Emerging Infectious Diseases
[Volume 5 No.6 / November - December 1999] 

  Perspectives

   Development of Orphan Vaccines:  An Industry
   Perspective

   Jean Lang and Susan C. Wood
   Pasteur Mrieux Connaught, Lyon, France

    The development of vaccines against rare
    emerging infectious diseases is hampered by
    many disincentives. In the face of growing
    in-house expenditures associated with
    research and development projects in a
    complex legal and regulatory environment,
    most pharmaceutical companies prioritize
    their projects and streamline their product
    portfolio. Nevertheless, for humanitarian
    reasons, there is a need to develop niche
    vaccines for rare diseases not preventable
    or curable by other means. The U.S. Orphan
    Drug Act of 1983 and a similar proposal
    from the European Commission (currently
    under legislative approval) provide
    financial and practical incentives for the
    research and development of drugs to treat
    rare diseases. In addition, updated
    epidemiologic information from experts in
    the field of emerging diseases; increased
    disease awareness among health
    professionals, patients, and the general
    public; a list of priority vaccines;
    emergence of a dedicated organization with
    strong leadership; and the long-term
    pharmacoeconomic viability of orphan
    products will be key factors in overcoming
    the complexity of orphan status and the
    limited need for vaccine.

   The Problem

   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.

   Disincentives for Orphan Vaccine Development

   Competing Costs

   Vaccine development involves a substantial investment
   in time, effort, and resources. Any private- or
   public-sector vaccine research and development process
   involves choices concerning the allocation of resources
   at all levels, including personnel and management. The
   costs from research to licensure, the risks inherent in
   vaccine development (e.g., technological constraints,
   regulatory approval) and the short- and long-term
   market financial evaluations (e.g., net present value,
   return on investment [2]) are key factors in the
   decision to develop a vaccine against a rare disease.
   In addition, long-term market evaluation and return on
   investment are often difficult to estimate because of
   the unpredictable nature of disease outbreaks and
   vector dynamics. Growing in-house expenditures
   associated with research and development projects in a
   complex legal and regulatory environment prompt most
   pharmaceutical companies to prioritize their projects
   and streamline their product portfolio (3). The same is
   true in the public health sector where the appearance
   of an orphan vaccine would increase the already tough
   competition for resources, as evidenced by the present
   shortcomings in developing countries' use of current
   and candidate Expanded Program of Immunization (EPI)
   vaccines (hepatitis B, measles, yellow fever,
   Haemophilus influenzae type b).

   Vaccine Pricing

   It has been repeatedly shown that one of the most
   accurate predictors of the successful use of an EPI
   vaccine, such as hepatitis B, is not necessarily the
   endemicity of the disease but instead the vaccine cost
   per dose (4,5). Thus, the research, development,
   production, marketing, and distribution of a safe and
   effective vaccine should be assessed to determine if
   its potential cost per dose would be acceptable in an
   already difficult marketplace (4). The limited economic
   prospects and size of the market, with probably no
   prospect for economies of scale in production, are
   particularly relevant in the vaccine industry. Economic
   models of vaccine production have shown an inverse
   relationship between the number of doses produced and
   the cost per dose (6). As a consequence, a tiered
   pricing strategy has been endorsed by the World Health
   Organization (WHO), in which high-cost but low-volume
   vaccine sales in industrialized countries could
   subsidize the low cost and larger volume of sales in
   developing countries, although this may not be feasible
   if the quantity of vaccines needed in developing
   countries is low (6,7).

   Patent Protection and Product Liability

   Introduction of new vaccines relies heavily on the
   strategic use of intellectual property rights to
   reassure investors that a candidate vaccine will
   provide a fair return on invested funds. The lack of
   patent protection or legal framework for intellectual
   property rights in some developing countries interferes
   with the long-term viability of a vaccine. In Western
   countries, liability issues associated with a candidate
   vaccine and its intended population (8) also affect
   development costs.

   Orphan Drugs and Vaccines Situation in the United
   States

   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.

   Orphan Drug Incentives

   To further encourage orphan drug availability,
   accompanying market-oriented incentives for orphan drug
   development were issued by the Office of Orphan
   Products Development, under the auspices of FDA (11).
   The sponsor makes the request for orphan drug status
   (before filing a New Drug Application or a Product
   License Application) on the basis of information and
   circumstances at the time the request is submitted.

   Funds for research through Orphan Products Grants
   Programs benefit from a 50% deduction tax credit for
   clinical trial expenses (9) and a market exclusivity of
   7 years. Protocol assistance in the form of written
   recommendations from the secretary of the Department of
   Health and Human Services for the nonclinical and
   clinical investigations needed for marketing approval
   are provided to accelerate the approval process. In
   this respect, a flexible approach has been adopted for
   the development of orphan drugs. For example, the
   preclinical dossier (i.e., the pharmaceutical and
   pharmacotoxologic data included in the registration
   file) may not have to include data on animal toxicity,
   and teratogenicity or carcinogenicity results may be
   waived in some cases (12). This flexibility in the
   registration requirements can be applied in certain
   cases to expedite the approval process but cannot be
   used in instances where it could compromise the safety
   of the consumer.

   The legislation states that the clinical dossier of an
   orphan drug or vaccine should be built on a realistic
   assessment of the qualitative and quantitative nature
   of the studies that can be performed. This measure is
   relevant because the orphan nature of the disease and
   its prevalence in regions with limited medical
   facilities and services may make it difficult to
   recruit a large enough number of qualified participants
   for a clinical trial. On the other hand, the drawback
   of basing a clinical dossier on a limited amount of
   data is the obvious difficulty in evaluating the safety
   profile of an orphan product with sufficient
   statistical confidence. On average, orphan drugs may be
   associated with greater hazard than other products. For
   example, during clinical testing, 31% of orphan drugs
   on the market had more pronounced adverse effects than
   nonorphan medicinal products (13). Likewise, after FDA
   approval, 13% of orphan products provoked more side
   effects than anticipated.

   To encourage development of novel orphan compounds, FDA
   stipulated that two products would be considered the
   same (and thus the latter one would not qualify for the
   incentives in the Orphan Drug Act), unless the second
   product was shown to be clinically superior to the
   first. This stipulation provides a clear incentive for
   the original manufacturer of a product likely to be
   reproduced, who funds the full costs of research and
   development. For example, in the case of two live,
   attenuated viral vaccines, only the first would be
   granted orphan status for a given preventive
   indication, unless the second vaccine proved clinically
   superior.

   Liability Coverage

   Although not definitely clarified, proposals have been
   made to solve some specific liability issues, including
   design defects, duty to warn, negligence in testing or
   manufacturing, and defining responsibility for no-fault
   injury (13). The National Vaccine Compensation Program
   (issued in 1986), which provides no-fault compensation
   for vaccine-related injuries, is financed by a trust
   fund created by an excise tax on every dose of vaccine
   sold (14).

   Orphan Drugs and Vaccines in Europe

   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.

   Orphan Drugs in Other Industrialized Countries

   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).

   Orphan Vaccines in Developing Countries

   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.

   Increasing Orphan Vaccine Availability

   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.

Table. Solutions and proposals for accelerating
orphan vaccine availability

1. Provide information, prioritize, and secure demand

  * Increase awareness of disease: set-up of special
    interest groups (patients, parents,
    professionals), expert groups, and national
    forums.
  * Acquire epidemiologic data on selected
    infectious diseases to guide decision-making:
    obtain access to data registries with comparable
    case-definitions across countries, and obtain
    information from specialized units and experts,
    scientific literature, patient organizations,and
    pharmaceutical manufacturers associations.
  * Establish the suitability of vaccine prevention
    vs. other options: realistic comparisons of
    vaccination with patterns and costs of other
    alternatives, such as treatment or vector
    control.
  * Ensure political support for orphan vaccine
    initiatives and organize tripartite partnerships
    between public, private, and nongovernmental
    sectors.

2. Facilitate vaccine research and development and
national/regional approvals

  * Promote innovative research and development
    technologies that could be applied to
    blockbuster vaccines or, alternatively, promote
    low-cost traditional vaccine technologies.
  * Encourage public/private sector links:
    academic/industrial research groups.
  * Set international standards of quality, safety,
    and efficacy and define minimum amount of data
    required for licensure.
  * Make recommendations on appropriate schedules,
    target ages.
  * Promote national and regional ex-U.S. and
    European Community incentives on Orphan Drug
    Policies (Latin America, Asia).
  * Expand and harmonize orphan drug policies as
    part of the ICH process (decrease time to
    regulatory approval).

3. Ensure market/funding visibility, production and
distribution

  * Reduce investment risks for manufacturers by
    providing realistic demand estimates.
  * Fund development of orphan vaccines for
    developing countries through various
    institutional bodies, such as CVI, WHO, UNICEF,
    PAHO, WB, USAID, NIH, CDC, PATH, other donor
    bodies, and nongovernmental organizations and
    foundations (e.g., Gates Foundation) on the
    basis of target assistance for the neediest
    countries based on total gross national product.
  * Strengthen political and public health
    collaboration between orphan programs (European
    Community, United States) and other countries to
    create a supranational office dedicated to
    orphan vaccines (World Office of Orphan Vaccine
    Development or CVI) that could harmonize and
    coordinate funding (from research to
    manufacturing) from various sources.
  * Identify and expand the pool of the committed
    purchasers based on expected coverage criteria.
  * Promote and support protection of intellectual
    property.
  * Clarify compensation programs that may assume
    responsibility for liability.
  * Evaluate tiered pricing (high/low) feasibility
    at two levels:
  * Multinational: traveler or military vaccines in
    industrialized countries, endemic community
    vaccines in developing countries.
  * National: a private market for the high GNP per
    capita subgroup, a public market for the low GNP
    per capita subgroup.
  * Establish manufacturing strategies, such as
    campaigning to subsidize orphan vaccine cost
    investments by large volume sales of EPI
    vaccines.
  * Strengthen the vaccine distribution network for
    the targeted population.

    ICH, International Conference on Harmonization; CVI,
    Children's Vaccine Initiative; WHO, World Health
    Organization; UNICEF, United Nation's Children's
    Fund; PAHO, PanAmerican Health Organization; WB,
    World Bank; USAID, U.S. Agency for International
    Development; NIH, National Institutes of Health; CDC,
    Centers for Disease Control and Prevention; PATH,
    Program for Appropriate Technology in Health; EPI,
    Expanded Program of Immunization.

   Providing Information, Prioritizing, and Securing
   Demand

   Although funding is a major obstacle to orphan vaccine
   development, it may not be the only impediment to the
   introduction of new vaccines (25). Reliable information
   on the epidemiology, disease severity, and effect on
   public health is essential to substantiating the need
   for a vaccine and may not be available to support the
   development decision. Market forces may not always be
   good cultivators of vaccines, which, unlike some
   chemical drugs, are not big money-making products. For
   this reason, the public and decision makers should know
   about the benefits of immunization, to increase disease
   awareness, and support an orphan vaccine initiative.

   Facilitating Vaccine Research and Development and
   National and Regional Approvals

   An accelerated procedure for final authorization and
   exemptions from all or part of the registration fee can
   reduce development costs, staffing requirements, and
   time to market and render the development of an orphan
   vaccine more attractive for the sponsor. Local
   initiatives may also speed the authorization process.

   Ensuring Market and Funding Visibility, Production, and
   Distribution

   Finally, increasing patent protection and the defined
   period of market exclusivity reduces investment risks
   for manufacturers. Furthermore, funding for orphan
   projects may be advanced from private bodies looking to
   capitalize on an ethical business image. Indeed, the
   private sector looks to take on an increasingly
   important role in international health development,
   especially in poorer countries (26). Increased world
   travel and the risk for transport of pathogens across
   borders (27) support tiered pricing between the western
   traveler and the disease-endemic country. In addition,
   an orphan infectious agent in a remote developing
   country requiring an orphan vaccine with limited need
   could, over time, become an emerging disease worldwide.
   HIV is a case in point: a disease originating in Africa
   that has successfully spread to the industrialized
   world.

   In Argentina, strong political and governmental
   support, aided by the U.S. Army Medical Research
   Institute of Infectious Diseases collaboration,
   ultimately culminated in a successful Candid 1
   vaccination campaign against Argentinean hemorrhagic
   fever in agricultural workers (28). Close collaboration
   between the pharmaceutical sector, WHO, and the Chinese
   government resulted in the development of the
   antimalarial drug artemisin (29).

   Conclusions

   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.

   Acknowledgments

   The authors thank Stanley Plotkin and the two reviewers
   whose constructive criticism and advice helped to
   improve this manuscript.

   Dr. Lang is a researcher at Pasteur Mrieux Connaught,
   the vaccine manufacturer. His clinical research
   interests include rabies, dengue, Japanese
   encephalitis, yellow fever, malaria, and antivenoms as
   part of the Vector Borne Vaccine Clinical Research and
   Development Program.

   Dr. Wood is responsible for education in vaccinology
   and vaccine policy for the international business unit
   of Pasteur Mrieux Connaught, which covers all
   countries outside Western Europe and North America.

   Address for correspondence: Jean Lang, Vector-Borne
   Diseases Clinical Program, R&D Clinical Development
   Department, Pasteur Mrieux Connaught, Lyon, France;
   fax: 33-47-273-7928; e-mail: jlang@fr.pmc-vacc.com.

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Emerging Infectious Diseases
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Atlanta, GA

URL: http://www.cdc.gov/ncidod/eid/vol5no6/ascii/lang.txt

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