Strengthening the Supply of Routinely Recommended Vaccines in the United States: Title and subTitle BreakRecommendations From the National Vaccine Advisory Committee

Beginning in late 2000, significant unprecedented and unanticipated shortages of routinely administered vaccines against 8 of 11 vaccine-preventable childhood infectious diseases occurred in the United States. Affected vaccines included diphtheria and tetanus toxoids and acellular pertussis (DTaP),¹ measles, mumps, and rubella (MMR), varicella,² and pneumococcal conjugate vaccines³ ; combined tetanus and diphtheria toxoids (Td) was also in short supply (Table 1).⁴

Vaccine supply disruptions affected private practices and public clinics because both sectors purchase vaccines from the same manufacturers. These shortages necessitated the Advisory Committee on Immunization Practices, the American Academy of Pediatrics, and the American Academy of Family Physicians to recommend deferral of certain immunizations and to set priorities for high-risk patients until vaccine supplies returned to normal.^{2 ,5 - 7} Although supplies of most vaccines returned to normal by the summer of 2002,^{8 - 10} the shortages have led to an examination of the causes and the strategies needed to stabilize and strengthen the vaccine supply.

The recent shortages have been frustrating for physicians, parents, and public health officials. Why did the problem occur at this time? Was the multiplicity of vaccine shortages an untimely confluence of manufacturing problems or a systemic problem in development, manufacturing, and regulation of vaccines? Why has an apparent fragility of vaccine supply occurred and what can be done to strengthen the supply?

In 2001, the US General Accounting Office received requests from several US senators and representatives to investigate the vaccine supply shortages.¹¹ At the same time, the Department of Health and Human Services (DHHS) requested that the National Vaccine Advisory Committee (NVAC) prepare a report on strengthening the supply of routinely recommended vaccines. Accordingly, an NVAC Working Group was appointed to identify potential causes of the vaccine supply shortages, develop a comprehensive list of strategies to prevent future shortages, and enlist key stakeholders to consider the applicability, feasibility, and effectiveness of these strategies.

To meet these objectives, the Working Group convened a national meeting of stakeholders including industry, regulatory authorities, public health officials, clinicians, purchasers, consumers, and legislators. The meeting, "Strengthening the Supply of Routinely Recommended Vaccines in the United States," was held in Washington, DC, from February 11 through February 12, 2002, and was organized around the discussion of 5 potential solutions to vaccine supply shortages. These potential solutions encompassed financial incentives, the regulatory process, government-directed programs, vaccine stockpiles, and liability protections. We summarize herein the meeting discussions, subsequent deliberations of the Working Group, and resulting conclusions and recommendations of the NVAC to the DHHS regarding possible long- and short-term pragmatic strategies. The strategies addressed the following goals:

While the confluence of vaccine shortages experienced between 2000 and 2003 is unprecedented and public awareness of this problem likely has been higher than at any time in history, concerns about disruptions of the US vaccine supply are not new. In 1976, for example, the Office of the Assistant Secretary for Health's request for advice from various constituencies resulted in 6 national immunization work groups. One work group, charged with making recommendations about vaccine production and supply, submitted a report in 1977 that expressed concerns about maintaining an adequate supply of vaccines in the face of "a steady attrition of specific pharmaceutical manufacturers from the entire field of biologics" (unpublished data, National Immunization Work Group on Production and Supply, March 15, 1977).

Two important federal initiatives implemented during the 1980s positively affected the supply of routinely recommended vaccines. In 1982, the Centers for Disease Control and Prevention (CDC) requested funds from Congress to create 6-month vaccine stockpiles to protect against temporary supply disruptions. The following year, the CDC received a Congressional appropriation of $4.6 million to begin development of dynamic storage and rotation stockpiles, in which new vaccines enter the stockpile as older vaccines are rotated into distribution and use.¹² At this time, the childhood immunization schedule was much less complicated than it is today, and the first stockpiles were to include only a 6-month supply of measles, mumps, and rubella, poliovirus, and diphtheria and tetanus toxoids and whole-cell pertussis (DTP) vaccines as well as combined diphtheria and tetanus toxoids (DT). According to the CDC, the stockpile has been used advantageously on at least 9 occasions since 1983 to alleviate vaccine supply problems.

The second initiative was the National Childhood Vaccine Injury Compensation Act of 1986, which created the National Vaccine Injury Compensation Program (VICP).¹³ This no-fault system compensates persons of any age for injuries or conditions that may have been caused by a vaccine recommended by the CDC for routine use in children. By addressing liability concerns, the VICP removed an important barrier for the production and routine administration of vaccines and provided an incentive for the continued manufacture of childhood vaccines.

In 1994, the DHHS revisited the issue of the vaccine supply by commissioning a study of vaccine industry economics. Despite the federal initiatives put into place during the preceding decade, this study found significant vulnerabilities in the stability of the US vaccine market and recommended an improved partnership between government and industry to "develop creative solutions to critical issues" to ensure a continuous, adequate supply of routinely recommended vaccines (unpublished data, DHHS, June 14, 1995).

Prevention of infectious diseases by immunization is one of the greatest public health achievements of the 20th century.¹⁴ The success resulted from the development, availability, and acceptance of vaccines as safe and effective products for prevention of disease. Nevertheless, vaccines often are undervalued,¹⁵ and many parents and physicians have limited first-hand experience with vaccine-preventable diseases. In addition, media reports and Web sites that focus only on vaccine risk cause alarm for parents and raise concerns about liability, which may disrupt the predictability of market demand.^{16 - 17}

Each year millions of vaccine doses are produced and distributed in the United States to meet routine and "catch-up" vaccination needs and to control outbreaks. For example, in 2001, approximately 200 million doses of vaccine were distributed, including 18.4 million doses of diphtheria, tetanus, and acellular pertussis–containing vaccine, 18.1 million doses of polio vaccine, 11.6 million doses of measles, mumps, and rubella vaccine, and 78 million doses of influenza vaccine (CDC, unpublished data, 2002). Vaccine purchase, distribution, and administration occur via a collaboration of public and private efforts. In 2001, approximately 57% of all childhood vaccines were purchased with federal, state, and local funds; the remaining vaccines were purchased privately (CDC, unpublished data, 2002).

Vaccine production involves complexities that are unique among pharmaceutical products. First, vaccines are most often produced from or use living cells and organisms as well as complex growth materials. Second, the production of most vaccines requires growing the immunizing agent (eg, bacteria, a virus) in the production facility, followed by purification of complex molecules from these organisms. Third, each vaccine lot must be carefully evaluated for composition and potency throughout the lot release process.

In the United States, the Center for Biologics Evaluation and Research (CBER), which is part of the Food and Drug Administration (FDA), is responsible for regulating vaccines.¹⁸ The unique features of vaccines result in a relatively long research and development period prior to the initiation of the regulatory process. The FDA continues its oversight of vaccines even after approval to ensure continuing safety. After licensure, monitoring of the product and of production activities, including periodic facility inspections, continues as long as the manufacturer holds a license for the product. In addition, the FDA may request that the sponsor conduct postmarketing studies to monitor for potential adverse events that may occur when a vaccine is administered to the general population.

Vaccines, typically developed by companies that manufacture a number of other pharmaceutical products, must often compete with other products within a manufacturer's portfolio. Because of the relatively long research and development period and the fixed market size (because vaccines are generally given only once or a few times to an individual), vaccines may have difficulty competing with other products. In addition, a number of vaccines do not reach the marketplace, despite considerable investment in research and development. Occasionally, vaccines that do the reach the marketplace are withdrawn (eg, Rotashield and Lymrix). Other economic considerations for vaccine manufacturers include the cost required to keep current with good manufacturing practices (GMPs)¹⁹ for older vaccines (eg, costly upgrades in a production plant) and the introduction of new products such as combination vaccines by competing firms.

Another important determinant of vaccine development cost is the data requirements for licensure. During the past decade, these requirements have increased substantially in certain respects, including safety, efficacy, and immunogenicity data. For example, immunogenicity data to support the concurrent use of vaccines to be administered routinely with the investigational vaccine are now usually required as part of the regulatory review process. The complexity of these data has increased as new vaccines have been added to the routine childhood immunization schedule. Not surprisingly, research and development expenditures for new vaccines have increased to keep pace with these data requirements.

Immediate factors contributing to the supply shortages are those believed to be directly responsible for the shortages. Such factors are typically vaccine-specific and may resolve over a short period. A list of immediate factors appears in Table 1. In addition, one immediate factor not specific to a particular vaccine involves problems complying with GMP-related inspections. During the 1990s, the composition of GMP inspection teams was modified to include more expertise in design and control. The focus of these inspection teams shifted to include quality systems, in-process testing, and facility and process validation. As a result, some facilities that had previously been acceptable now required significant physical changes to plants, quality systems, and processes.

Contributing factors are long-standing issues and problems that create vulnerability in the vaccine supply. The most important contributing factors include (1) a relatively low valuation of preventive measures such as vaccines contrasted with that of therapeutic medicinals, which is reflected in the price that individuals and public and private payers are willing to pay for vaccines; (2) the high cost and complexity of the development, approval, manufacturing, and distribution of vaccines; (3) the lack of continued investment in some vaccine manufacturing facilities; (4) barriers to communication between stakeholder groups, including proprietary information and confidentiality requirements that inhibit the recognition of evolving problems and development of effective responses; and (5) a relatively small number of vaccine manufacturers (Figure 1).

The small number of manufacturers is important not only because it might result in insufficient vaccine doses but also because it limits the ability of the vaccine market to respond in a timely manner to unanticipated changes in market share when another manufacturer has production problems or drops out of the market. In fact, despite the decreasing number of manufacturers over the past 2 decades, sufficiency of the vaccine supply is supported by childhood vaccination coverage rates at or near all-time high rates²⁰ in the face of a substantial increase in the number of routinely recommended vaccines. Tracking accurately the number of doses of vaccine produced during the past 2 decades is difficult because such information is considered proprietary. Although the CDC collects vaccine distribution information from manufacturers on a routine basis, these data are collected voluntarily for planning rather than for regulatory purposes and are incomplete and not validated.

Manufacturers should be able to obtain appropriate profit for the research, development, approval, and distribution of vaccines for the public well-being. Appropriate incentives must exist that encourage companies to enter and remain in the manufacturing business. Companies leave the marketplace when a product no longer provides a reasonable return on investment. Pricing of a successful product must include the costs of failed products. Incentives for research, development, and production to provide a fair return on capital expenditure may be made available by means other than increased price. Such incentives could include tax relief for new facilities or reconstruction of old facilities, other forms of subsidy, and guaranteed market and price. In 2003, the Institute of Medicine concluded a study on vaccine financing that recommends the use of value-based pricing as an incentive for manufacturers.²¹ Understanding the implications of this strategy will require additional study.

Developing contracts between the government and manufacturers that reward performance, such as delivering an adequate supply of vaccine in a predictable manner, should be explored. This type of contract could encourage manufacturers to maintain an adequate inventory as a buffer against unexpected problems in production.

Preventive services need to be appropriately compensated. Proposed reductions in reimbursement and compensation for administering vaccines are disincentives for clinicians. The rates should include a realistic administration fee that reflects clinician work as well as professional liability and practice expenses.

The FDA is the regulatory authority responsible for ensuring that licensed vaccines meet standards of safety and efficacy to protect public health. Vaccine development and regulatory processes are complex, labor-intensive, expensive, and time-consuming. Nonetheless, consensus exists that vaccine safety issues and maintaining credibility with the public require a rigorous regulatory process. The following specific steps should be considered to enhance and streamline the regulatory process.

Harmonization. Efforts should be directed at harmonizing the content and format for regulatory submissions of license applications in the context of the International Committee on Harmonization (eg, the Common Technical Document)²² and working with other national regulatory authorities to achieve mutual recognition of lot release tests for various vaccines.

Review of GMP Standards. Implementation of GMP standards should be reviewed to ensure that science-based regulatory processes are used and that these standards do not have an unduly negative impact on vaccine supply. The GMP standards should be dynamic, with changes that incorporate technological advances and maintain or improve facilities to current standards, but allow sufficient flexibility to ensure continued vaccine production within the context of safety and effectiveness. The FDA is undertaking such a review as part of an initiative called Pharmaceutical Good Manufacturing Practice Standards for the 21st Century: A Risk-Based Approach.²³ Launched in mid 2002, the impact of this review will require careful evaluation.

Increased Funding for CBER. The CBER plays a critical role in the translation of basic research to licensed products through applied research. In the past, CBER scientists have made important contributions, including the standardization of assays for potency of vaccines, improvements in neurovirulence testing for viral vaccines, and the development of novel methods for the detection of adventitious agents. Increased funding is needed to enable CBER to continue the recruitment and retention of highly qualified scientists.

Streamlining the Regulatory Process. Efforts to facilitate streamlining the regulatory process include early and frequent communication between the FDA and sponsors regarding the conduct of research that facilitates product development, fast track, priority review, and accelerated approval programs. Legislation has been enacted to enhance and expedite the review process during the past decade; this legislation currently extends to 2007.^{24 - 25} Further study is needed to determine if these provisions have fulfilled the intent of the legislation or whether additional legislation is needed.

Reviewing the Regulatory Process for Vaccines and Biologics. The review of the regulatory process should include whether vaccines and biologics should be regulated differently from drugs. Also, current policies and practices for vaccine regulation should be evaluated to determine if possible impediments to an adequate supply of safe and effective vaccines are inadvertently created.

Through the National Vaccine Program Office (NVPO) and NVAC, a mechanism exists to identify federal priorities related to the US immunization program and to coordinate activities across the federal government and with external partners.²⁶ The responsibilities of the NVPO are to coordinate and ensure collaboration among the many federal agencies involved in vaccines and minimize gaps in federal planning of vaccine and immunization activities. The NVPO should be supported in this critically important role. The mission of the NVAC is to recommend ways to encourage the availability of an adequate supply of safe, effective vaccines; recommend research priorities to enhance the safety and efficacy of vaccines; advise the Director of the National Vaccine Program; and to identify the most important areas of governmental and nongovernmental cooperation needed to implement the national immunization program.

The recent vaccine supply shortages have raised questions about the appropriate role of the federal government in vaccine production. Government-owned or government-operated facilities may be important for national defense needs and those of the military, but are less likely to be advantageous for production of routinely administered vaccines for which a commercial market exists. If the federal government were to become a vaccine manufacturer, the pharmaceutical industry might have difficulty competing in production of vaccines, resulting in further withdrawal of private manufacturers from the US marketplace, with a resultant loss of innovation and introduction of new products.

The national vaccine stockpile program appears to be the most advantageous short-term solution to prevent future shortage crises. At the present time, partial vaccine stockpiles exist for measles, mumps, and rubella, varicella, inactivated poliovirus (IPV) vaccines, as well as diphtheria and tetanus toxoids (DT). Orders have been placed for future delivery of limited amounts of hepatitis A, hepatitis B, Haemophilus influenzae type b, and pneumococcal conjugate vaccines.²⁷ The CDC should be provided with additional resources to purchase sufficient quantities of all routinely administered vaccines. A recent federal budget allocation of $171.7 million for fiscal year 2003 provided partial funding to support this expansion of the national stockpile program.²⁷ Further, the development of strategic inventories has risks and limitations, and the federal government needs to assume the financial risk of unused vaccines or vaccines for which no demand exists.

In addition to increased funding for the national vaccine stockpile program, a comprehensive plan is needed. This plan should address important logistical considerations, such as size of the stockpiles, the formulation of vaccine (ready-to-ship vs unpackaged or unlabeled product), procedures for monitoring and accountability, procedures for stockpile activation, and the costs for vaccine purchase, storage, and rotation. In addition, the plan must incorporate policies to address the need for variable storage conditions, changes in vaccine formularies, varying market share, and the time required before the supply of a new vaccine is sufficient for inclusion in a stockpile.

Despite the success of the program, criticism of the VICP could lead to significant legislative changes, including a more relaxed burden-of-proof standard for determining eligibility for compensation. Today, litigation (in the form of class-action lawsuits) threatens vaccine program stability. The suits that have been filed involve vaccines that contain thimerosal as a preservative.

While current vaccine shortages do not appear to be liability-related, the VICP should be maintained and strengthened as supported by scientific evidence, including continuing expansion to include additional vaccines as they are recommended for routine administration to children. The VICP coverage of vaccines should recognize that a vaccine includes the active ingredients as well as preservatives, additives, and other excipients. Strengthening the VICP will benefit manufacturers, clinicians, and consumers and further safeguard the vaccine supply.

Manufacturers and Government Officials. Because information about vaccine production is proprietary, no requirements currently exist regarding advance notification about the decision to withdraw from the vaccine marketplace. Manufacturers should be required to provide such notice to the DHHS to allow public health officials sufficient time to plan for strategies to mitigate vaccine shortages. Further, the DHHS should be permitted to use proprietary vaccine supply forecast information so long as the information remains confidential. The CDC and/or the FDA should continue to share (in confidence) proprietary information to maximize the efficiency of vaccine supply. Development of a mechanism for providing information to manufacturers is needed to permit increased capacity and address supply limitations that threaten the public health while protecting proprietary information.

The Public. The transparency of information for opinion leaders and consumers should be increased. The frustration of consumers and physicians results from the uncertainty and vagueness of information about the causes of vaccine shortages and the time to obtain adequate supplies. The role of a readily accessible Web site, such as that of the CDC,²⁸ that provides current information about vaccine supply, should be enhanced so that physicians and consumers can plan catch-up immunizations and have confidence in vaccine programs.

Public's Confidence in Vaccines. A national campaign should be conducted to emphasize the safety and efficacy of vaccines. Public awareness of prevention as the most effective tool against disease and immunization as a cornerstone of prevention of infectious disease needs to be increased. Appropriate use of vaccines should be encouraged by a coordinated program involving government, industry, academia, professional societies, and consumers. This communication also should emphasize efforts to review and evaluate potential vaccine safety concerns, such as those currently performed by the Institute of Medicine.²⁹

Disruptions to the supply of routinely administered vaccines are likely to continue to occur. Action to implement short- and long-term solutions should be considered and initiated now.

Solutions that may be implemented in the immediate future:

Solutions that are more complex and will require more study:

The NVAC and its Working Group will continue to consider the issues critical to strengthening the supply of routinely recommended vaccines in the United States and make additional recommendations to the Assistant Secretary for Health as appropriate. One immediate task for the NVAC is the development of a prioritized list of specific implementable recommendations.