Orphans and Incentives: Developing Technology to Address Emerging Infections (1997)

Since it is hard to predict those diseases that may have future significance, worldwide and in the United States, CDC emphasizes preparedness. The CDC strategy for addressing emerging infectious diseases derives from recommendations in the 1992 IOM report and is structured around four goals:

Goal 1: To improve surveillance and response capacity.

Goal 2: To address applied research needs.

Goal 3: To strengthen prevention and control programs.

Goal 4: To repair public health infrastructure at local, state, national, and international levels.

• CDC's extramural research program, halted in 1973, was reinstated at a level of $800,000 for FY97. Funding priority is assigned to research projects focused on:
• • antimicrobial resistance (including mechanisms of resistance, development of better diagnostics, and strategies to improve prescribing practices); and
  • tickborne disease (Ehrlichia and Babesia).
• Founding role in development and implementation of the CISET report.
• Organization and implementation of three sentinel networks: a physician network in collaboration with the Infectious Disease Society of America; one with the International Society of Travel Medicine; and one with a network of 11 academically based emergency departments in the United States, each focused on diseases and syndromes identified in their particular environment.

The CISET report represents collaborative thinking by 17 different federal agencies about how to work more effectively, together and with the private sector, toward implementing the CISET plan without duplicating efforts. At the operational level, interactions between CDC, NIH, FDA, and DOD are good.

CDC's core infectious disease budget decreased in real dollars through the 1980s into the early 1990s, but that trend was reversed in the last three budget years. The cost of implementing the CDC emerging infectious disease strategy is estimated at $125 million annually.

For FY97, the agency received an appropriation of $44 million toward implementation of the strategy, including international sentinel activity. The bulk of funds goes to domestic issues, but the plan is to allocate a higher proportion in each successive year to global needs.

CDC has requested an increase in the FY98 budget of $25 million, $15 million for emerging infectious diseases and $10 million for food safety.

• Continuing need to engage the private sector more effectively than in the past.
• Need to collect good data on drug resistance trends in community-acquired infections, since resistance appears to have been a factor in some of the mortality associated with pneumonia, diarrhea, tuberculosis, malaria, and perhaps HIV.
• The Public Health Service Act authorizes CDC to be involved internationally in epidemics and other unspecified high-priority situations. The agency, with the support of the Secretary of Health, has been trying to influence legislation that would provide a clearer international mandate, permit earlier involvement in crisis situations, and allow specific appropriations for international work, particularly as related to infectious diseases with a potential impact on the United States and to "bioterrorism."
• Aging, overcrowding, compromised security and safety, and general deterioration of the federal, state, and local public health laboratories.
• Need for a new laboratory for research on infectious pathogens requiring medium- to high-level containment.

Use of biological agents in combat and terrorist events, and development in some countries of offensive biowarfare capability motivated recent entry into biowarfare defense by DARPA, DOD's principal R&D agency. The overall goal of DARPA's Biological Warfare Defense Program is to reduce threat of biological weapons (including bacterial, viral, and bioengineered organisms) as factor in U.S. military operations. Its objective is to foster development of innovative technologies with potentially high payoff, even if also high risk, and to mobilize biotechnology industry capabilities to that end.

DARPA's R&D program in this area has four major thrusts:

1. Real-time sensing (detectors).
2. Informatics, with emphasis on integrating information systems into field awareness and logistics systems.
3. Advanced diagnostics: development of rapid diagnostic tests (e.g., array based) permitting real-time identification of responsible organisms/toxins and capable of diagnosing presently unknown or bioengineered agents (a new program).
4. Pathogen countermeasures (development of multiagent yet specific advanced therapeutics) to target common mechanisms of pathogenesis and functions or structures shared by groups of pathogens, or to modulate human biological response to pathogens; also interest in mucosal defense and countermeasures against toxins and mid-spectrum agents.

5. Implementation

   • Broad agency announcements, with committed funding, in program areas; current solicitations, until September 1997, in pathogen countermeasures and advanced diagnostics.
   • Information available on World Wide Web (http://www.darpa.mil).
   • DARPA remains strongly committed to protecting proprietary business information and intellectual property rights of inventors. It has developed instruments to ensure inventors and producers of retention of those rights and to provide other incentives for commercialization, while also ensuring government access to the products involved. DARPA prefers to have most of its work open and publishable rather than classified. It has also been given special latitude with respect to regulations that have discouraged industrial involvement heretofore, and its legal and contracting offices have worked to reduce paperwork and adopt procedures more akin to standard commercial arrangements.

• DARPA is also dedicated to rewarding good performance with renewed and often increased support.

DARPA has a unique mission to anticipate and develop breakthrough technologies for the future, thus complementing work at other DOD agencies, CDC, and NIH.

DARPA has traditionally worked closely with other agencies and industry in microelectronics, materials science, and other high-tech areas. The agency hopes that its approach to targeting potential threats and focusing on mechanisms of pathogenesis or underlying mechanisms of disease will offer opportunities for commercialization and seeks to work closely with other agencies and the industrial community to help in transition of these products to commercial use.

DARPA is an extramural funding agency, its annual budget about $2 billion. An initial budget round allocated $20 million to the pathogen countermeasures program, with two more announcements (pathogen countermeasures and advanced diagnostics) in 1997, at about $25 to $30 million each).

• Developing partnerships (including an industrial advisory panel) with these objectives:
• • fostering and sustaining liaisons with the industrial community;
  • identifying promising new areas;
  • keeping the agency abreast of state-of-the-art technologies;
  • identifying gaps in DARPA's biological warfare defense program; and
  • partnering on technology development and transition planning.
• Facilitating development of products resulting from the research it supports.
• Developing a community in the relevant R&D areas, with partners including industry, academic researchers, and government.

NIAID has five goals in three broad areas.

Areas:

1. Increasing basic understanding of complex interactions among environment, microbe, and host influencing emergence.
2. Strengthening ability to develop and validate new prevention and control strategies.
3. Ensuring maintenance of research and training infrastructure adequate to meet current and future needs.

• Program announcements, with funding behind them, to stimulate research in emerging infections.
• Support for special programs in areas such as clinical trials and international research.
• Allocation by NIH director of $3 million of own FY97 reserve to establish emerging diseases research networks that encourage interactions and collaborations among investigators working on related research issues, and to expand international research on emerging and reemerging diseases, including opportunities for young U.S. physicians and scientists to gain research experience working in areas where these diseases are currently found.

• Clinical and regulatory affairs group dedicated to interacting with the FDA on investigational new drugs, and harmonization.
• Support of intramural and extramural facilities for production of pilot lots of drugs and vaccines, toxicity and other preclinical testing, as well as clinical trials.
• Diseases being addressed through various funding mechanisms available to NIAID include arboviral diseases, aspergillosis, cholera, ehrlichiosis, emerging viral infections, hantavirus, Helicobacter pylori, hepatitis C, Lyme disease, measles, mycoses, plague, respiratory pathogens, STDs, streptococcal infections, and TB.

• Under U.S.-Japan Cooperative Medical Science Program, organized international conferences (1996, 1997) on emerging diseases, with State Department, USDA, CDC, Japanese Ministries of Health and Welfare and Foreign Affairs.
• Support of cellular pertussis vaccine clinical trials overseas.
• Awarded grant supplements for use of remote-sensing geographic information systems to predict infectious diseases distribution, in collaboration with NASA (FY95).
• Cooperative Research and Development Agreements and other less formal relationships with the private sector.
• Contracts with clinical trial groups, such as viral encephalitis, now expanded to herpes viruses and hepatitis; coordinated clinical trial network on fungal infections.
• Collaboration with Burroughs-Wellcome on use of acyclovir for herpetic encephalitis in infants (a small market).
• Collaboration with USAMRIID on antiviral compounds effective against Ebola.
• Organized U.S.-Italy conference on emerging diseases in 1997.
• Issued RFA and RFP for malaria vaccine development in collaboration with AID.

NIAID spent $334 million on non-AIDS infectious diseases research in FY96. Of this amount, $63 million was dedicated to emerging diseases research.

• Enhancement of complementarity and synergy between research and surveillance.
• Additional partnerships with private-sector firms and their greater capacities in development, importantly scale-up, chemistry, and manufacturing.

The State Department's interest in infectious disease is threefold. It is part of:

1. the economic agenda for foreign policy,
2. the science and technology agenda, and
3. the national security agenda.

State works to create conditions that are conducive for agencies to do science and technology research overseas, including promotion of international intellectual property rights, as well as tax and other incentives to R&D.

Infectious disease and its potential for counterterrorism are a growing concern for national security. State is working to safeguard infectious disease research activities within the foreign policy agenda. The department is also working to promote global preparedness within the context of infectious diseases, as part of both the national security and economic development agendas.

State is involved in implementing a global infectious disease surveillance response network. Its strategy stresses use of embassy officials to understand and convey the importance of the connections between human health and healthy economic development.

As part of implementation of the NSTC/CISET Report on Emerging and Re-emerging Infectious Diseases, State is working with CDC and the White House Office of Science and Technology Policy to develop methods to bring the private and public sectors together to address the problem of supply shortages and strategies for quick response to emergency situations. Three CISET task force committees have been created to implement collaborative effort on setting up a global surveillance network:

1. Surveillance and Response, cochaired by CDC and DOD;
2. Capacity Strengthening, cochaired by CDC and USAID; and
3. Research and Research Training, chaired by NIAID.

State is responsible for finalizing agreements for cooperative R&D arrangements and works continuously to create an environment that promotes voluntary compliance among nations.

In 1996 infectious diseases and HIV/AIDS were on the presidential agenda for the G-7 conference for the first time and commitments were made to collaborate to contain the spread of infectious diseases and work on a global surveillance network. At the 1997 G-7 summit, State will work to reinforce those commitments so as to translate them into provision of technical and financial resources.

State has international partnerships with the European Union under the new Transatlantic Agreement, whose agenda includes a focus on collaboration to contain infectious diseases. Similar efforts have begun with Japan, South Africa, and Russia, among others.

A U.S.-Brazil common agenda is being expanded.

Progress is being made with the Department of Commerce and the FDA to address product availability issues. A message is being drafted for the pharmaceutical industry to clarify the department's needs in this area and to suggest areas in which industry can assist in implementing department goals.

No data.

• To develop a composite message that stresses the importance of infectious diseases to each nation.
• To do better at defining public-sector interests and enhancing public awareness and knowledge of what the specific issues are, for the public and private sectors, in the United States and outside its borders.
• To create the conditions necessary for cooperation around the challenges of antimicrobial resistance.

The VA's agenda is primarily domestic, one exception to which is a congressional mandate requiring the agency to back up the military in times of disaster, including use of weapons of mass destruction.

In the area of emerging infections, the VA will be working in three priority areas:

1. Surveillance, to obtain timely data of good quality that are essential to good demographic knowledge and making decisions regarding resource allocation.
2. Intervention, as a way to develop partnerships in communities and in VA facilities, and the development of common guidelines and tools for assessing outcomes in a standardized manner.
3. Research, with emphasis on areas of mutual interest to VA and DOD.

The VA is working with two primary databases for its emerging infections surveillance initiative:

1. Annual Census. An annual census of all VA facilities has collected yearly data on specific diseases and provides good and fairly complete retrospective data. The cumbersome data-entry requirements for this census have motivated system improvements and further, dramatic improvements are expected as a consequence of the agency's new Emerging Pathogens Initiative.
2. Emerging Pathogens Initiative. This national tracking system will automatically extract specific data on pathogens and diseases of choice from VA computer systems nationwide and transmit them on a monthly basis to the appropriate location. Initially, data will be gathered on 14 diseases or pathogens, including bloodstream candida infections, clostridium difficile, cryptosporidium, E. coli 0157, some resistant organisms including penicillin-resistant pneumococcus, frankly and intermediate penicillin-resistant pneumococcus, group A streptococcus, vancomycin-resistant enterococcus, and hepatitis C antibody-positive persons. Data will also be collected on dengue, legionella, malaria, and tuberculosis.

The census system will provide numerator data. Beginning in early 1997, the VA also obtained denominator data from a rolling 12-month database typically derived from workload data, such as ICU and hospital days. The data are expected to be of fine quality and to lend themselves readily to statistical analysis, thus permitting the agency, in a more timely fashion than has

previously been the case, to track its interventions and determine whether objectives are being met.

In 1997, the agency will fund an Emerging Pathogen Research Initiative that will support investigator-initiated research. The funding level remains to be determined, but grants are currently coming in and a review process is in place.

VA will be working with DOD on a mutual research agenda.

No data.

• Problems of inconsistency of reporting data at the state level, at least partly owing to the Privacy Act and public laws related to patient privacy required by the agency's oversight group, the U.S. Congress.
• Questions as to whether treatment algorithms provided for certain diseases are, or could be, consistently followed across all 170 VA hospitals and by its thousands of physicians.
• Questions about degree to which VA databases are adequately representative of the total U.S. population.
• Possibilities for VA information base to provide useful data on susceptibilities in its populations to bacterial pathogens in the general population.

The Bank sees its primary mission as promoting socioeconomic development in low-income countries. It has increasingly come to recognize the critical role of investments in health in that development.

The Bank has recently begun to focus on prospects for integrating capitalization of health product development into its agenda, motivated by a 1995 meeting of the Committee for Health Research and Development at which needs to promote health product development for low-income countries were discussed. The Bank believes the private sector is an essential component in any such endeavor, one so far largely neglected by the public sector.

The Bank is considering a range of options for its involvement and trying to determine what gaps it might fill most usefully. A possible priority is the longstanding need for a malaria vaccine.

The Bank is modifying its policy of funding on a country-only basis to offer leeway for activities around generic, cross-cutting issues affecting a number of countries in comparable fashion. This will permit the Bank to act as a corporate entity with a corporate policy in a substantive area, in this case one encompassing health product development. It will be able to play a catalyzing role through corporate statements in support of cross-cutting health product missions (e.g., immunization).

After much consideration, the Bank has decided to focus initial activity on pharmaceuticals and vaccines, with possible later attention to development of diagnostics.

With the Rockefeller Foundation, the Bank is working to promote public-/private-sector collaboration in health product development for low-income countries. The first step was to survey high-level representatives from the pharmaceutical industry to determine what industry is and is not doing regarding infectious diseases, and to identify barriers to private-sector involvement. The survey and later discussions yielded concrete suggestions on what the public sector might do to encourage such involvement.^*

The World Bank/Rockefeller Initiative, as above.

Through its Country Assistance Strategy, the Bank can motivate attention at the country level to catalyze greater activity in areas it sees as high priority. The Bank has discussed with the Department of State the possibility of designating infectious diseases as one of those areas. The two institutions are also discussing the potential of the Bank's new policy flexibility and support for developing products for meningitis and malaria.

The Bank also co-sponsors the International AIDS Vaccine Initiative (IAVI), a fulcrum for multisectoral collaboration on a specific technology for a specific disease.

No data.

• The Bank is seeking commitments from industrial firms to take a lead in selected initiatives. At such time as a given industry expresses genuine interest, the Bank will embark on a preliminary design stage focused on two to three products to which value can be added, and/or provide support for products approaching testing in particular markets.
• The main issues emerging from the Bank's pharmaceutical industry survey were:
• • Lack of adequate information on research under way in universities, research councils, and biotechnology companies worldwide; for example, on receptors, enzymes, and compounds industry could screen to generate more product leads.
  • The need to reduce costs and duration of clinical trials without compromising safety and efficacy.
  • The need to increase market potential of products primarily for diseases in developing countries.