licensed sources. Section 311 of
the act authorizes HHS to work closely with the states and provide
’medical supplies“ in the prevention and control of communicable
diseases and to address other health emergencies. [Footnote 26]
CDC Lacks a Comprehensive Strategy for Expanded Use of Stockpiles:
Expanding the number of CDC vaccine stockpiles will require a
substantial planning effort”an effort that is not yet complete. CDC has
not yet determined key aspects of vaccine stockpiles to ensure their
ready release, including the quantity of each vaccine to stockpile, the
form of storage, and storage locations. Also, to ensure that use of a
stockpile does not disrupt supply to other purchasers, procedures would
need to be developed to ensure that stockpiles are additional to a
manufacturer‘s normal inventory. CDC‘s current approach to stockpiling
lacks clear direction on the following fronts:
Quantity to stockpile: CDC officials have not yet determined what
quantity of vaccine most accurately constitutes a 6-month supply. To
date, stockpile purchases have been based on estimates of the U.S.
birth cohort (about 4 million babies per year) and ACIP
recommendations”but this may not be enough to cover the actual need.
For example, for each child to receive the recommended two doses of
MMR, roughly 8 million doses of MMR would be needed annually. However,
manufacturers report nearly 12.7 million doses were distributed in
2001. Overvaccination due to lost immunization records, wastage from
refrigerator outages or multiple dose packaging, and make-up
immunizations could account for the difference.
Vaccine experts are also beginning to consider whether stockpiles should
be expanded to include more than a 6-month supply. Recent shortages
have lasted from 9 to 20 months. A catastrophic event, such as a major
plant fire, could disrupt production for several years while a plant is
being reconstructed. CDC has not yet fully evaluated the logistics of
maintaining larger stockpiles or developed contingency plans for major
supply disruptions.
Form and location of storage: [Footnote 27] Stockpiled vaccines can be
held in three forms: labeled (ready to ship), unlabeled (in vials, but
not ready to ship), or bulk (product still must undergo final lot
testing, filling, and labeling). Stockpiled vaccines requiring
additional processing or packaging need to be closer to the
manufacturing facility and require more time for release. Each storage
method has advantages and disadvantages. For example, while labeled
vaccine can be stored off site and distributed most rapidly, changes in
package inserts could require a labor-intensive task of opening all the
packages to replace the insert. Label changes are less of an issue for
vaccines in unlabeled or bulk form, but these vaccines must still
undergo additional processing, making them vulnerable to plant
disruptions. This became apparent in fall 2001, when modifications at
the manufacturing plant necessitated shutdowns that delayed the release
of the MMR vaccine held in stockpile. In response, CDC is reevaluating
the amount of stockpiled vaccines required to be stored in final form
and the location of storage.
Maintenance of effort: CDC‘s current stockpile program is designed to
ensure a quantity of vaccine in addition to manufacturers‘ normal
inventory. However, current CDC stockpile contracts do not contain a
’maintenance of effort“ requirement to ensure that production for the
stockpile is additional to normal production levels. Without such a
requirement, CDC efforts to use a stockpile could simply result in stock
being drawn from a manufacturer‘s normal deliveries, without an overall
increase in the amount of product being available for release into the
market in times of shortage. [Footnote 28]
During the MMR shortage, CDC became aware that the manufacturer could
not release more of the MMR stockpile without affecting its deliveries
to the private sector. The manufacturer used nearly 1 million doses
from the stockpile during the winter of 2001-2002 (leaving about 2
million doses remaining), but was unable to release more vaccine needed
to ease the shortage. The manufacturer had recently adopted additional
quality control procedures that temporarily limited the amount of
vaccine that could be released during that period. CDC officials said
that the recent MMR experience points to the need for additional
contractual assurances that stockpiling represents a ready reserve of
additional vaccine, and they are considering including maintenance of
effort provisions in future stockpile contracts.
Critical Information Needed to Manage Stockpiles Is Lacking:
Once sufficient quantities of vaccines are stockpiled in the appropriate
form, CDC needs to make wise decisions on when to deploy the
stockpiles. However, CDC currently lacks important information to help
do so. Timely release of the stockpile requires accurate prediction of a
number of variables related to the early identification, severity, and
duration of the supply disruption. CDC currently has data that it uses
to screen for disruptions in vaccine supply to state immunization
programs, but does not have data to anticipate a supply disruption or
to fully evaluate the potential severity and duration of a supply
disruption, especially to private providers. With such information, CDC
could set priorities for or resize states‘ orders and determine how
much stockpiled vaccine to release and when to release it. Timely
information is important, because releasing vaccine from a stockpile
can take up to 30 days. Some of this information may already be
available within HHS, but other information is available only from
manufacturers or state immunization programs.
Information from FDA: FDA has important information about
manufacturers‘ levels of vaccine production and plant conditions that
could affect production through its facility inspections and approval of
each production lot. [Footnote 29] On occasion, this information could
help CDC anticipate supply disruptions and independently assess their
potential severity, but it is only available to CDC by written request.
Because of the lack of routine sharing of FDA information, CDC would
likely be unaware of problems identified in FDA inspections that could
cause the manufacturer to temporarily shut down a production line,
unless notified by the manufacturer. This communication may not occur.
For example, when FDA inspectors identified potential sterility issues
at one facility, the manufacturer temporarily stopped production during
the inspection, which eventually led to a shortage. But FDA did not
inform CDC of the disruption. CDC officials told us they were first
made aware of the disruption through media reports several weeks later.
Information from manufacturers: There is no formal mechanism in place
for CDC to obtain critical information from manufacturers on prolonged
vaccine production disruptions, such as shutdowns due to maintenance or
repairs, that could precipitate the need to use the stockpile. CDC
officials cite the value of having timely information on manufacturers‘
capacity, current and future production levels, and any circumstances
that could affect production”information that is often considered
proprietary by manufacturers. Particularly during shortages, CDC does
obtain some supply information from manufacturers, but they do not
always provide it consistently or promptly. In addition, there is no
requirement for vaccine manufacturers to notify CDC or FDA of business
decisions to withdraw vaccines from the market. Although the Food and
Drug Administration Modernization Act of 1997 requires sole
manufacturers of a drug that is lifesaving or prevents a debilitating
disease to give FDA a 6-month notification prior to discontinuance,
[Footnote 30] this requirement does not extend to vaccines. The four
major vaccine manufacturers told us they would not object to a similar
requirement that they give FDA a 6-month notification of their intent
to cease production of a vaccine. [Footnote 31]
Information from states: To identify critical shortages and manage
distribution of public supplies, CDC needs an accurate, ongoing
accounting of state inventories. State immunization programs can provide
early indications of supply problems if states accumulate back orders.
State immunization programs also maintain working inventories (often a
3-month or greater supply), which during times of nationwide vaccine
shortages could also help cushion supply disruptions. Prior to the
recent vaccine shortages, CDC did not routinely monitor the vaccine
inventory levels in state depots. In response to recent shortages, CDC
instructed state immunization programs to inventory their stock-on-hand
and submit monthly reports. CDC program managers are considering
monitoring states‘ inventory levels in nonshortage periods, but
automated systems to facilitate uniform and timely reporting are still
under development. In order to help ensure that inventories in excess
of state needs are not maintained, CDC is also recommending that states
maintain a 3-month inventory during normal supply situations,
decreasing to a 1-month inventory during shortages, thus providing a 2-
month cushion.
Conclusions:
A steady and reliable supply of childhood vaccines is critical to
maintain the substantial U.S. public health achievements in combating
infectious diseases. However, the vaccine shortages experienced over
the last 2 years demonstrate the vulnerability of the vaccine supply.
Long lead times, sometimes a year or more, are needed to produce
vaccines and alter existing production volumes. Because there are so
few manufacturers (and increasingly, just one) producing a particular
vaccine, even short-term disruptions in a manufacturer‘s production
volume can create a shortage. This condition is not likely to change in
the near term. Therefore, federal agencies are continually challenged
to take a proactive approach within their existing missions to help
mitigate the effects of future disruptions to the vaccine supply.
An often-cited approach that can help provide a cushion against
disruptive effects of future shortages is to expand CDC‘s reserves, or
stockpiles, of childhood vaccines. While CDC is required to stockpile
childhood vaccines under the VFC program, authorizing legislation does
not address the extent that stockpiles can be used to support the needs
of children not eligible under the program. In addition, stockpiling
vaccines is not a panacea and, if poorly implemented, may provide
little in the way of value. Expanding the stockpiles poses operational
challenges that need to be addressed through strategic planning. For
example, there is a need to establish a timetable for purchasing
vaccines in a way that does not disrupt normal distribution, as well as
a need to make decisions on the most desirable form and storage
location for each vaccine. Implicit in these efforts to expand and
manage a stockpile is the need for more timely information on the
nature and extent of possible shortages. While working with
manufacturers has shown some promise, opportunities exist to leverage
other sources of available information, such as the results of FDA
vaccine plant inspections and state vaccine inventory levels.
Although disruptions in supply can occur when manufacturers must stop
production in order to bring their facilities into compliance with FDA
standards, these standards are critical to helping ensure the safety,
purity, and potency of vaccines. As FDA strengthens its process for
measuring compliance with these standards, communication of
expectations with manufacturers is important. FDA should provide
manufacturers with available guidance about the expectations of what
constitutes compliance”a situation that has not always occurred in the
past.
The prospect of additional vaccine products has potential to help reduce
the intensity of future disruptions to the supply of existing vaccines,
but introduction of new products faces challenges. On one hand,
manufacturers have economic incentives to bring new childhood vaccines
to market. For example, introduction of new vaccines against additional
childhood diseases or new combinations of existing vaccines
traditionally sell for higher prices and offer manufacturers new
opportunities to compete for market share. On the other hand, it is an
involved and time-consuming process, often taking several years, to
obtain a license to sell these products in the U.S. market, even if the
products are licensed for use in other countries. A substantial number
of vaccines are in the development pipeline. While FDA has mechanisms
available to shorten the review process, they are not used for most
vaccines under development.
FDA‘s policy, in effect, applies the expedited processes to address an
unmet medical need for a new product, while childhood vaccines under
development often involve not new products, but existing vaccines or
combinations of existing vaccines. However, the fragility of the vaccine
supply itself demonstrates an unmet medical need because when supplies
are lacking, children may become more vulnerable to the spread of
disease. This possibility warrants FDA‘s reconsidering its policy
regarding expedited review to help prevent or mitigate vaccine
shortages.
Matter for Congressional Consideration:
To help ensure that stockpiled vaccines are available for use by all
children, and in light of CDC‘s development of vaccine stockpiles under
the VFC program, the Congress may wish to consider amending the
program legislation to specifically address whether vaccines stockpiled
under this program may be made available to children not otherwise
eligible.
Recommendations for Executive Action:
To ensure a well implemented strategy for expanding HHS‘s stockpiles of
childhood vaccines, we recommend that the Secretary of HHS direct the
Director of CDC to develop a strategic plan that addresses the
operational difficulties involved. At a minimum, such a plan should
include:
* a timetable, developed with manufacturers‘ input, for the purchase of
specific quantities of vaccine;
* a determination of form and location of storage of the vaccine;
* procedures to ensure that stockpiles of vaccines are incremental to
manufacturers‘ normal inventory levels;
* procedures for systematic interchange of information between FDA and
CDC on potential childhood vaccine manufacturing interruptions; and;
* steps for monitoring childhood vaccine inventory in state VFC depots.
To help strengthen the vaccine supply without compromising standards
that ensure safety, we recommend that the Secretary direct the
Commissioner of FDA to:
* take steps to ensure widespread distribution of all forms of
compliance guidelines to vaccine manufacturers and ensure that these
guidelines are kept up-to-date and;
* consider revising FDA policies for fast track and priority review
approval of vaccines currently under development to allow their use,
even in periods of nonshortage, in cases where FDA determines that
applying them would help address the unmet need of a stable and
sufficient overall vaccine supply.
Agency Comments and Our Evaluation:
We obtained comments on our draft report from HHS. In its general
comments, the department stated that it agrees with the report‘s
findings and that it has initiated action to implement the report‘s
recommendations. In regard to our recommendation on the need for HHS
to develop a strategic plan for stockpiling childhood vaccines, HHS
stated that CDC has arranged site visits to manufacturers for the
purpose of discussing the specific stockpiling issues raised in the
report. Further, after these site visits are completed, CDC would
develop a comprehensive vaccine stockpiling program strategy. HHS also
cited actions it was taking in regard to our recommendations that FDA
be directed to ensure the widespread distribution of all forms of
compliance guidelines to manufacturers. HHS stated that FDA was working
with a contractor to post all Vaccine Compliance Program guidance on
its Web site.
HHS expressed some reservations in its comments about our
recommendation that the Secretary direct FDA to consider revising FDA
policies for fast track and priority review approval of vaccine products
currently under development. HHS stated that in shortage situations, FDA
has the flexibility to work as expeditiously as possible with
manufacturers of new or existing vaccines to alleviate the shortage. It
also stated that critical vaccine shortages could allow for the
designation of a vaccine as a fast track product. Often, however,
shortages are temporary and are over before even the most expeditious
review can be completed. As a result, HHS indicated that formal
designation for expedited review process would have little impact on
relieving the shortage.
We did not intend that our recommendation apply only in times of
existing vaccine shortages. Rather, the purpose of the recommendation
is to provide HHS with another option to help prevent or mitigate the
effects of future shortages. The potential exists to strengthen the
childhood vaccine supply by selectively using the expedited review
procedures to increase, as quickly as possible, the number of
alternative vaccine products and suppliers. As a result of the
department‘s comments, we have modified the wording of our
recommendation to make it clearer that it is directed at using existing
expedited review tools as a strategic approach to help strengthen the
overall vaccine supply.
HHS did not comment on our matter for congressional consideration
concerning amending legislation under the VFC program, but did provide
technical comments, which we incorporated in the final report where
appropriate. We also provided sections of the draft report on factors
that contributed to vaccine shortages and new vaccine products under
development to the four major vaccine manufacturers. We incorporated
their technical and clarifying comments where appropriate.
As agreed with your offices, unless you publicly announce the contents
of this report earlier, we plan no further distribution until 30 days
after its issue date. At that time, we will send copies of this report
to the Secretary of HHS, the Director of CDC, the Deputy Commissioner
of FDA, and other interested parties. We will also make copies
available to others on request. Copies of this report will also be
available at no charge on GAO‘s Web site at [hyperlink,
http://www.gao.gov].
If you or your staffs have any questions, please contact me at (202)
512-7119. Other contacts and major contributors are included in
appendix II.
Signed by:
Janet Heinrich:
Director, Health Care”Public Health Issues:
List of Requesters:
The Honorable Edward M. Kennedy:
Chairman:
Committee on Health, Education, Labor, and Pensions:
United States Senate:
The Honorable Henry A. Waxman:
Ranking Minority Member:
Committee on Government Reform:
House of Representatives:
The Honorable Jeff Bingaman:
The Honorable Hillary Rodham Clinton:
The Honorable Richard J. Durbin:
The Honorable Bill Frist:
The Honorable Jack Reed:
United States Senate:
The Honorable Gary A. Condit:
House of Representatives:
[End of section]
Appendix I: Comments from the Department of Health & Human Services:
Department Of Health & Human Services:
Office of Inspector General:
Washington, D.C. 20201:
September 4, 2002:
Ms. Janet Heinrich:
Director, Health Care - Public Health Issues:
United States General Accounting Office:
Washington, D.C. 20548:
Dear Ms. Heinrich:
Enclosed are the department's comments on your draft report entitled,
"Childhood Vaccines: Ensuring an Adequate Supply Poses Continuing
Challenges." The comments represent the tentative position of the
department and are subject to reevaluation when the final version of
this report is received.
The department also provided several technical comments directly to
your staff.
The department appreciates the opportunity to comment on this draft
report before its publication.
Sincerely,
Signed by:
Janet Rehnquist:
Inspector General:
Enclosure:
The Office of Inspector General (OIG) is transmitting the department's
response to this draft report in our capacity as the department's
designated focal point and coordinator for General Accounting Office
reports. The OIG has not conducted an independent assessment of these
comments and therefore expresses no opinion on them.
Comments of the Department of Health and Human Services on the General
Accounting Office's Draft Report, "Childhood Vaccines: Ensuring an
Adequate Supply Poses Continuing Challenges" (GAO-02-987):
The Department of Health and Human Services (department) thanks the
General Accounting Office (GAO) for undertaking this important study
and providing the department with the opportunity to comment on the
draft report. In general, the report calls needed attention to the
challenges and resource needs of mounting an effective response to
assure an adequate supply of childhood vaccines. The department agrees
with the GAO report, which generally presents an accurate and
informative summary of the key issues that impact on vaccine shortages.
Immunization is considered one of ten great public health achievements
of the 20th Century. Indeed, vaccine preventable disease levels are
currently at or near all-time lows, and childhood immunization coverage
levels have been at all-time high levels during the last several years.
This success is in no small part due to the innovative and highly
effective role of the private sector (often in partnership with
innovators in academia and government) in vaccine development and
production in the United States and abroad, and the widespread use of
licensed vaccines. Many of the childhood vaccines routinely recommended
in the U.S. and elsewhere in the world, such as Polio, Measles, Mumps,
and Rubella (MMR), Haemophilia influenzae type b (Hib), hepatitis B,
and Pneumococcal conjugate vaccines, were first brought to the market
by private companies. Furthermore, competition among private
pharmaceutical companies has resulted in substantial innovation, such
as new and safer vaccines, which saves lives and prevents disease and
disability.
For more than 15 years, our nation's children have had steady access to
vaccines. The minor disruptions in production that have occasionally
occurred in the past have been resolved through mobilizing vaccine from
national stockpiles, and through the department's Food and Drug
Administration (FDA) and Centers for Disease Control and Prevention
(CDC), and partners working with manufacturers to increase vaccine
supplies. Nevertheless, the unprecedented recent disruption in supply
documents that vaccine supply cannot be taken for granted and that
critical actions are needed to avert future shortages.
Below are general comments on the GAO report and specific comments to
GAO's executive recommendations.
General Comments:
The department agrees with the GAO's findings and has initiated actions
to implement their recommendations. The department agrees that the
Vaccines for Children (VFC) Stockpile authority in section 1928(d)(6)
of the Social Security Act (42 U.S.C. I396s(d)(6)), requires that
stockpiles of childhood vaccines be maintained. Several programmatic
reasons occurred that have slowed the development of CDC stockpiles.
These include the following:
* Implementation of the VFC program took considerable time and
resources. Priority was given to recruiting providers to serve eligible
children and establishing new contracts with vaccine manufacturers to
supply vaccine to the eligible children.
* The CDC had prioritized acquisition to establish stockpiles in a
systematic and efficient manner. One year after fully implementing the
VFC program, CDC began to expand its stockpile program utilizing VFC
program funds. In the late 1990s, CDC focused its efforts on fully
establishing single source vaccine stockpiles for highly contagious
diseases such as polio and measles. Historical experience with multiple
manufacturers indicated that it might not be efficient to have
government-funded stockpiles in all instances due to the following:
changing market shares, evolving vaccine technology (i.e. new
combination vaccines), and open market.
* Any changes to the already complicated vaccine schedule or abrupt and
unanticipated changes to the vaccines themselves, such as removal of
thimerosal, require concomitant adjustments in stockpiles either by
stockpiling new vaccines, drawing down existing stockpiles while
increasing stockpiles of new vaccines, or changing existing stockpiled
vaccines. Contracts used to establish the stockpiles had previously not
had the flexibility to rapidly respond to such changes.
In light of the recent vaccine shortages, as well as the GAO
recommendations, CDC is undertaking steps to establish and expand
stockpiles as soon as feasible.
Comments on Recommendations for Executive Action:
GAO Recommendation:
To ensure a well-implemented strategy for expanding HHS's stockpiles of
childhood vaccines, we recommend that the Secretary of HHS direct the
Director of CDC to develop a strategic plan that addresses the
operational difficulties involved. At a minimum such a plan should
include:
* A timetable, developed with manufacturers' input, for the purchase of
specific quantities of vaccine;
* A determination of form and location of storage of vaccine;
* Procedures for systematic interchange of information between FDA and
CDC on potential childhood vaccine manufacturing interruptions, and;
* Steps for monitoring of childhood vaccine inventory in state VFC
depots.
Department Comment:
The department agrees with GAO's recommendation to develop a strategic
plan to expand stockpiles of childhood vaccines. Stockpiles have been
very effective in the past in alleviating brief disruptions in vaccine
supply and are an important resource to maintain. The CDC has already
been engaged in a reassessment of its vaccine stockpile and has
initiated discussions with the manufacturers to determine their
projections of product availability for establishment/expansion of
vaccine stockpiles. Site visits to manufacturers have been arranged to
discuss issues raised in the GAO recommendation related to timetable,
stockpile form, storage location and maintenance. The CDC will develop
a comprehensive vaccine stockpile program strategy after the site
visits are completed.
GAO Recommendation:
To help promote the availability of existing and future vaccine
products without compromising standards that help assure safety, we
recommend that the Secretary direct the Commissioner of FDA to take
steps to ensure widespread distribution of all forms of compliance
guidelines to vaccine manufacturers and ensure that these guidelines
are kept up-to-date.
Department Comment:
Compliance guidance directed to vaccine manufacturers has been made
available to them through public postings on the FDA website and
through many outreach meetings held with industry and their trade
associations. The FDA is working with a contractor to post all
compliance programs, including the Vaccine Compliance Program, on its
website. In the meantime, inspectional guidance for FDA investigators
concerning vaccine-manufacturing inspections will continue to be
available in the Vaccine Compliance Program through the Freedom of
Information Act.
GAO Recommendation:
To help promote the availability of existing and future vaccine
products without compromising standards that help assure safety, we
recommend that the Secretary direct the Commissioner of FDA to consider
revising FDA policies for fast-tracking and priority review approval of
vaccine products currently under development to allow their use in
cases where FDA determines that applying them is in the public health
interest to address the unmet need of strengthening the overall vaccine
supply.
Department Comment:
There appears to he some confusion about "fast track" and "priority
reviews" and how these might or might not speed up the approval time
for the licensing of new vaccines or existing vaccines that are in
short supply.
The department recognizes the seriousness of vaccine shortages or
potential vaccine shortages and, in either the presence or absence of
any given formal expedited approval process (i.e., fast track or
priority review), FDA has reviewed, and will continue to review,
license applications or their supplements in the most expeditious
manner possible. The FDA does and will continue to organize priorities
based on medical need. For example, FDA expedited the review of
influenza vaccine supplements because of shortage situations or to
avert potential shortage situations and, recently, the review of
Daptacel (Aventis Pasteur's diphtheria and tetanus toxoids and
acellular pertussis vaccine adsorbed [DtaP]) was conducted as
expeditiously as possible.
Biologic License Applications (BLA) may be formally designated for a
priority review. The FDA has 6 months to complete its review for a new
BLA; in contrast, it has 10 months for a so-called standard review. A
BLA for vaccines in short supply would qualify for a priority review.
However, even in the absence of a formal designation for a priority
review, the application would be reviewed as expeditiously as possible.
East track, which applies to products that are intended to treat or
prevent life-threatening or serious conditions, allows for submission
of a partial application that can be reviewed before the entire license
application is complete. Most fast track products are eligible for
priority, 6-month review. Critical vaccine shortages could allow for
designation of a vaccine as a fast track product.
It is necessary to consider the practical aspects of priority and fast
track reviews. Often, shortages are temporary and are over before even
the most expeditious review can be completed; in such cases, the formal
designation for the review process has little impact on the shortage.
Thus, as a practical matter, it will be infrequent that a new vaccine
will become licensed expressly and in time to alleviate a shortage.
During the recent shortage of DTaP, Daptacel was approved. The review
of this application was a priority for the FDA's Center for Biologics
Evaluation & Research (CBER), and this was consistent with a previous
determination, stemming from several years ago, that all acellular
pertussis vaccines would he considered a priority, and reviewed
expeditiously. The message that we wish to stress is that in a shortage
situation CBER has the flexibility to work as expeditiously as possible
with manufacturers of new or existing vaccines to alleviate the
shortage.
As an aside, Prevnar, the pneumococcal conjugate vaccine, was
designated as a fast track drug product and the sponsor was allowed to
submit a partial application for review before submitting their entire
marketing application. This was done because there was a clear unmet
medical need, viz., no existing vaccine for the prevention of invasive
pneumococcal disease, a serious disease, in infants (< 2 years of age).
Conclusion:
The department appreciates the attention the GAO has brought to the
issue of childhood vaccine shortages. The GAO's stockpile
recommendation will he a useful tool in ensuring an adequate supply of
childhood vaccines. The CDC has begun the planning process to address
the recommendation regarding stockpiles.
[End of section]
Appendix II: GAO Contacts and Staff Acknowledgments:
GAO Contacts:
Frank Pasquier, (206) 287-4861:
Terry Saiki, (206) 287-4819:
Staff Acknowledgments:
In addition to those named above, Julian Klazkin, Jennifer Major, Linda
McIver, Leslie Spangler, and Stan Stenersen made key contributions to
this report.
[End of section]
Footnotes:
[1] CDC supports 64 immunization programs nationwide”50 states, 8
territories, 5 cities, and the District of Columbia. For simplicity,
throughout this report we refer to them as state immunization programs.
Fifty-two of the 64 state immunization programs responded to our
survey.
[2] The CDC recommended immunization schedule comprises the coordinated
recommendations approved by the Advisory Committee on Immunization
Practices, the American Academy of Pediatrics, and the American Academy
of Family Physicians.
[3] A state-owned facility in Massachusetts produces a limited quantity
of tetanus and diphtheria booster.
[4] 42 U.S.C. sec. 247b.
[5] In 1993, legislation was enacted that established price caps for
vaccines purchased through existing CDC contracts. Of the eight
currently recommended vaccines, two (polio and haemophilus influenzae
type b) are selling below their price caps, one (MMR) is selling at its
cap, and one (tetanus and diphtheria booster) is not available because
manufacturers are not willing to sell it to CDC at its price cap; the
remaining four are not subject to price caps because CDC had not
contracted for them prior to May 1993.
[6] This total is based on the minimum price of vaccines under CDC
contracts needed to complete CDC‘s suggested normal immunization
timetable for children through 6 years of age (excludes adolescent
tetanus and diphtheria booster).
[7] The guidelines for the prioritization of Td and DTaP were issued by
CDC and were approved by ACIP. Initially these shortages were
anticipated to be brief, and therefore no official modifications were
made to the immunization schedule by ACIP.
[8] We distributed the survey in February 2002 and conducted follow-up
on the results through May 2002.
[9] A CDC survey that was limited to three vaccines and conducted in
fall 2001 showed comparable results. For example, 48 percent of the
state immunization programs surveyed reported that they had reduced
immunization requirements for tetanus and diphtheria boosters in
schools.
[10] NIS is a random-digit-dialing telephone survey sponsored by the
National Immunization Program and conducted by CDC‘s National Center
for Health Statistics.
[11] In August 2002, CDC reported that a limited study in Puerto Rico
found a marked decrease in DTaP coverage consistent with CDC‘s
recommendation to defer the fourth dose of DTaP. See Centers for
Disease Control and Prevention, ’Impact of Vaccine Shortage on
Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Coverage
Rates Among Children Aged 24 Months-Puerto Rico, 2002,“ Morbidity and
Mortality Weekly Report, vol. 51, no. 30 (2002): 667-668.
[12] NIS statistics reflect national coverage rates for the following
immunization series: four or more doses of DTaP, three or more doses of
IPV, one or more doses or any measles-containing vaccine, three or more
doses of Hib, and three or more doses of Hep B vaccine. NIS does not
include varicella or PCV in the combined series. NIS began in 1994;
however, we only reviewed years 1995 through 2001 because the 1994
survey did not include coverage of Hep B in the combined series.
[13] For a review of studies of health effects of ethyl and methyl
mercury, see Institute of Medicine, Immunization Safety Review:
Thimerosal-Containing Vaccines and Neurodevelopmental Disorders
(Washington, D.C.: 2001).
[14] FDA, the Environmental Protection Agency (EPA), and the Agency for
Toxic Substances and Disease Registry (ATSDR) have developed guidelines
for safe exposure to methyl mercury. Thimerosal contains ethyl mercury,
but since no federal guidelines exist for safe exposure to ethyl
mercury, FDA used the guidelines for methyl mercury. FDA found that the
cumulative amount of mercury a child could be exposed to from vaccines
exceeded EPA‘s guidelines for safe exposure to methyl mercury but were
below those of FDA and ATSDR.
[15] The joint statement by AAP and PHS also stated that the large risk
of not vaccinating children far outweighs the unknown and probably much
smaller risk, if any, of cumulative exposure to thimerosal-containing
vaccines in the first 6 months of life.
[16] In addition to the one major nationwide supplier of Td, a second
manufacturer produces a small amount of Td, primarily for local
distribution, and makes some available for nationwide distribution.
[17] The company had entered into a consent decree in October 2000 in
which it agreed to implement a series of measures aimed at ensuring
that products manufactured at two of its facilities are in compliance
with FDA good manufacturing practices regulations.
[18] For example, in the case of the combination vaccine that protects
against hepatitis B and Haemophilus influenzae type b (Hep B-Hib), CDC
data show that about 4.8 million doses of the combination vaccine were
distributed in calendar year 2000, compared to 23.7 million doses of
hepatitis B vaccine and 11.4 million doses of Hib vaccine.
[19] See 21 U.S.C. sec. 356. Acceptance of a portion of the application
does not necessarily mean that the review will start before a complete
application is received. According to FDA, when the review is started
will depend on many factors including staffing, competing priorities,
and the perceived efficiency of starting the review before the
submission of the complete application.
[20] Priority review is ordinarily open to fast track products as well
as non-fast-track products.
[21] FDA‘s review time is the actual amount of time FDA spends
reviewing a new drug or BLA. The approval time”from first submission of
the BLA to BLA approval”could be much longer. The approval time
includes the sum of FDA review time for the first submission of the
BLA, plus any subsequent time during which a sponsor addresses
deficiencies in the BLA and resubmits the application, plus subsequent
FDA review time.
[22] At a recent hearing, the Deputy Commissioner of FDA suggested that
if a vaccine were approved in another country and CDC indicated its use
would help ameliorate shortages in the United States, FDA would
consider requests to make these products available as investigational
vaccines. Under FDA regulations, these vaccines could be administered to
children in the United States with informed consent from their parents.
However, the Director of the National Immunization Program within CDC
said the use of investigational vaccines in a routine vaccination
program could pose problems in achieving public acceptance.
[23] See S. 2053, H.R. 1287, and H.R. 3741.
[24] CDC also maintains small stockpiles of pediatric DT and oral polio
(neither recommended for routine use) for use in the event of
outbreaks.
[25] Td is not available for stockpiling under this mechanism because,
as previously noted, manufacturers are not willing to sell it to CDC
under the VFC price cap.
[26] CDC also identified section 317 of the Public Health Service Act,
which, as mentioned earlier, authorizes state grants for preventive
health services, as additional authority to stockpile vaccines.
[27] To establish a stockpile, CDC contracts with a qualified
manufacturer to purchase the vaccine. CDC then pays the manufacturer an
annual fee to store and rotate the stockpile. As portions of the
stockpile approach 12 months of remaining shelf life, the manufacturer
will rotate the stockpile into normal distribution and replace it with
stock having a more distant expiration date. Because stockpiled
vaccines are often stored in unfinished form and are periodically
rotated with newer lots, stockpiles are typically held at the
manufacturer‘s production location.
[28] Maintenance of effort requirements are particularly important for
manufacturers that have multiple products that share the same
production facilities, because efforts to use a stockpiled vaccine
during a time of shortage could create or exacerbate a shortage of other
important drugs or vaccines that would be displaced by shifting
production resources.
[29] FDA also secures some supply information through reports it
requires manufacturers to submit on the quantity of vaccines they
distribute (see 21 C.F.R. sec. 600.81). Currently, such reports are
required every 6 months.
[30] The 6-month notification requirement may be reduced if a public
health problem could result from continued production, manufacturers
face financial loss, there is a shortage of drug components, or other
hardship would occur. 21 U.S.C. sec. 356c.
[31] A bill was recently introduced in the Senate (S. 2049) that would
amend the notification provision by requiring manufacturers to give FDA
at least a 12-month notice before discontinuing biological products,
including vaccines.
[End of section]
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