In considering the development of a new vaccine, preventive immunization, generally considered the most cost-effective health intervention, should be ranked against other strategies for disease control, such as case management (treatment of disease) or control of environmental factors linked to vector prevalence and dynamics (e.g., overpopulation, rural-to-urban migration, economic status, vector control, inadequate domestic water supply or sewage disposal) (1). Evaluating vaccination options and economic impact is particularly important for vaccines against low-prevalence or geographically contained emerging infectious diseases with limited demand, for which development costs may not be recovered. Thus, consensus should be reached on the mid- to long-term public health significance (e.g., vector dynamics and potential control, age prevalence and targets, risk categories, case-fatality rates, and possible future epidemiologic scenarios) of any vaccine-preventable disease. Without clear premises and long-term commitment, the development of vaccines for rare infectious diseases or those of narrow scope (e.g., geographically limited but regionally important diseases such as arboviral or diarrheal diseases) or for which development costs offset the market potential, called here orphan vaccines, may be considered a precarious venture that most organizations would hesitate to pursue.

The United States was the first nation to propose a legal framework to overcome the disincentives to developing orphan drugs and encourage their development and availability (9,10). The Preamble on Orphan Drugs to the legislation passed by the U.S. Congress contained the following points: 1) Many diseases and conditions (so-called orphan diseases) exist that affect very small numbers of persons; however, the overall group of patients affected by such diseases totals 20 million or more in the United States; 2) adequate drugs for orphan diseases have not been developed; 3) pharmaceutical companies may reasonably expect to generate relatively small sales in comparison to the cost of developing an orphan product; and 4) costs of developing such drugs should be reduced, and financial incentives should be provided.

The legislation defines two classes of orphan diseases. The first class comprises diseases that affect fewer than 200,000 Americans. In this case, sales of a drug, vaccine, diagnostic test, or blood product intended for use in such a disorder would be insufficient to offset the costs incurred during development and marketing of the product. This program is directed at public health needs beyond the U.S. borders, providing a stimulating factor for the U.S. pharmaceutical community to develop products to meet the needs of populations elsewhere. The second class of orphan diseases affects more than 200,000 Americans but has no potential recovery costs from U.S. sales. Thus, the program may also apply to specific subpopulations of patients with a more common disease for which the sponsor does not expect to offset development and marketing costs in the first 7 years of sales.

Concerning vaccines, the U.S. Food and Drug Administration (FDA) stipulated that, when establishing the claim for orphan status, the intended population should reflect the number of persons who would receive the vaccine annually as of the date of designation.

In 1994, the European Commission (the legislative body of the European Union [EU]) stated its interest in orphan diseases. In 1998, with close collaboration of the French Ministry of Health (15) and the European Medicine Evaluation Agency, a text was approved recommending the creation of a European Office for Orphan Drugs along the same lines as the U.S. Office of Orphan Products Development.

The proposed European criteria for classification of a drug as an orphan drug (including vaccines) are almost identical to the U.S. criteria, except that they are based on a disease prevalence of 5 per 10,000 Europeans (falling between the United States [7 per 10,000] and Japan [2.5 per 10,000]), when no current methods of diagnosis, prevention or treatment, or major contribution to current patient care exist.

The legislation will provide incentives to the European pharmaceutical industry in terms of research and development assistance (protocol assistance, normal evaluation, possible form of centralized but fast-track approval procedures), fee waiver, tax credits, funds from the European Orphan Product Grant Program, and market exclusivity for 10 years (interim period 6 years) and will encourage national policies (subsidiary principle, e.g., the French compassionate use authorization [Autorisation Temporaire Utilisation]) (16).

The role of patient groups in increasing awareness of orphan drug development has been widely recognized for pharmaceutical orphan drugs in the United States and has been emphasized in the European project. The potential end-users of an orphan product may not be aware of therapeutic or preventive options. The European Office of Orphan Products Development will therefore support the establishment of groups of persons with the same rare conditions to play a role in increasing awareness of the disease within the population and will coordinate their activities at national and community levels. It remains to be seen how this initiative will apply to vaccine-preventable infectious diseases in communities where individuals or groups may not be aware of the risk for infection and thus the value of the vaccine.

To clarify the extent of patent protection and the right to benefit from the orphan incentive package, the European Commission (DG24 committee) recently defined "similarity" between orphan products as the same substance, or a substance that differs from the original substance in molecular structure, source material, or manufacturing process, or an organism (living or nonliving) that is comparable with the original substance or organism in terms of biologic action and properties (including efficacy and safety) and ability to act through the same mechanism. In the same way as the U.S. legislation, this would favor the development of novel orphan products by the innovative company.

In June 1999, the European Parliament's committee on the environment, public health, and consumer protection adopted a report by one of its senior members in favor of the Policy on Orphan Drugs and proposed some amendments to widen the scope of the legislation. Among other changes, the committee requested more flexibility in the proposed provisions for clinical trials, allowing (under specific conditions) availability of the product before final authorization is granted. The committee proposed extending the definition of orphan drug status to cover products intended for serious and chronic diseases. It also recommended, as in the United States, additional incentives for developing medicinal or biologic products for diseases that occur mainly in tropical regions but rarely within EU territory. Finally, the committee called for an Orphan Medicinal Product Innovation Promotion Fund to be financed from the sales of orphan drugs after the proposed 10-year period of market exclusivity. The European Orphan Drug Policy could be enacted early in the year 2000.

After the U.S. Orphan Drug Act, similar legislation was enacted in Japan in 1993. An Australian orphan drugs program based on the U.S. program began in 1998 (17). Since then, the Therapeutic Goods Administration has designated two biological drugs as orphansrabies immunoglobulin and recombinant enzyme imiglucerase for replacement therapy in patients with Gaucher disease. A cross-national comparison of orphan drug and vaccine policies has been made for different countries, including Japan, Canada, France, Sweden, and the United Kingdom (12).

The availability and use of orphan vaccines in developing countries are complex since these countries have yet to ensure optimum use of existing priority vaccines (17). The limitations and obstacles involved in expanding the use of these priority vaccines are further multiplied for orphan vaccines of limited need. Within the framework of WHO, the Children's Vaccine Initiative set the development of vaccines with commercial prospects as a priority measure (7). This cost-oriented definition reflects mainly the difficulty of developing vaccines and drugs for tropical diseases, even those as prevalent as malaria (19,20). The Children's Vaccine Initiative's role has been problematic for various reasons (21), and this structure has faced increasing difficulties in maintaining its visibility.

Nevertheless, other noneconomic factors (3) could justify an industry's decision to develop and market an orphan vaccine: desire to enhance the company's ethical profile by fulfilling a medical or social need; capacity to develop, produce, and market the drug; a larger company strategy (e.g., part of a product range); and possible additional uses that would increase the drug's future economic viability. The latter point may be less relevant for vaccines, which are usually tailor-made to their infectious agents.

In the development of any vaccine against an emerging infectious disease, certain general rules apply (4,6,18,22), for example, developing strong research and development capacity, obtaining reliable scientific results and training in industrialized and developing countries; bulk filling arrangements; licensing technology; negotiating partnerships for specific products; joint venture agreements with western research and development manufacturers (economic value of the alliance); identifying the neediest countries on the basis of a banding strategy that classes countries according to their gross national product per capita, thereby allowing tiered pricing among them (6,23); and creation of funding mechanisms. Some could argue that from an industry perspective, if all of these criteria cannot be met, the vaccine should not be developed.

No trade-off on the quality of an orphan vaccine is ethically justified or accepted. For the pharmaceutical industry, therefore, the costs incurred in development, ensuring tight quality controls, and establishing industrial good manufacturing procedures for an orphan vaccine are similar to those incurred with a traditional vaccine. For this reason, the development of any orphan vaccine should be broadly supported by measures to increase the awareness of immunization benefits at three levelsthe decision-makers, the caregivers, and the patients.

Development of orphan vaccines is guided by the limited need for or market potential of the product, with the accompanying regulations, as well as the specific characteristics of the vaccine and those who need it (24). Because of the pitfalls related to these limitations, few orphan vaccines have reached the neediest populations. For example, in the United States, by the end of 1997, 837 medicinal products had been designated orphan drugs; 152 of these obtained authorization. This number was a clear improvement over that of the previous 14 years, during which 34 medicinal orphan products obtained authorization. However, our website review found only eight vaccines registered with orphan status (seven for therapeutic indications [e.g., cancer and sickle cell anemia], one to prevent an Asiatic infectious diseaseJapanese encephalitis virus) and, to our knowledge, none has yet obtained final authorization. In addition, "It is not vaccines that save lives but vaccination." Even when orphan vaccines are available, we have to examine the feasibility of getting them to the intended population.

Various strategies, proposals, and recommendations for overcoming limitations inherent in orphan vaccine development and availability are listed in the Table.

The dilemmas intrinsic to the development and distribution of orphan vaccines against emerging infectious diseases reflect many of the issues faced by policy makers worldwide with regards to cost, quality of care, access to care, and the role of government intervention in regulating the health-care market (30). In view of the current globalization of trades and markets, worldwide orphan vaccine policies and a specialized organization with a strong leadership and commitment similar to the Children's Vaccine Initiative project for a National Vaccine Authority may be needed (6,18). This kind of organization could be responsible for establishing a list of priority orphan vaccines and indicating reasons for not including other vaccines. The organization could also oversee all stages of vaccine development and have access to funds that could rapidly be mobilized. Such a global structure could serve as a forum for discussing the current limitations on orphan vaccine development and availability. Nevertheless, the problems recently faced by the Children's Vaccine Initiative indicate the difficulties in mounting and maintaining such a worldwide initiative.