Priority Setting

The decision-making process for the development and production of vaccines should be guided by an assessment of critical public health needs. Priorities should be established and the desired vaccine characteristics should be defined. In this way, the vast resources of the U.S. and international public and private sectors can be directed to a set of common and complementary goals.

There have been major efforts over the past decade to establish priorities for vaccine development (Institute of Medicine, 1986a,b; National Institute of Allergy and Infectious Diseases, 1992a,b; World Health Organization, 1991; World Health Organization/Children's Vaccine Initiative, 1992c). As discussed in Chapter 3, much of the basic vaccine research conducted by the National Institute of Allergy and Infectious Diseases (NIAID) targets the development of priority vaccine candidates identified in 1986 by the Institute of Medicine (Institute of Medicine, 1986a,b; National Institute of Allergy and Infectious Diseases, 1992a,b), and much progress has been made (National Institute of Allergy and Infectious Disease, 1992b).

At present, new efforts are under way to develop priorities for vaccine R&D. The Task Force on Priority Setting and Strategic Plans of the World Health Organization's (WHO's) Children's Vaccine Initiative (CVI) recently completed a major cost-effectiveness assessment of vaccine-development priorities, and the WHO/United Nations Development Program's (UNDP) Program for Vaccine Development maintains a list of priority areas for vaccine development. In addition, the World Bank, as part of the World Development Report of 1993, Investing in Health (World Bank, 1993), is using Disability Adjusted Life Years to estimate the burden of disease and priorities for intervention.

Whatever priorities are set by the public sector, the ultimate decision to develop and manufacture a vaccine for general use in the United States rests entirely with the commercial vaccine manufacturers (see Chapters 3, 4 and 5 and Appendix H). Commercial manufacturers vigorously pursue the development of those products with market potential (see Chapter 4). Vaccines used exclusively in the developing world hold little promise of significant returns on investment, and companies are reluctant to invest in developing such high-risk and commercially unattractive products (see Chapter 5).

The committee believes that priority setting and characterization of desired vaccine products is a critical stage of vaccine development, particularly for vaccines of low commercial interest but acute public health need. In this regard, the committee urges all groups involved in vaccine R&D for international public health applications to focus on a common and complementary set of vaccine priorities.

Basic and Applied Research

The fundamental scientific advances that make vaccine development possible arise from basic research. The full implications and ultimate applications of discoveries made in the basic research laboratory may be unanticipated, even by the investigators involved. Basic research relevant to vaccine development includes such things as the identification and isolation of the protective antigens of a specific pathogen, methods for DNA cloning, the creation of new vector systems, and the development and immunologic evaluation of new adjuvant systems.

Basic research is conducted primarily by federally funded academic and government scientists. Once a basic scientific finding is thought to have significant and practical applications, the research moves on to applied R&D (the exploratory development phase). Much applied research and almost all product-development activity are conducted by private industry. Both biotechnology firms and vaccine manufacturers invest in developing new technologies to deliver and enhance the quality and efficacy of vaccines. Unfortunately, some CVI-specific vaccine technologies (e.g., heat stabilization of viral vaccines) are unlikely to be pursued by U.S. firms, because such technologies would have little comparative advantage in the domestic market. The committee believes that additional incentives can be provided to university-based researchers, commercial vaccine manufacturers, and biotechnology companies to stimulate the development of such technologies and their subsequent handoff from basic research to the product-development stages. Possible incentives are discussed in Chapter 7.

Clinical Evaluation

Good vaccines must meet basic criteria of safety, purity, potency, and efficacy. When a product has completed preclinical studies (usually involving animal models) and the sponsor is considering clinical trials in humans, an Investigational New Drug (IND) application is submitted to the U.S. Food and Drug Administration (FDA). The IND application contains information on the vaccine's safety, purity, potency, and efficacy (see Appendix C). These parameters are then evaluated in clinical trials, which are usually carried out in four phases (Table 6-1). Phase I trials are short-term studies involving a small number of subjects and are designed primarily to evaluate the safety of the candidate vaccine, its ability to induce an immune response (immunogenicity), the optimal dose range, and the preferred route of administration to achieve the most effective immune response. Studies are usually conducted in individuals at low risk of acquiring natural infection in order to avoid confusing results.

TABLE 6-1

Characteristics of Clinical Phases of Vaccine Research.

Following the successful completion of phase I trials, phase II trials are conducted; these may involve up to hundreds of subjects. Phase II trials are usually double-blind studies with a placebo-control group; phase II trials expand the evaluation of the safety and immunogenicity of the vaccine and may include the responses of individuals at risk of acquiring the infection. For a treatable pathogen, trials can be conducted in susceptible adults under controlled conditions to assess the ability of the vaccine to confer protection against experimental challenge. The results of these pilot studies can provide the information necessary to proceed with phase III studies.

Phase III trials are usually conducted in a double- or single-blind, placebo-controlled, randomized manner and in hundreds to thousands of individuals at risk for acquiring the infection or disease. Because of the lengthy observation period that may be required, the longer-term safety of the vaccine can also be assessed in a large number of subjects. Such trials are expensive, require a well-developed health infrastructure and large study groups (sometimes in non-U.S. populations), and, as with all stages of clinical investigation, demand experienced personnel and laboratory capacity for surveillance. Additional expenses are incurred if testing of live attenuated or live recombinant vaccines requires isolation facilities for phase I and II trials. Study design, data collection, and analysis are all of critical importance for ensuring the quality of trial results for licensing a candidate vaccine.

Phase IV trials may be conducted after a product is licensed, as part of postmarketing surveillance. They provide information about the safety and effectiveness of the vaccine in the general population, usually under normal (nonstudy) conditions.

Clinical trials are time-consuming (sometimes taking years), complex, and costly. Clinical trials for CVI vaccines, which are targeted for infants and young children, will be more challenging and time-consuming than those for vaccines designed for adults and older children. The safety and immunogenicity of many CVI vaccines will need to be demonstrated in trials successful can CVI vaccines be tested in young seronegative infants. Given in adult volunteers and then in older children. Only if those studies prove safely and ethical considerations, efficacy studies in infants may not permit challenge with the naturally virulent organism, but may require documentation of the prevention of natural infection compared with that in a placebo-controlled group. This progression of trials through younger age groups can be a lengthier process than that for strictly adult trials.

CVI vaccines will probably have to be tested in international field sites, since many of these vaccines are intended to prevent diseases from which children in the United States do not suffer. Ethical principles applicable to research with children would argue against subjecting healthy children to the risks of investigational vaccines that, even if proved effective, will be of no benefit to them or even to children in the same population. In addition, a CVI vaccine tested in healthy children in the industrialized, world may not perform adequately under certain conditions of sanitation, malnutrition, and concurrent infection that exist in the developing world. To the committee's knowledge, there are very few field sites equipped to evaluate vaccines definitively in infants. Such sites require an epidemiologically well-characterized population, adequate clinical and laboratory infrastructures, political commitment, local expertise, and on-going epidemiological field studies.

The United States, through various government agencies, including the U.S. Agency for International Development, the Centers for Disease Control and Prevention, the U.S. Department of Defense, and the National Institutes of Health, has considerable resources for conducting and evaluating clinical trials. The committee encourages these agencies to expand and make their international resources available to public-and private-sector entities interested in developing and testing CVI-related products. New sites capable of conducting vaccine trials in infants may have to be established, preferably in association with existing activities.

Licensure

Vaccine manufacturers apply to the FDA for a license to manufacture a vaccine by submitting a Product License Application (PLA). The PLA describes the firm's vaccine manufacturing process, quality control, and the results of clinical studies documenting the vaccine's safety and efficacy. Manufacturers also submit a second document, the Establishment License Application (ELA) or ELA amendment, describing the facilities, equipment, and personnel involved in the manufacturing process. Vaccine manufacturers also have to satisfy the FDA that they have followed establishment licensing standards and current Good Manufacturing Practices, an extensive body of regulations for manufacturing pharmaceuticals and biologics (the full range of the regulatory aspects of vaccine development are discussed in Appendix C).

The FDA's Center for Biologics Evaluation and Research (CBER) has come under criticism from the U.S. Congress and the pharmaceutical industry for the length of time—approximately 3 years—that it takes to approve PLAs and ELAs. Lengthy approval times are due in part to a rapidly increasing number of applications, many of which are for technologically new products, in the face of a level budget and staffing. The work overload has also made it difficult for CBER staff to devote time to their ongoing research projects and to keep abreast of technological developments. Although application approval times are likely to shorten over the coming years, the licensing of biologics will almost always be a lengthy process because of the high safety and efficacy standards that are required. Considerable time is required to acquire substantiating data from clinical trials, and this process is especially time-consuming for new vaccines.

In an effort to promote faster approval of drugs and vaccines, the Drug User Fee Act (P.L. 102-571) was passed in 1992. Under the new law, pharmaceutical companies must submit fees of $100,000 or more per application. The additional funds will be used to boost the size of FDA's application review staff from the current level of 1,000 to 1,600 over 5 years (Kessler, 1992). CBER's share of the increase will be on the order of 300 staff members. By 1997, the agency expects to review and act on completed PLAs and ELAs for priority applications within 6 months; for standard applications, the review time will be no more than 1 year (Kessler, 1992a). There is some concern that companies will be unwilling to pay the fees for CVI vaccines, which will be used primarily in the developing world. The user-fee law also may force the FDA to curtail many of its international activities and, instead, focus on domestic issues. FDA staff currently serve on international committees and work on bilateral projects to advise selected developing countries on regulatory policies. The committee addresses some of these regulatory concerns in Chapter 7.

Production

Pilot Production

Pilot production, which occurs at or near the end of the applied research phase, is a critical stage in vaccine development. It is during the pilot manufacturing stage that vaccine is produced for use in safety and immunogenicity tests. Pilot vaccine manufacturing should be performed by using current Good Manufacturing Practices and, ideally, should be done on a scale sufficiently large to closely simulate the scale that will be used in commercial manufacturing. This is important if technical problems during scaleup are to be avoided, to ensure that the vaccine lots used in human efficacy studies will be similar to those produced commercially, and to facilitate the transfer of vaccine technology to commercial vaccine manufacturers in the United States and/or to manufacturers in developing countries.

As part of the IND application process, pilot lots of vaccine are produced (using Good Laboratory Practices or, preferably, current Good Manufacturing Practices). Careful attention is paid to controlling the steps of production so that a consistent product is obtained each time. Procedures for process control and for final product characterization are developed and then performed on each lot.

The United States has a limited number of facilities that are capable of producing pilot lots of vaccine and that meet Good Laboratory Practices and current Good Manufacturing Practices standards. In the public sector, only the Michigan and Massachusetts departments of public health, as well as the U.S. Department of Defense (through a contract with the Salk Institute in Swiftwater, Pennsylvania, and using a newly reconstructed plant at the Forest Glen section of the Walter Reed Army Medical Center have the capability of producing pilot lots of viral, bacterial, and antiparasitic vaccines (Table 6-2).

TABLE 6-2

Existing U.S. Public-Sector Vaccine Development and Manufacturing Facilities.

Commercial vaccine manufacturers in the United States and Europe have the greatest capability of producing pilot lots of vaccine, but their facilities are often oversubscribed and precedence is given to products with the highest commercial potential. Indeed, the private sector has shown little interest in producing pilot lots of developing-world vaccines for such organizations as the UNDP/World Bank/WHO Special Program for Research and Training in Tropical Diseases (United Nations Development Program/World Bank/World Health Organization Special Program fo Research and Training in Tropical Diseases, 1992). Vaccines that have an immediate and defined market and less risk of technical failure, such as influenza vaccines, will always command priority in the vaccine development and production pipeline of commercial vaccine manufacturers. Indeed, a recent U.S. Department of Defense phase II trial of a candidate malaria vaccine had to be scaled back to involve half the number of volunteers needed because the Department of Defense's commercial partner could not produce a second batch of vaccine because other vaccine candidates had priority for the company's pilot facilities (Jerald C. Sadoff, Walter Reed Army Institute of Research, personal communication, 1993). Indeed, for all practical purposes, commercial manufacturers' pilot production facilities have been unavailable to multilateral organizations and members of the public sector seeking to develop those vaccines that have a high technical risk and that are likely to be of limited commercial value (Tore Godal, Director, UNDP/World Bank/WHO Special Program for Research and Training in Tropical Diseases, personal communication, 1993).

Contracting out pilot production to specialized private-sector firms is a limited option for both private-sector firms and the public sector, including the U.S. Department of Defense. Only a handful of small privately held firms in the United States can make peptides according to current Good Manufacturing Practices, and even fewer have filling and bottling capabilities, with the consequence that filling and bottling must be completed elsewhere. Many private companies, most particularly start-up biotechnology companies, are reluctant to contract pilot production to others for fear of losing proprietary technology and know-how (Lance Gordon, President, ORAVAX, personal communication, 1993). The end result of the shortage of vaccine pilot production facilities is considerable delay (sometimes years) in producing pilot batches of required vaccines.

The difficulties and delays associated with contracting out pilot production and bottling and filling prompted the U.S. Department of Defense to reconstruct its own pilot production facility at Forest Glen, Maryland. Even though the Forest Glen facility is not yet operational, WHO, the U.S. Agency for International Development, several institutes at the National Institutes of Health, and several small biotechnology firms are entering into agreements with the Department of Defense to access the pilot production capability (Jerald C. Sadoff, Walter Reed Army Institute of Research, personal communication, 1993). Indeed, it appears that the Forest Glen facility will be oversubscribed before it becomes fully operational.

In the committee's view, the lack of pilot production facilities is a major bottleneck in the development of vaccines in general, and CVI vaccines in particular. This concern is addressed in the committee's recommendations in Chapter 7.

Recommendations for Use

As part of the licensure process, recommendations for vaccine use are made by the vaccine manufacturer with the approval of the FDA and appear as part of the package insert. The package insert describes, among other things, the target group and dosage regimen, outlines contraindications, and provides information on side effects.

Recommendations for general vaccine use in the U.S. public sector are made by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention. Separate and sometimes slightly different recommendations are produced by the Committee on Infectious Diseases of the American Academy of Pediatrics (AAP; the so-called Red Book committee) for use in the private sector (see Appendix G). Recommendations for use in the international sphere are often determined by WHO in conjunction with national governments.

ACIP recommendations are made on the basis of all available data regarding the vaccines under consideration presented to the ACIP both verbally and in written form. There have been instances in which some parents and pediatricians would have favored the ACIP and AAP going beyond the manufacturer's recommendations for use. For example, the first vaccine against Haemophilus influenzae type b (HibTITER) to be licensed in the United States was approved in December 1988 for use in children 18 to 60 months of age. It was not approved for use in infants until October 1990, when additional clinical studies were completed. The same scenario is now being played out with the acellular pertussis vaccine, which currently is approved for use only as a fourth booster dose. Although some may argue that there is little need to delay the use of vaccines in infants when trials in slightly older children indicate that they are safe and effective, it is impossible to predict whether vaccines will be as safe and effective in different age groups, especially in immunologically naive infants.

Recommendations to include new vaccines in the immunization schedule in the United States are made only after a vaccine has been licensed by the FDA. This can and has posed problems for vaccine manufacturers in the past when new vaccines are not recommended for integration into existing immunization schedules. For example, a polysaccharide pneumococcal vaccine for adult use was marketed in 1978. However, the ACIP's 1978 recommendations were so lukewarm that they effectively discouraged greater coverage among the elderly populations (Centers for Disease Control, 1978; Sisk and Riegelman, 1986). Because manufacturers can never be certain whether a licensed vaccine will be included among recommended immunizations, there have been suggestions that the ACIP and AAP make recommendations for use while the vaccines are in clinical trials. This would effectively commit the federal government to large-scale purchases of vaccine relatively early in the clinical testing phase and might give vaccine manufacturers the confidence to proceed with development (Institute of Medicine, 1986c).

There are several problems with this approach, however. First, most manufacturers need to assess the potential market for a product well before it reaches the clinical trial stage. Second, there are problems in recommending a vaccine for use when data concerning the target group are not available. Third, it is not possible to predict the outcomes of clinical trials, particularly in specific target groups tested in the later stages of a trial. Finally, FDA licensure and recommendations concerning an incompletely tested product cannot be predicted, nor expected.

Procurement

Worldwide, the United Nations Children's Fund (UNICEF) and the Pan American Health Organization (PAHO) are the largest purchasers of vaccines for use in the developing world (see Chapter 4). More than two-thirds of the vaccines supplied to UNICEF and PAHO are produced by European manufacturers; none are made by U.S. manufacturers.

The federal government is the largest purchaser of childhood vaccines in the United States. The public sector, through the Centers for Disease Control and Prevention (CDC) and the states, procures more than half of the vaccines used in this country, and the Army buys all of the vaccines used by the U.S. military (see Chapter 3). The private sector, through hospitals, clinics, and pediatricians, procures vaccines directly from the manufacturers. CDC's fiscal year 1992 vaccine purchases amounted to $154 million; the Army buys between $10 million and $30 million worth of vaccines annually.

In early 1993, the Clinton administration proposed that the federal government assume a larger role in purchasing childhood vaccines (the Comprehensive Childhood Immunization Act of 1993 [H.R. 1640 and S. 732 and S. 733]) (Clinton, 1993; Marks, 1993; Washington Post, 1993).

Currently, the CDC negotiates a federal purchase price for priority vaccines with key manufacturers. These public-sector rates are substantially lower than those listed in the private sector (see Chapter 4). The CDC then makes grants to the states to purchase the vaccines, passing on the lower prices. The federal government negotiates procurement contracts anew every year. Some have argued that the 1-year contracts serve as a disincentive to vaccine innovation, since companies have no guarantee that the products they develop and manufacture will be purchased for any substantial length of time. Others argue that extending the procurement contract could effectively shut out other manufacturers and lead to their exit from the vaccine business. Consequently, there is some concern that if the U.S. government emerged to be the sole purchaser of all pediatric vaccines, the little competition that exists among vaccine manufacturers in the United States would diminish even further. In addition, industry representatives have indicated that companies may be reluctant to invest in costly R&D if the government were to be the sole buyer (see Chapter 5) (Douglas, 1993).

Distribution and Delivery

Organizing effective and efficient vaccine distribution and delivery systems and communicating the importance of routine immunization to parents and health professionals are critical to ensuring adequate immunization coverage in the United States and around the globe. In much of the developing world, vaccines are distributed by ministries of health through EPI and by various nongovernmental organizations. The EPI has established a target to immunize 90 percent of children under 1 year of age by the year 2000. Achieving this level of immunization is anticipated to be an enormous challenge and is expected to require improved information and epidemiological surveillance systems to identify pockets of unvaccinated children and regions of persistent disease transmission, enhanced social mobilization, and additional resources to strengthen vaccine delivery. In addition, the introduction of new vaccine products into EPI will require close coordination among the implementing agencies.

Surveillance

Surveillance is key to monitoring important characteristics in a population in which a vaccine is introduced. These aspects include (1) the immunization rates attained in the targeted group, (2) the efficacy of the vaccine in preventing the disease, (3) the frequency and attributes of vaccine-related adverse reactions, and (4) the recognition of new infectious disease problems that require public health attention. Likewise, surveillance will be a fundamental component in monitoring the efficacies of CVI vaccines and any adverse reactions and contributing to the establishment of new vaccine development priorities.

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