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Establishment of a national vaccine authority

Note: This report represents information on this subject as of December 1996.

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Resolution 416 (A-94) asks the American Medical Association (AMA) to review the 1993 Institute of Medicine (IOM) report,  The Children's Vaccine Initiative: Achieving the Vision,1 to assess whether the United States Public Health Service has a sufficiently broad mandate to encourage the vaccine development process and, further, to examine the strategy for the development of vaccines of limited commercial value in the United States, but of potentially great value to worldwide public health. The Council on Scientific Affairs was asked to prepare a report for the House of Delegates in response to this resolution. This report provides background on the IOM report and the Committee's recommendation to establish a National Vaccine Authority. It includes responses from leaders in the vaccine manufacturing industry, academia, and the federal government regarding US strategies to develop vaccines of global public health interest.

Background

The concept of the Children's Vaccine Initiative (CVI) was launched in 1990 at the meeting of the World Summit for Children in New York City. The CVI's purpose was to harness new technologies to advance the immunization of children. It was considered that the ideal vaccine would be given as a single dose, effective when given near birth, heat stable, contain multiple antigens, effective against diseases not currently targeted, and affordable. The US Agency for International Development (AID) and the US Public Health Service, the two agencies charged with the responsibility for formulating the US response to the CVI, requested that the IOM prepare a report advising them on how to maximize US private- and public-sector participation in the CVI. The IOM, together with six US Public Health entities, the Pharmaceutical Manufacturers Association, the United Nations Development Program, and the World Health Organization CVI conducted an 18-month study to: 

  • "identify and explore major economic, legal, regulatory, policy, and other factors that influence, both negatively and positively, the development, production, introduction, and supply of vaccines; and   
  • recommend ways to enhance cooperation and participation among all relevant US sectors in the realization of the CVI." 

The 18-member Committee of the IOM issued its report, cited above, in 1993. A section of that report entitled,  A Strategy to Enhance US Participation in the Children's Vaccine Initiative, recommended the establishment of a National Vaccine Authority (NVA) that would encourage the development, production, and procurement of new and improved vaccines of limited commercial potential, but of global public health need. The Committee considered three strategies to enhance US public- and private-sector participation in the CVI and to ensure that appropriate vaccines were developed, manufactured, and made available to national immunization programs in developing countries: 

  • provide supplemental funds to existing federal agencies to support CVI-related activities;   
  • increase the federal government's role in all phases of vaccine development;   
  • establish effective partnerships among government, universities, and the private-sector (e.g., biotechnology firms, vaccine manufacturers). 

The first two strategies were rejected because neither capitalized on the strengths and expertise of the emerging biotechnology firms and vaccine manufacturers, and neither strategy was considered to result in the timely development, production, and introduction of affordable vaccines to developing countries. In the Committee's opinion, the optimal way to maximize public- and private-sector participation in global CVI programs was to empower an entity to organize and manage an integrated process of CVI vaccine development and manufacture that had the capability and the mandate to manage the vaccine development process from beginning to end. Further, it was the Committee's view that the development of new and improved vaccines for use in both industrialized nations and the developing world was unlikely to occur unless there was an entity that had the mandate to manage and oversee the process from start to finish.

As envisioned by the IOM, the NVA would be an organization within the government with the capability of reducing costs and risks to industry associated with the development of CVI vaccines. It would encourage private-sector firms and academic and public-sector entities to develop products required for the CVI and also would have an in-house capability to conduct applied research and development and manufacture pilot lots of vaccine. Activities also might include guaranteed purchases of vaccine, investment-tax credits for firms undertaking CVI-related activities, access to an NVA pilot production facility, financial and technical assistance with clinical trials, and provisions for limiting liability. The NVA would retain the right to transfer the technology that it owned to developing countries in its agreements with private-sector partners.

The NVA would support six areas of vaccine product development: 

  • "vaccines used primarily in developing countries (e.g., shigella, cholera, salmonella, malaria, and dengue);   
  • improvements in existing vaccines which, while not leading to a high market return, would make them easier to distribute and administer or that would allow them to achieve immunity earlier in high-risk populations (e.g., heat-stable polio, single-dose controlled-release tetanus toxoid and other childhood vaccines, and a more immunogenic measles vaccine);   
  • development of simple, low-cost vaccine manufacturing technologies that could be transferred easily to vaccine manufacturers in developing countries;   
  • exploitation of vaccine technologies that are nonproprietary and, therefore, of little interest to commercial manufacturers who desire market exclusivity;   
  • adaptation and introduction of currently available vaccines (e.g., pneumococcal conjugates) and new vaccines, including combination vaccines, to developing countries;   
  • vaccines for which there are small or limited markets or that are otherwise unprofitable." 

The Committee felt that the US system of vaccine research, while producing high-quality vaccines for the domestic market, was not likely to produce the majority of CVI vaccines because most of these are targeted to developing countries that lack the market potential of vaccines intended for industrialized country markets. The Committee determined that a major bottleneck in the development of low-profit vaccines was the lack of pilot production facilities that were capable of meeting the Food and Drug Administration's (FDA) standards of current Good Manufacturing Practices. It felt that pilot manufacture of vaccine products of low commercial value was postponed for months or even years in commercial facilities, while the small number of public-sector facilities remained oversubscribed.

The Committee estimated that the initial start-up costs for the NVA could range from $30 million to $75 million. Each year the NVA would require between $25 million and $45 million for grants, contracts, cooperative agreements, and other mechanisms to support its goals. The annual operating budget was estimated at $30 million, assuming a complement of 150-200 full-time staff and operating costs of $150,000-$200,000 per person. A total budget of $55 million to $75 million would be required. It was suggested that the NVA also could subsidize vaccine prices paid by UNICEF and other agencies and could provide higher returns to private developers and manufacturers where appropriate. 

Response of vaccine manufacturers

Nearly all of the vaccines produced in this country are made by private manufacturers (in the public sector, only Massachusetts and Michigan currently produce selected vaccines). Since this situation is unlikely to change in the near future, the AMA contacted the four US vaccine manufacturers (Connaught Laboratories, Inc., Lederle-Praxis Biologicals, Merck & Co., Inc. and Smith-Kline Beecham Pharmaceuticals) to solicit their comments regarding the IOM proposal to establish a National Vaccine Authority. The two respondents, Lederle-Praxis and Merck & Co., Inc, are major producers of vaccines in the United States and have been involved in a number of national vaccine committees. While there were some minor differences of opinion between the designated spokespersons of these two companies,2 there was substantial agreement between them. Their comments are summarized in the following paragraphs: 

  • Both felt that the IOM report was a good report but were not enamored at the prospect of there being yet another government authority involved in vaccine issues. It was felt that there is a dearth of collaborative forums in which all of the interested parties could share an agenda, put together long-range plans, establish long-term scenarios, and develop work plans. Such a forum would be better indicated by the word "commission" rather than "authority." The only such forum that currently exists was suggested to be the National Vaccine Advisory Committee (NVAC).   
  • It was felt that the Committee's proposal for a role of an NVA that would include a new government-funded and -operated applied research and pilot production facility was quite problematic. It was expressed that the Committee had underestimated the existing capabilities for such activities in the private sector and inadequately assessed the high risks and costs of such a mission. This recommendation was made without much evidence that the industry would fail to respond to appropriate grants or contracts or other inducements to provide or create such facilities.   
  • It was strongly believed that the IOM Committee grossly underestimated the investment required to build, equip, maintain, and staff a new "stand-alone" research and pilot production facility. It was also pointed out that it would take the same time (i.e., 3 to 5 years) to build and validate the proposed IOM facility as it would a new manufacturing facility. In addition, the Committee had not considered how, because of new technology, future upgrades of the facility would be funded.   
  • Both manufacturers felt that there was no real shortage of pilot plant production facilities in the United States and recommended that this issue be further studied. Prior to making a recommendation to build a government-operated pilot plant facility, it was suggested that a committee fully evaluate the potential in the private sector for expansion of overall vaccine R&D capability in response to a mix of legislative mandates and financial subsidies.   
  • Although the concept appeared acceptable, technology transfer from the United States to a developing nation was seen to be a very complicated issue. Technology is now developing at a very rapid pace. Transferring technology to an underdeveloped country, even if it is feasible, may not be workable. Such countries may not have a good educational base or a good infrastructure to support the kind of technology that could be transferred. It was stated that a more intermediary type of transfer of technology (e.g., shipping of a highly technologic bulk vaccine for filling, packaging and labeling) may be more appropriate. Finally, it seemed to the manufacturers that the whole concept of technology transfer depends on the extent to which the US government wants to be a part of a global health improvement effort.   
  • The manufacturers agreed with the IOM  Committee that the United States has a responsibility to support vaccine development for the Third World and that the stimulation and integration of the US response to the needs of the Third World is an appropriate role for the US Government, with the US contribution to be integrated with the contributions of many other nations. 

AMA staff also contacted the directors of the two state-run vaccine manufacturers about the IOM report and the proposed National Vaccine Authority. Both officials indicated that the IOM proposal was reasonable and could provide a needed impetus for improving the funding of state laboratory and production facilities.3 Both directors emphasized that their states would be unable to continue funding their vaccine production facilities in the future without additional (outside) support. 

An alternative recommendation

In one of a series of articles on immunization issues that appeared in  Science in September of 1994, Barry R. Bloom, PhD, Professor of Microbiology and Immunology at the Albert Einstein College of Medicine, Bronx, New York, addressed the question of the NVA recommended by the IOM Committee.4 He indicated that immunization is a complex and fragile enterprise and argued that it is possible within existing legislation and funding to establish a national vaccine authority with the ability to facilitate planning, coordination, public information, government-industry cooperation, and resolution of immunization issues. 

Dr. Bloom points out that the development, testing, production, distribution, and use of vaccines in the United States depends on the functioning of more than 20 federal agencies, as well as state departments of health, vaccine manufacturers, biotechnology companies, professional medical societies, voluntary organizations, and large numbers of public and private health care personnel. The government agencies involved include the FDA and its advisory committees and the Centers for Disease Control and Prevention (CDC) and its Advisory Committee for Immunization Practices (ACIP). The CDC also oversees the public distribution of vaccines and allocates federal resources to the states for immunization programs. Other government agencies involved include the Advisory Commission on Childhood Vaccines (ACCV), which acts under the National Vaccine Injury Compensation Act to make recommendations on compensation for adverse effects of vaccines; the National Institutes of Health (NIH), which primarily is responsible for research and scientific development of new vaccines; and the Department of Defense (DoD), which is concerned with military vaccine needs and global emergencies. Ultimately, however, private industry determines which vaccines will be developed and produced, and establishes their cost. Dr. Bloom concludes that in this complex enterprise major government agencies tend to compete with each other, the vaccine manufacturers seek to maximize profits, and the public is ill-informed and confused.

Dr. Bloom cites two key issues that may affect US participation in the Children's Vaccine Initiative: 

  • In 1980, there were 14 vaccine manufacturers in the United States but by 1989 there were only four major producers. This result came about largely because of problems with liability and profitability. Industry fears that the 1993 Omnibus Budget Reconciliation Act, which placed price caps on vaccines and allowed states to purchase vaccines at a lower fixed price, will reduce their resources for R&D, and the biotechnology companies fear that such measures will greatly affect their ability to raise venture capital for new vaccines.   
  • UNICEF purchases vaccines for this program at discounted prices from approximately 12 manufacturers in Europe, Canada, and Japan and supplies about 40 percent of all the vaccines in developing countries. However, no US manufacturers bid on UNICEF contracts in part because they were excoriated in congressional hearings for charging higher prices in the United States and lower prices to the Third World. This position was taken by Congress despite the fact that a UNICEF study concluded that such a multi-tiered pricing system had overall positive effects for everyone.5 This system allows developing countries to obtain at affordable prices the most cost-effective intervention to protect the health of their children and enables the manufacturers to benefit from the economies of scale and to produce vaccines at lower unit cost. Under the multi-tiered pricing system, the upper tiers act as an understood subsidy for the needy children of the world to obtain necessary vaccines. 

To address these and other vaccine issues, Dr. Bloom suggests that a National Vaccine Commission be constructed from the existing National Vaccine Advisory Committee (NVAC). The NVAC reports to the Assistant Secretary for Health and is charged to recommend ways to increase the availability of vaccines in the United States, to recommend research priorities, and to identify important areas where government and nongovernment cooperative action is required. Members include vaccine manufacturers, clinicians, academics, public health officials, and members of the lay public, as well as liaison representatives from the NIH, CDC, FDA, AID, and DoD. Thus, the NVAC currently is the only forum that includes all of the players involved in childhood immunizations.

The National Vaccine Commission (NVC) should have the potential to provide the leadership and coordination needed for an effective national vaccine program. The responsibilities of the new NVC would be to provide scientific expertise and guidance to government agencies, as well as accurate information to the public about immunization policies and practices. Specifically, Dr. Bloom recommends that the NVC should: 

  • serve as a forum in which all the major vaccine players are brought together;   
  • formulate recommendations on vaccine policy and priorities;   
  • interact with the global Children's Vaccine Initiative;   
  • provide support and continuity for ongoing efforts in government agencies and industry;   
  • promote cooperation between the government and private sector in vaccine efforts; and   
  • assure that the government obtains a good value for the public funds it invests. 

According to Dr. Bloom, the authority of the NVC would derive from the power of an independent group with wide vaccine expertise and experience that is charged with representing the public interest, both domestic and global. If there is no commercial interest, the NVC should have the authority to coordinate public and private resources and ensure the necessary cooperation to initiate the production of vaccines urgently required for developing countries and for emergent microbial threats to the United States. The budget for the NVC should be sufficient to maintain a small, competent staff to research major policy, innovation, and implementation issues. However, it should have access to funds that can be rapidly mobilized when there are national needs or emergencies. Dr. Bloom suggests that these additional funds be taken from any excess in the trust established under the National Vaccine Injury Compensation Act.

Establishing partnerships

According to a CDC official, the NVAC has had ongoing discussions regarding the establishment of partnerships between the sectors involved in vaccine research, development, and administration to specifically discuss issues raised in this report.6 The CDC is preparing two documents which can serve as a blueprint for future vaccine activities. The first report addresses the development of partnerships between the public and private sectors and academia; the second report deals with future vaccine procurement policies and options.

The CDC official added that the National Vaccine Program Office (NVPO) could serve as a focus for convening a study group to examine issues raised in this report and expressed interest in AMA's participation in such a forum. The NVPO is responsible for facilitating the coordination of vaccine-related activities among federal-sector partners and provides staff support to the NVAC and (through the NVAC, and in conjunction with CDC's National Immunization Program) has already begun discussions with vaccine manufacturers regarding many of the issues raised in this report. 

Commentary

The Council on Scientific Affairs feels that currently, there is no properly functioning comprehensive national strategy for ensuring and coordinating the development of vaccines of limited commercial value in the United States, but of potential great value to worldwide public health. It is for this reason that the IOM committee referred to in this report recommended the establishment of a National Vaccine Authority. However, there are problems with this proposal as well as the one from the academic community for the development of a National Vaccine Commission.

The Council received comments from leading vaccine manufacturers indicating sufficient discomfort to warrant a re-examination of the proposed NVA and careful study and possible modification of the proposed NVC. It does not appear that there is a sufficient mandate to encourage the vaccine development process under the proposed NVA among all the players in the vaccine development area, especially the manufacturers who play a critical role in the whole process. The IOM Committee's proposal that the NVA's role include a new government-funded and -operated research and pilot production facility seems unreasonable in view of the potential cost for building, maintaining, staffing, and updating such a facility. Further, there are no data to suggest that such a facility is even necessary in view of the capabilities of the private sector. Stimulation of this sector to develop additional or improved facilities through grants and contracts appears to be a more reasonable course of action. 

The NVC, as proposed by Dr. Bloom, is an attractive alternative to the NVA, but more needs to be done to refine the operations of this Commission. Establishing the NVAC as the new NVC is a good idea as it would provide both a home and a forum for all players in the vaccine effort. The NVAC is concerned with enhancing vaccine research and development, expanding coverage of recommended vaccines in the United States, and enhancing vaccine safety. While the NVAC is well constituted to address the issues raised by the Council on Scientific Affairs in this report, it lacks the authority, staff, or budget to set priorities and coordinate or fund research and development.7

It is not clear how the NVC would acquire the resources needed "to initiate the production of urgently required vaccines and for emergent microbial threats to the United States." It also is not clear how this body would interact on a global basis to meet worldwide needs. Funding for the NVC is another problem, especially regarding the need for emergency funds to meet pressing national needs or emergencies that may arise. Such "no year" funding will be difficult to obtain from Congress. Dr. Bloom's suggestion that funds be accumulated in the current trust fund created in the National Vaccine Injury Compensation Program beyond the level needed to assure coverage of projected injury claims could only be done by increasing the current excise tax on vaccines, thus increasing their cost. This could act as an impediment to national immunization programs.

Although the discovery of a process for making a new vaccine can occur in academia or in one of the government research laboratories, the development and production of nearly all vaccines for the public in the United States occurs primarily in the private sector. Vaccine manufacturers, understandably, are profit driven, as indeed they must be. Various studies have shown that the private sector clearly is a more cost-effective producer of vaccines than the public sector. Vaccine manufacturers are pivotal in any immunization program and, thus, it is essential that they always be adequately represented on national vaccine committees, commissions, or authorities that formulate policies and develop strategies. This is especially true in the planning stages for such bodies.

According to the current NVAC chairperson, Edgar K. Marcuse, MD, MPH, the central policy question is the extent to which the United States is interested in global public health and particularly child health. The benefits of sustained meaningful funding of vaccine programs (e.g, for the control of malaria, tuberculosis, and rotavirus diarrhea) in less developed countries are not generally appreciated in the United States and require that Congress and the public have a better understanding of why such programs are of national interest both from economic and public health perspectives.7 

Recommendations

The following actions, recommended by the Council on Scientific Affairs, were approved by the AMA House of Delegates at the 1996 AMA Interim Meeting. 

  1. The AMA encourages the US Public Health Service to form a study group, consisting of experts in vaccinology and including vaccine manufacturers, to carefully examine proposals that can provide the necessary leadership to facilitate and encourage the vaccine development process in a cost-effective manner and develop rational strategies for the development, production, and procurement of new and improved vaccines, which may have limited commercial value in the United States but potentially significant value to global public health.  
  2. The AMA will monitor the deliberations of the study group and interact with it as appropriate.   
  3. The AMA will carefully examine the final report of the study group, support the recommendations with which it agrees, and publicize its support. 

References

1. Committee on the Children's Vaccine Initiative: Planning Alternative Strategies Toward Full US Participation, Institute of Medicine.  The Children's Vaccine Initiative: Achieving the Vision. Washington, DC: National Academy Press;1993. 
2. Saldarini R. President, Lederle-Praxis Biologicals. Personal Communication. December, 1994. 
3.Vernon TM. Executive Director, Medical, Scientific and Public Health Affairs, Merck & Co, Inc. Personal Communication. November, 1994.
4. Grady GF. Former Assistant Commissioner and Director of Laboratories, Massachusetts Department of Health. Personal communication. May, 1995. 
5.Myers R. Director, Michigan Biologics Laboratories, Michigan Department of Public Health. Personal communication. September, 1995. 
6. Bloom BR. The United States needs a national vaccine authority.  Science. 1994;265:1378-1380.
7. National Vaccine Advisory Committee.  Developing a National Childhood Immunization Information System: Registries, Reminders, and Recall. Washington, DC: US Department of Health and Human Services;1994. Cited by Bloom above.
8. Snider Jr DE. Associate Director for Science, Office of the Director, Centers for Disease Control and Prevention. Personal Communication. August, 1996. 
9. Marcuse EK. Director, Ambulatory Care Services, Children's Hospital and Medical Center, Professor of Pediatrics, University of Washington School of Medicine. Personal Communication. August, 1996.

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