Childhood Vaccines: Ensuring an Adequate Supply Poses Continuing Challenges
Published: 2002-09-13T00:00:00

Fast Facts:

Highlights:
section_title: What GAO Found
paragraphs: 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.

section_title: Letter
paragraphs: 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, 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.
subsections: section_title: Background
paragraphs: 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). 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 tetanus- diphtheria 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.
subsections: section_title: Consolidation Resulted in Four Companies Engaged in Vaccine Manufacturing
paragraphs: 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. 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.
section_title: Federal and State Governments Play Key Roles
paragraphs: 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, 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. For example, as of May 2002, the CDC  contract price for vaccine doses needed to complete the immunization  schedule was about $413. 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).
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.
section_title: Vaccine Shortages Have Peaked and Most Supplies Are Returning to Normal
paragraphs: 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.
section_title: Shortages Prompt Actions to Reduce Immunization Requirements
paragraphs: 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.
subsections: section_title: Federal Immunization Recommendations Scaled Back
paragraphs: 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. 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.
section_title: States Reduce Immunization Requirements
paragraphs: 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). 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.
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. 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.
section_title: Deferred Immunizations Likely to Lower Vaccination Coverage and May Increase the Risk of Outbreaks
paragraphs: 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) 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.
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.  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.
section_title: Problems Causing Shortages Largely Resolved, but Shortages Could Recur
paragraphs: 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.
subsections: section_title: Many Factors Affected Supply of and Demand for Vaccine
paragraphs: 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.
subsections: section_title: Production Problems
paragraphs: 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.
section_title: Removal of Thimerosal
paragraphs: 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.  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. 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.
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.
section_title: Manufacturer’s Decision to Discontinue Production
paragraphs: 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.
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.  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.
section_title: Unanticipated Demand
paragraphs: 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.
section_title: Underlying Factors Could Allow Shortages to Recur
paragraphs: 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.
section_title: Vaccines on Horizon May Increase Supply
paragraphs: 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. 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.
subsections: section_title: FDA Policies Restrict Use of Expedited Approval Processes
paragraphs: 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.
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. FDA’s goals are to review and take action on priority  submissions in 6 months, compared to 10 months for standard reviews.
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.
section_title: Product Approval Requirements Are Not Standardized among Countries
paragraphs: 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.
section_title: No Clear Path Yet to Resolve Ongoing Supply Issues
paragraphs: 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.
subsections: section_title: NVAC Studying Strategies to Strengthen Vaccine Supply
paragraphs: 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.  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.
section_title: Expansion of Stockpiles Is under Consideration
paragraphs: 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.
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. 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.
section_title: CDC Lacks a Comprehensive Strategy for Expanded Use of Stockpiles
paragraphs: 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: 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.
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.
subsections: section_title: Critical Information Needed to Manage Stockpiles Is Lacking
paragraphs: 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. 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, 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.
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.
section_title: Conclusions
paragraphs: 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.
section_title: Matter for Congressional Consideration
paragraphs: 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.
section_title: Recommendations for Executive Action
paragraphs: 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.
section_title: Agency Comments and Our Evaluation
paragraphs: 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 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.
section_title: Appendix I: Comments from the Department of Health & Human Services
section_title: Appendix II: GAO Contacts and Staff Acknowledgments
subsections: section_title: GAO Contacts
section_title: Acknowledgments
paragraphs: In addition to those named above, Julian Klazkin, Jennifer Major, Linda  McIver, Leslie Spangler, and Stan Stenersen made key contributions to this  report.