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Annex 3: Prioritising Pharmaceutical R&D in a Public Health Context

By Dr Warren KaplanMarch 30 2004

Background to Review Paper

It seems beyond question that for even the most developed countries, the demand for healthcare outweighs the supply of resources allocated to finance it. As a result, the ability of national policy makers to set priorities for their health care system or for new technologies within the health care system is most often conducted under conditions of resource scarcity and in the face of varying degrees of evidence about the safety, effectiveness, and appropriateness of particular interventions. Thus, priority setting is a real challenge for every health care system in the world. As yet, it is safe to say that there are no widely accepted models for legitimate and fair priority setting in health care.

Pharmaceutical innovation includes many different options: development of a completely new medicine for an otherwise incurable disease; modifications of known medicines; development of less invasive administration routes; use of simpler administration schedules. Presently, the availability of innovative medicines depends mainly on the ability of a market-based multinational manufacturing industry to invest in research and development (R&D) that drives innovation. From the viewpoint of public health, the pharmaceutical sector`s goal should be making efficacious, high quality and safe medicines, including the more recent and innovative ones, to all those who need them, regardless of their income or social status.1 Unfortunately, a large number of the current markets are saturated with symptomatic relief drugs or drugs that offer little therapeutic advance over prior versions.

For a number of diseases of high prevalence, no effective and safe medicinal curative treatment is yet available (e.g. certain cancers, genito-urinary diseases, CNS disorders (particularly neurodegeneration, cognitive impairment)) so there exists an obvious “pharmaceutical gap” between burden of disease and clinically effective medicine. Public funding for pharmaceutical research, in relation to preventive and curative gaps with considerable public health impact, should therefore be considered. In this regard, the appropriate use of public funds for R&D calls for careful and transparent prioritization of treatment needs. From a public health viewpoint, it is important to identify research needs which are also relevant for countries in economic transition (including several new EU members) and, if possible, also for developing countries – so that a maximum benefit may be derived from this obvious common interest.

This paper presents a concise, critical review of methods for prioritizing research and development (R&D) in a public health context, with particular emphasis on prior attempts at prioritizing R&D for pharmaceuticals and/or for specific diseases. In Section 1, we review prior attempts based on information from several reports: the Commission on Health Research for Development (COHRD: 1990), World Development Report (1993), the Ad Hoc Committee on Health Research (1996), the WHO Advisory Committee on Health Research (1997), the IOM Report on the National Institutes of Health (1998), the Global Forum for Health Research (2000), prioritization efforts by Medicins Sans

1 PHARMACEUTICALS AND PUBLIC HEALTH IN THE EU: PROPOSALS TO THE HIGH LEVEL COMMITTEE ON HEALTH FOR POLICIES AND ACTIONS IN THE FRAMEWORK OF THE TREATY OF AMSTERDAM 28 March 2000 Report of the Working Group on “Pharmaceuticals and Public Health” of the High Level Committee on Health.

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Frontieres (MSF: 2002), and the joint initiative of the UN Development Program/World Bank/ World Health Organization- the Special Program on Research and Training in Tropical Diseases (TDR) (2002). We provide a brief overview of the significance of their methodology in a larger context. The Global Forum for Health Research (2002) has provided a more detailed summary of prioritisation methods of some these organizations (reference) and we suggest readers to consult this document. In Section 2, we provide a brief summary of the conclusions drawn, if any, by these entities as to research prioritisation on pharmaceutical R&D. Further, we summarize the conclusions of several other groups. We note that Section 2 is not intended to be a comprehensive review of all prior R&D prioritisation efforts. In Section 3, we present a new framework and methodology for looking at “pharmacological gaps” in the context of pharmaceutical R&D. This framework builds on the work of prior efforts described in this paper but extends it in a way that we believe will provide new insights into areas heretofore neglected. Section 4 is our summary and conclusions.

1. Background Information

The Commission on Health Research for Development (COHRD: 1990)2 was an independent international initiative formed in 1987 with the aim of improving the health of people in developing countries through a focus on research. The Commission had a multinational membership and the work was supported by 16 donors from Europe, North America, Asia and Latin America. A central theme of the group was that “…while research in industrialized countries on diseases such as cardiovascular diseases and cancer can benefit citizens of developing countries…” such research was not made with developing country citizens as intended beneficiaries. The Commission concluded that there is a mismatch between the burden of disease, primarily located in the developing world, and investment in health research which is centered on health problems of people in developed countries. The Commission identified equity of opportunity as a goal of development, for which research is crucial. Furthermore, the COHRD was explicit in its insistence that such research should be done in the developing countries themselves. The idea of country-specific research became manifest as the Essential National Health Research (ENHR) concept. ENHR will be briefly summarized below but a recent publication3 provides a more detailed review of ENHR priority setting. The COHRD was a visionary document that imagined a linked worldwide health research system (effectively pre-world wide web) to address national and global health problems.

The COHRD document reviewed the global health burden using mortality data and compared research investments to mortality data. COHRD estimated the former as research dollars spent /year/death. COHRD strongly suggested that a research allocation framework should use disability adjusted life years (DALYs) as the key health burden indicator in conjunction with costs of addressing the problems. This document was clear that diseases with the most DALYs should be attacked first but recognized that research prioritisation for public health includes “ethical judgments” as well as inclusion of factors that favor a successful outcome: (feasibility, human/organization; capacity for research). Significantly, there was no real discussion of research prioritization methods in this document.

2 Results of the Commission`s work were published as Health Research:Essential Link to Equity in Development. New York:Oxford University Press (1990).3 Priority setting for health research: lessons from developing countries, 2000, MA Lasang et al., Health Policy and Planning, vol. 15, p. 130

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A more systematic approach to research prioritisation can be found in the COHRD vision of country-level health research priority process/database called Essential National Health Research (ENHR). Since much of the value added of the COHRD report lies in explicit criteria to reflect the promotion of equity and development, ENHR prioritization methods were meant to “capture” diseases common only in marginalized groups or in a few inaccessible localities. Without a consideration of equity issues, such diseases would not rank highly in priority lists.

The objective of an ENHR exercise is to generate descriptive information on the type, distribution and trends in disease, paying attention to such issues as geography, income and social class, gender and age-group (e.g., infants, adolescents or elderly). Information on deficiencies in the health care system, for example, human resource issues, poorly functioning equipment, lack of emergency transport or poor prescribing practices, are all relevant to developing an ENHR program. The ENHR concept describes several general questions to ask when prioritising research:

How big and urgent is the problem ? This includes considerations of the burden of illness, perceived demand and urgency. In particular, the burden of illness may be assessed by mortality and morbidity statistics, DALYs or similar indices. What research is currently being undertaken? Where does the money come from? What areas of research are being addressed (topics, content)? Who is doing this work (university departments, research groups, the ministry of health, private institutes)? Where is the work being done (which institutions, urban or rural, etc.) ? What research has previously been done ? Is it feasible to do the proposed research ? What and when is the expected impact of the research ?

In our view, the ENHR methods are quite useful to quantify “gaps” in existing healthcare interventions, particularly at the level of healthcare delivery. We note, however, that there is little documentation from the countries that have adapted these guidelines on the actual process of selecting criteria and applying these to the priority-setting exercise. However, the two most commonly used criteria have been the burden of illness (as defined by health statistics or perceived need) and the expected impact of the solutions ensuing from the research. Technical capability or feasibility, has not been reported as frequently. In addition, the criteria used in the countries have differed. This ranges from the absence of explicit criteria to a long list of criteria, such as: burden of illness; urgency; perceived demand; extent of previous research; technical, economic, political and cultural feasibility; relevance to the national health plan; and expected impact of proposed interventions. Where there were criteria, few countries had explicit guidelines on how to apply them. In addition, most countries did not specify who developed the criteria, nor on what objective and ethical bases decisions were made.

The South African experience with ENHR is a useful example. The available documentation (Proceedings of the First Essential National Health Research Congress on Priority Setting. 1996. DIRECTORATE RESEARCH COORDINATION AND MANAGEMENT DEPARTMENT OF NATIONAL HEALTH) is impressive in the clarity of presentation of its prioritisation scheme and the candid review of the problems encountered. It is worth reviewing in some detail.

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The first step taken was a ranking of priority health problems/disease on the basis of Mortality, Morbidity and Years of Potential Life Lost (YPLL's), (Morbidity data was based on hospital discharge rates), trends in disease profile, and, most significantly, on the perceptions of participants and community. Participants in the ranking exercise were randomly allocated to 10 working groups and were asked to rank the top 20 health problems based on the criterion. Each participant in a work group was asked to reassess their choice of the top 20 diseases after a period of discussion within the working group. The discussions included identification of the obvious gaps in the identified diseases and clarification of diseases versus cross-cutting issues. At the end of the discussion period, the facilitator was tasked with compiling a group vote based on inverse score ranking of the total votes per health problem area, per working group.

The composite ranking of health status includes broad categories and risk factors. The appearance of broad categories (e.g., cancer, nutrition) on the list made prioritization more difficult. An analysis of individual participants recommendations, indicates that the areas of concern within the category of cancers were confined to 3 or 4 specific conditions and not all 207 cancer types. Participants at the meeting tried to identify broad research areas within the highest burden diseases. Significantly, groups were asked to consider the following questions as a way of identifying “gaps” in knowledge and tools:

1. What are the current interventions available to address the problem?2. Are these interventions successful?3. In which way are these interventions not successful?4. Is a new intervention indicated?5. What type of research is required for the "new" intervention, by discipline?

The World Development Report (WDR) 4 was the 16th in a series of World Bank reports prepared in conjunction with the WHO. The key technical considerations were methods for assessing global burden of disease (in DALYs) and associated technical analyses that informed the report. The WDR was based upon an external advisory committee, assisted by various external consultations and seminars within and outside the World Bank. More than a dozen bilateral and multilateral organizations, foreign assistance agencies, and academic institutions provided support. The document has extensive tables and large and useful bibliographic support. The primary relevant objectives of the WDR were to set priority policy issues and actions likely to be important for low- and middle-income countries as well as the former socialist countries and to present a measure of global disease burden that could identify cost-effective interventions and guide resource allocation. The WDR was important for the World Bank as it signalled an indication that there is a direct role for governments in the health sector, beyond the role it already had in influencing food, water, education policy, among others- and beyond the role that markets play. The recognition that in some respects, the state can provide better outcomes in the health sector than can the private sector was a shift for the World Bank.

Probably the greatest value added was the use of the DALY – arguably a major advance in methodology- to help guide resource allocations towards reducing the greatest burden of disease and for which there are cost effective responses. In short, the WDR would have governments redirect resources from 4 Results were published as World Bank. 1993. World Development Report 1993: Investing in Health. New York: Oxford University Press.

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interventions that have high costs per DALY to those with the highest cost-effectiveness gained (i.e., those that could dramatically reduce the burden of disease without increasing expenditures). The emphasis in the WDR was on priority setting for allocating resources for healthcare interventions, rather than priority setting for pharmaceutical research. Thus, if the global burden caused by a disease is large, if no cost-effective interventions exist, and if experts believe that such intervention might be developed, there is a case for greater investment in research and product development.

Nonetheless, the WDR describes no explicit methodology with regard to setting research priorities. Stated simply, however, priority should go to those health problems that cause a large disease burden and for which cost-effective interventions are available.

The Ad Hoc Committee on Health Research5 (1996) was established under WHO auspices and was formed based on conclusions of the WDR as well as interest by funders and foundations in health R&D. The objective was to review global priorities for health R&D, prospects for funding this R&D, and recommend changes at the national and international level that might enhance productivity of ongoing R&D. The report was also designed to address development of products and procedures to convert research into practical tools and so paid some attention to the private sector. The Committee focussed on needs of low to middle income countries but realized that “private sector” product development considerations (magnitude of the problem, basing cost-effectiveness of new therapies and products on scientific judgment) can inform debate about priorities for public sector R&D as well. A major contribution of this document was the identification of specific high priority product development opportunities. This approach was a significant advance in prioritising and allocating research.

It involved a five step process, briefly summarized below: 1. Measure the burden of disease or risk factor for the disease: The

DALY was the main unit.2. Identify the reasons why the disease burden persists. That is,

does this DALY burden persist because of lack of basic knowledge about the disease or lack of good tools or health system failure to use good tools effectively, or some mixture of these? Using data on efficacy of interventions and reasoned judgments or evidence as to the fraction of a population receiving the interventions, it is possible to estimate the relative shares of the burden that can and cannot be averted using existing tools. A correct application of this would provide an indication of the relative distribution of the effort required to provide effective coverage in a population. This is a key advance.. Assume the whole square in Figure 1 (below) is the total DALY burden for a given disease. The horizontal axis is the extent to which cost-effective treatment is reaching the population. The vertical axis is the combined efficacy of this mixture of interventions. There are 4 subdivisions of the total DALY burden, as indicated. The term “efficiency” in the central subdivision refers to efficiency in delivering existing cost-effective interventions via the health care system. Ideally, the relative share occupied by each subdivision should be estimated as it can help identify areas for research.

5 Published as Ad Hoc Committee on Heath Research Relating to Future Intervention Options. Investing in Health Research and Development. WHO, Geneva, 1996 (TDR/Gen/96.1)

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3. Determine if the current knowledge base can support development of new interventions. This relies in the subjective judgment of key researchers. If the current knowledge is adequate, then the cost-effectiveness of new products may be able to be compared to existing ones. If current knowledge is not enough, then strategic research may be important.

4. Determine the likelihood of success of a particular R&D effort. What is the expected cost-effectiveness of a new intervention and its likelihood of success (answered by looking a drug pipelines, existing knowledge base).

5. Assess the current level of R&D effort.

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Figure 1 (taken from Figure 1.1 of the Ad Hoc Committee Report, p.7)

Prior approaches did not explicitly use the DALY to assess risk factors, nor did they explicitly analyze the reasons for the persistence of disease burden in selected areas. The Committee tried to make some first estimates of the cost-effectiveness of desired interventions. The Committee actually analysed several diseases to quantify the relative importance of each of the three reasons for its persistence (see Figure 1 above). These diseases were, pneumonia, acute watery diarrhea, tuberculosis, and pneumococcal disease. The Committee did not perform such analyses for noncommunicable diseases. In this regard, the conceptual framework developed in Figure 1 might provide a useful first step. However, common conditions about which little is known globally (e.g., certain nocosomial infections) cannot be attacked with this method since the initial boundaries cannot be estimated.

The WHO Advisory Committee on Health Research is the primary expert WHO advisory body on scientific research and practices. They set themselves the extremely ambitious undertaking of objectively and transparently analysing health status to guide a global health research agenda.6 This was clearly another visionary document. With regard to health system statistics, they created the Visual Health Information Profile (VHIP). The VHIP, is a relatively sophisticated software and visual which displays over 80 health status aggregate indices (life expectancy, access to care, adult literacy, GNP, food production per capita etc.) as a radial segment of a circular graph. The VHIP provides subdivisions/rankings within each radial segment as to whether or not the health situation in the segment requires improvement. Their methodology for setting research criteria7, 8 is written in only the broadest terms. This is perhaps not surprising considering that the aim of this group was to provide a

6 Published as A Research Policy Agenda for Science and Technology to support global health development. WHO, Geneva, 1997, WHO/RPS/ACHR/97.3.

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Averted with current mix ofinterventions

and populationcoverage

Avertable withimproved

“efficiency”

Avertable with existing

butnon-costeffective

interventions

Relative shares of the burden that can and cannot be averted with existing tools

0%

100%

Z

X Y0% 100%

Unavertable with existing interventions

Population coverage withcurrent mix of interventions

Maximum achievablecoverage

Combined efficacy of a mix of all available interventions


framework for global health research of all kinds to discover “whether there are new effective, rational methodologies that can help different parties set priorities for health development research, and perhaps also lead in the direction of a better global consensus.” Briefly, the WHO Advisory Committee considered criteria also found in other documents such as burden of disease; “likelihood of success of research”; and “research capacity”. The Committee identified that myriad cultural, cost, human resource constraints exist on any action and that such constraints must be taken into account. The Committee suggested that analyses of the various “constraints” on research be done by searching through many solutions and using the existence and nature of the constraints to discard solutions that are not acceptable. They suggested that fields such as organizational analysis and strategic management of technology and innovation might provide useful models but gave no examples.

IOM Report on the National Institutes of Health (1998) 9 In the late 1990s, the Institute of Medicine (IOM) was asked by the National Institutes of Health (NIH) to review the factors used by NIH to determine U.S. funding allocations for disease research; the process by which such funding decisions are made; and how the public gets involved in the priority-setting process. These were, and still remain, issues of considerable interest inasmuch as the vast majority of medical research funding ($13.6 billion of the $16 billion in federal funds allocated in 1998) goes to the NIH. In 1998 there were 21 (now 27) separate research institutes under the NIH. The NIH interacts with many stakeholders: research scientists outside NIH, clinicians who apply research results; patient/provider advocacy groups; Congress; and the media.

There were several reasons for this outside review. First, Congress was concerned that there generally should be more of a direct relationship between the allocation of funding by disease and the distribution of disease burdens and costs to population (i.e., why was NIH spending more per death from HIV than from cancer, stroke, and heart disease?). Second, Congress and the NIH were under increasing pressure from disease-specific interest groups. Third, there was (and still is) a general view that NIH had potentially conflicting needs to among basic vs. clinical vs. epidemiologic research- need-driven vs. science driven, disease specific vs. cross-cutting research. In particular, the IOM was concerned that NIH was not explicit in how in practice it combined health indicators (such as demographic data) in setting its research priorities or how these indicators are integrated with others such as the feasibility of research. At the time, the NIH did not have a systematic process for collecting and analysing health indicator data- so how would it know it was meeting its research criteria?

Generally, research prioritisation occurs at the level of NIH director and at the level of Institute director. There are, however, important constraints on changes in NIH research direction. The NIH director can set NEW priorities ONLY with additional funds from Congress. Each Institute gets a separate Congressional appropriation. Budgets are put together from the bottom up and reconciled with budget limits and program priorities. Individual Institutes have

7 A Research Policy Agenda for Science and Technology to support global health development. WHO, Geneva, 1997, WHO/RPS/ACHR/98.1.8 World Health Organization. Advisory Committee on Health Research. Title: A Research policy agenda for science and technology to support global health development / Advisory Committee on Health Research. Geneva : World Health Organization, 1998, at http://whqlibdoc.who.int/hq/1998/WHO_RPS_ACHR_98.1.pdf 9 Published as Scientific Opportunities and Public Needs, Improving Priority Setting and Public Input at the National Institutes of Health, National Academy Press, Washington, DC 1998.

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some opportunity for creating priorities, i.e., which grant applications to support and which research topics to authorize as part of their portfolio. Actual mechanisms for priority setting are diverse since the NIH is so decentralized. Methods vary from Institute to Institute and in areas within each Institute. IOM thought this decentralization was “ appropriate” because “those closest to the problem are in the best position to decide on approaches” and thought that this variability was fine because institutes “vary in their mission, leadership, size, and complexities.”Most of the NIH budget supports individual research projects conceived of and conducted by either government scientists working on research on the NIH campus (about 1000 Principal Investigators in 1998 — tenured and tenure track) or scientists based elsewhere (about 45,000 NIH fellows, research grant recipients, and trainees in 1998), at universities, medical, dental, nursing, and pharmacy schools, schools of public health, non-profit research foundations, and private research laboratories. In fiscal year 2000, approximately 10 percent of the NIH budget was spent internally within NIH (intramural) and more than 83 percent of the NIH budget was used to fund research by scientists working elsewhere across the country.

The NIH believes that allocating research funds within the NIH cannot be done according to a single set formula since various ways of measuring the health needs of the U.S. and distributing research funds have advantages and drawbacks. For example, NIH has asserted that using the number of individuals affected by a condition as the primary criteria for research funding would emphasize common diseases, but might have a limited effect on overall health and survival (much research would be done on the common cold and allergies and little on childhood cancers). Having the primary criteria be the number of deaths would neglect chronic diseases that produce long-term disability and high costs to society, such as mental illness, arthritis, and heart diseases. Moreover, having as the primary criteria disability (e.g., DALYs) or economic cost raises questions about how well disability or economic costs can be quantified, and whether only the direct costs of medical care should be counted or whether indirect costs (e.g., lost productivity), which are difficult to measure, should also be included.10 Funding according to the economic cost of illness would under-fund diseases that result in a short illness and rapid death (this choice would provide a great deal of funding for Alzheimer's disease and muscular dystrophy and little, or none, for sudden infant death syndrome or certain types of cancer). Funding based solely on immediate dangers to public health may divert funds from areas of research of much broader long-term impact (this choice would mean that a great deal of research would be done on AIDS and tuberculosis and little on Parkinson's disease and asthma).

We have found only the most general information on the mechanisms of research prioritisation at the Institutes within the NIH. For instance, the National Institute of Allergies and Infectious Diseases (NIAID) uses twice a year planning “retreats”- although we have no details yet on prioritisation methods used. The National Eye Institute has a formal planning process although details are not known at this time. The National Cancer Institute (NCI) NCI plans, promotes, and carries out disease-specific research, through advice from expert Progress Review Groups (PRGs). Over a nine-month period, each PRG identifies gaps in understanding of the diseases under study, barriers to progress, and key research priorities. The process culminates in the release of PRG findings and priorities in a comprehensive report. Generally, the operational structure is as 10 We note that none of these particular criticisms refer to underfunding, overfunding, or neglecting chronic diseases-but only on the methodology for determining DALYs, a subject which will continue to create debate in any case.

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follows: NCI leadership appoints PRG co-chairs, PRG co-chairs identify & invite PRG members, PRG members plan roundtable, the Roundtable meets & develops research recommendations and prepares reports, PRG co-chairs present recommendations to the Advisory Committee to the NIH Director. Specifically, we describe the activities of the Leukemia, Lymphoma and Myeloma (LLM) PRG as a reasonable representation of how the NCI prioritises their research agenda. The LLM PRG is charged with identifying and prioritizing areas of research that could advance progress against leukemia, lymphoma, and myeloma. At a group meeting, the LLM PRG organizes a Roundtable to consider progress and identify needs across the continuum of LLM research. Roundtable participants are chosen and topics selected for breakout sessions, to which the Roundtable participants are assigned. PRG members served as co-chairs for the breakout sessions. The LLM PRG Roundtable of approximately 180 participants meets and members of breakout groups are instructed to identify top research priorities for the next 5-10 years. In support of the priority-setting process, NCI provides the Roundtable participants with analyses of its LLM research portfolio and extensive information about ongoing NCI initiatives and activities that might address some of the needs of the field. Reports from the breakout groups usually show a high degree of agreement on many of the crucial needs of the field. Using these reports, the PRG identifies the highest priority areas for research and writes descriptions and justifications for them.

What is strikingly absent from this summary is the actual methodology used. Did the members base their priorities on experience? On evidence? Did they vote and/or rank priorities?

Global Forum for Health ResearchThe Global Forum for Health Research has created a framework (Combined Approach Matrix: references) brings together in a systematic manner all information (current knowledge) related to a particular disease or risk factor. This framework is a very useful way of organizing information. It identifies gaps in knowledge and future challenges. In part, its value is in its ability to help set priorities for national, regional or global diseases. The framework allows identification of “common factors” by looking across diseases or risk factors. The framework utilizes the 5 step process of the Ad Hoc Committee (above) but requires completion of these questions in a matrix format for a variety of levels within the healthcare system (individual/family/community, health ministry/health research institutions/health systems, sectors other than health, central government, macroeconomic policies). Completing the matrix should highlight the “blank areas”, i.e., where there are gaps in information needed to make rational decisions.

TDR The TDR approach to prioritization is an expansion of the Global Forum matrix to include two new criteria: information on TDR's comparative advantages and, based on this, conclusions as to TDR's strategic research emphasis. Prioritization is done on a disease-by disease basis (reference). TDR has completed this prioritisation exercise for African trypanosomiasis, Dengue, Leishmaniasis, Malaria, Schistosomiasis, Tuberculosis, Chagas disease, Leprosy, Lymphatic filariasis, and Onchocerciasis. For each disease, the analysis was undertaken by the TDR in consultation with outside experts.

DNDi (Drugs for Neglected Diseases Initiative)Médecins sans Frontières has developed a conceptual framework to identify and better characterize “neglected diseases”. The criteria and characteristics for

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defining “neglected diseases” includes consideration of a variety of scientific and societal issues and many of them are extremely relevant to consider in the context of discovering “pharmacological gaps” because similar considerations may apply. Although little effort was made to create a quantitative scoring or other metric, the MSF approach is very useful because it suggested that one should look at several ways of analyzing the same information. For example, one can look at current treatment options since whether or not treatment exists in the first place (as well as the number of therapeutic options) is a marker of a “neglected” disease. Further considerations apply to the quality of any diagnostic tests and treatments. Significantly, MSF would inquire into whether the available medicine is “easily applicable”. This includes a consideration of duration of the treatment, delivery mechanism (i.e., oral versus intravenous) and whether or not the treatment is easy to comply with. Criteria to determine disease impact in terms of mortality might include the Case Fatality Rate (CFR) and DALY’s although these might miss other factors. Additional criteria can highlight alternative and complementary perspectives. MSF suggested that criteria such as the number of articles published on a certain disease in the past 5 years, or even the number of people working on a certain disease in the WHO headquarters in Geneva, can add a different perspective to the discussion. With regard to specific pharmaceuticals, MSF looked at the number of New Chemical Entities (NCE) marketed in the last 25 years as compared to drugs under clinical development. Another criteria is the absolute cost, per patient, for a complete treatment cure for a given disease. Rather than compare this to the GNP or health expenditure per capita, which will differ from country to country, the absolute cost can give a global impression to whether the treatment is cheap, affordable, expensive or prohibitive.

Section 2. Conclusions of prioritisation efforts with regard to pharmaceutical R&D

PRIORITIZATION SCHEME

ACUTE CONDITION

S

CHRONIC CONDITIONS

COMMENTS See Also Notes a

COHRD

ENHR-South Africa

Diarrheal diseases

Acute Respiratory Infections

Infectious Diarrhea

HIV/AIDS

TB

Diarrheal Diseases

Acute

HIV/AIDS

Vaccine Development for HiB, Measles and pneumonia

Effectiveness of chemotherapyPneumoccal vaccine trials

Rotavirus vaccine testingC/E of rotavirus vaccine

Vaccine DevelopmentVertical transmission drug development

Alternative drug delivery systemsBCG vaccine efficiency

PROBLEM SCOREINJURY /TRAUMA/ VIOLENCE 1713

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ACUTE CONDITION

S

CHRONIC CONDITIONS


Respiratory Infections

Infectious Diarrhea

TB

Malaria

TB 1589 NUTRITION 1501 HIV/ AIDS 1224 STD'S 1198CANCER (ALL) 1123DIARRHOEA 1051 RESPIRATORY INFECTION 777 MENTAL HEALTH (EXCL. SUBSTANCE ABUSE

685 MALARIA 57

World Development Report

Respiratory Infections

Diarrhoeal Diseases

Childhood Diseases (polio, measles, tetanus, diphtheria)

TB

Pneumococcal vaccine, inexpensive, simple antibiotic regimens

Rotavirus/toxigenic E. coli vaccine, improved V. cholera vaccine

“New, improved vaccines”

“New and cheaper drugs”

Associated DALY loss (millions)Developing countries

Respiratory Infections (119)Diarrheal Diseases (99)Childhood Diseases: (polio, measles, tetanus, diphtheria) (67)TB (46)

Ad Hoc Committee Maternal complications

Diarrhoeal diseases

Childhood infections

Pneumonia

Diarrheal diseases: Shigella vaccine;

Vaccine preventable childhood infections: alternative delivery to vaccination of very young babies;

Pneumonia: Haemophilus vaccine, S. pneumonia vaccine

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ACUTE CONDITION

S

CHRONIC CONDITIONS


Pneumococcal Diseases

Malaria

MDR-TB

HIV/AIDS

Helminth infestations

Pneumococcal disease: Child vaccine in low income countries; Resistant malaria: New vaccine and drug candidates;

MDR-TB: Improved formulations (Fixed dose combinations), better, longer acting injectibles, vaccine;

HIV/STDs: HIV vaccine, Vaginal microbicide

Advisory Committee Childhood diseases

Burns

Infectious cancers

Cardiovascular Diseases

Heriditary diseases (CF, blood disorders)

Osteoporosis

Glaucoma

Heat stable, single dose vaccine as aerosol/oral. Slow release microencapsulated vaccines, Rotavirus vaccine

Monoclonal antibodies, recombinant approaches (antisense, gene therapy)

New and improved drugs like anticoagulants, new NSAIDS, tamoxifen-like anti estrogens,

Gene therapy

Nasal form of calcitonin

New drugs for glaucoma

Reduce edema via new medicines.

Global Forum for Health Research/TDR

Lymphatic Filariasis

Malaria

Tuberculosis

Onchocerciasis

Chagas disease

New drugs to manage hydrocele; microfilaricides requiring chronic administration treatment, efficacy/safety of albendazole combinations; improved drug delivery strategies

Better drugs, vaccine

Rapidly acting drugs, better vaccineDrugs that sterilize/kill adult wormBetter drugs and diagnosis

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ACUTE CONDITION

S

CHRONIC CONDITIONS


Schistosomiasis

Leishmaniasis

Dengue

African Trypanosomiasis

Additional drugs

Better drugs

Vaccine

Better drugs

National Cancer Institute

Lymphoma, leukemia, melanoma PRG

Defining therapeutic targets (e.g., signal transduction pathways mediated via tyrosine kinases), inducing selective apoptosis in myeloid cells,Monoclonal antibodies directed at key targets on malignant cells

Drugs for Neglected Diseases Initiative (MSF)

Human African Trypanosomiasis

Visceral Leishmaniasis

Malaria

Melarsoprol: becoming ineffective in some areasEflornithine: Difficult to administerNifurtimox: for Chagas disease but not approved in HATMegazol as an anti-infective drug.

Antimonials ineffective where incidence is highest. Lipid formulated Amphotericine B is unaffordable and Amphotericine B is toxic. Miltefosine may be limited by gastric in tolerance. Paromomycin is cheap, well-tolerated but finished injectable product is notavailable.

Various artemisinin-type combinations: artesunate + S/P), artesunate/amodiaquine, artesunate/mefloquine fixed combinations, artemether + lumefantrineartesunate + chlorproguanil/dapsone, artesunate + pyronaridine)

European Initiatives Cardiovascular diseases (ischaemic heart disease and stroke)

CNS (particularly neurodegeneration, cognitive impairment and autism) and metabolic/endocrine disorders.

Mental disorders,

Research difficult or few therapeutic alternatives

Research difficult or few therapeutic alternatives

Non-toxic anxiolytics.Disease-modifying drugs

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ACUTE CONDITION

S

CHRONIC CONDITIONS


Genito-urinary and gastro-intestinal infections, MDR-TB, S. aureus infections

schizophrenia

Asthma

Menopausal and other hormonally determined conditions such as osteoporosis

Relief of intractable pain

rather than palliatives.

Disease-altering drugs

New compounds to treat

Few effective analgesics

New classes of broad-acting antibiotics

Fostering Competitiveness in Europe`s Biotechnology Industry

Pediatric diseases

Pediatric diseases

Neurodegenerative diseases in CNS and PNS

Cardiovascular, neurodegenerative or neoplastic disorders

Inherited diseases (cystic kidney diseases, neuromuscular, metabolic and central nervous system disorders, haemoglobinopathies or immunodeficiencies

Diabetes, liver cirrhosis

Novel therapeutic substances

Identification of new targets for innovative treatments (nitric oxide and eicosanoid signalling).

Improved gene delivery systems for therapy

Improved gene delivery systems for therapyStem cell therapy and tissue engineering for regenerative treatment

a. Additional notes: COHRD: The added value of the Commission was the concept of Essential National Health Research. Summary statements of the ENHR priorities in various countries have been presented by the Global Forum on Health Research (2000 Annual Report). Few, if any, country reports refer specifically to priorities for pharmaceutical R&D.

WDR: This report listed some priorities for research and product development, ranked by the top six contributors to the global burden of disease. Priority areas that involve pharmaceutical development are listed above.

Ad Hoc Committee: The Committee identified reasons for the persistence of a disease as being inadequate basic knowledge, inadequate tools (i.e., medicines and diagnostics) and health system

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inefficiencies. Using the framework of Figure 1 as a guide, the Committee ranked various diseases/conditions based on these reasons for its persistence from a score of 1 (reason for persistence not important) to 4 (reason very important). The summary relationship between the scores for inadequate tools and health system inefficiency are presented in the Figure in Appendix 1 (for ease of graphing, datasets were slightly modified to separate diseases with the same score). Health system inefficiencies are clearly more important than lack of available medicines for certain diseases, and there is a rough inverse relationship between the two although it is not immediately obvious why there should be such a relationship. (Data obtained from Table 3.4 page 27 of 2002 report). What was much more difficult were prioritisations for chronic diseases. The Committee identified a lack of basic knowledge and medicines as the main reason for persistence of unipolar depression, bipolar disorder, schizophrenia, ischaemic heart disease, stroke, various “infectious” cancers (cervical, liver).

IOMPrioritization methods within the NIH are not entirely obvious. Some sense of the priorities of various institutes within NIH can be obtained by looking at the NCI PRG reports and the various NCI links (e.g., http://prg.nci.nih.gov/llm/rschportfolio.html which has MEDLINE links as well to papers by authors and lists of clinical trials). The NIAID website http://www.niaid.nih.gov/dmid/dmidover.htm also has a useful summary of its relevant research priorities and these are listed in Appendix 1.DNDiSee http://www.accessmed-msf.org/upload/ReportsandPublications/20920021729337/2-3.pdf (Immediate Drug Development Projects for Five Targeted Drugs in Three Neglected Diseases, Piero Olliaro, Visweran Navaratnam, Bernard Pécoul, Els Torreele, Yves Champey).

European Initiatives:

European Pharmaceutical Research, Development and Innovation; Assessment of the Socio-Economic Impact of New Drugs March 1997 , http://www.jrc.es/pages/ourrole/policy/pharma/Pharma_i.html

July 2003, Work Programme for the specific programme for research, technological development and demonstration:"Integrating and strengthening the European Research Area" Life Sciences, Genomics and Biotechnology for Health

Section 3: Towards a New Framework for Prioritizing Pharmaceutical R&D

We can begin this process by developing a “map” of priorities by burden of disease and clinical “effectiveness”. This “mapping” exercise is designed to identify those conditions that ARE curable or whose treatments ARE effective. The remaining conditions (i.e., the “gaps”) are those that will be of interest. The key outcome is to distinguish between diseases for which effective treatments exist but are not accessed due to health system inefficiencies and those conditions for which effective treatment is not available even in well-functioning health systems. We can create a first mapping (see Figure 1 below) in which disease burden (by one or more measurements) is plotted against some measure of “effectiveness”. The Y axis could represent the present best judgment (based on a quantitative, evidence-based assessment) of the clinical efficacy of specific interventions. We might imagine identifying those indications whose treatment is less than 50% “effective” as worthy of further, detailed review since these would be the “priority” diseases for which medicines are needed (e.g., for which research is needed to move them into the upper level of the figure (small vertical arrows in Figure 2).

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http://www.jrc.es/pages/ourrole/policy/pharma/Pharma_i.html

http://www.accessmed-msf.org/upload/ReportsandPublications/20920021729337/2-3.pdf

http://www.niaid.nih.gov/dmid/dmidover.htm

http://prg.nci.nih.gov/llm/rschportfolio.html


Section 4. Summary and Conclusions

In spite of the variety of organizations with disparate mandates and orientations and stakeholders, some common themes exist.

1. Clearly, priority setting is most difficult under conditions of resource scarcity. It is this condition which, more or less, informs the discourse put forth by the organizations reviewed here.

2. Under most reasonable circumstances, we strongly urge that influx of new money for pharmaceutical research and development be subject to scrutiny under a rational research prioritisation method. Moreover, we recommend that existing financial resources be similarly reviewed through the “lens” of a research prioritisation model.

3. Research prioritisation methods of the Commission on Health Research for Development, World Development Report, the Ad Hoc Committee on Health Research, the WHO Advisory Committee on Health Research coincide in some fundamental way with the utility of applying the global burden-of-disease methods to priority setting, in defining magnitudes of diseases and in defining cost-effectiveness of interventions to address various diseases.

4. The priority setting mechanisms of the NIH are the significant exception to the explicit use of burden of disease analyses. The NIH is decentralized and must deal with many stakeholders and many research institutes of varying missions. In particular, its budget is driven in large part by Congressional and political mandates. Therefore, it will not commit to a specific method of research prioritisation. NIH makes the case that selection of public health

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Burden of Disease

“Index ofEffectiveness”

50%

0%

100%


criteria is a selection of different values and applying any one criteria exclusively would cause the neglect of some classes of diseases altogether.

There are clearly other issues with regard to criteria for research prioritisation that should be discussed. Several come to mind:

1. The number and kind of adverse effects generated by a particular medicine is an important component. Should the actual adverse effects of existing drugs and/or the projected adverse effects of new drugs be considered in prioritising pharmaceutical R&D? Are there local/regional variations in clinical effectiveness of a particular medicine?

2. Is the public health impact of a medicine greater if the medicine improves existing methods of alleviating symptoms or actually cures the disease? Should these considerations be included in priority setting mechanisms for particular indications?

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Appendix 2:Antiviral ResearchChronic Fatigure Syndrome (CFS)Emerging Diseases

Hantavirus and Other Emerging Threats Evolution of Infectious Diseases

Fungal DiseasesHepatic Diseases (http://www.niaid.nih.gov/dmid/hepatitis/ )Enteric Diseases (http://www.niaid.nih.gov/dmid/enteric/)

Hepatitis Animal Models Hepatitis C Virus Cooperative Research Centers (HCV CRCs) Investigative Group for Hepatitis Enteric Pathogens Research Unit (EPRU)

Tropical Disease Research (http://www.niaid.nih.gov/ictdr/) International Collaboration in Infectious Disease Research (ICIDR) Tropical Disease Research Units (TMRU) Tropical Medicine Research Centers (TMRC)

Lyme Disease (http://www.niaid.nih.gov/dmid/lyme/) Animal Models Basic Research Clinical Trials

Malaria (http://www.niaid.nih.gov/dmid/malaria/ ) Malaria vaccine design and development Plasmodium falciparum genomic sequencing project Clinical research and trial preparation sites in endemic areas Malaria Research and Reference Reagent Resource

Respiratory Diseases Maternal Immunization Respiratory Pathogens Research Unit Acellular Pertussis Vaccine Trials

Sexually Transmitted Diseases(http://www.niaid.nih.gov/dmid/stds/ ) Animal Models for STDs Research on Molecular Immunology of STDs (ROMIS) STD Clinical Trials Unit (CTU) Topical Microbicides Program

Tuberculosis (http://www.niaid.nih.gov/dmid/tuberculosis/) Animal Models for Tuberculosis Tuberculosis Diagnostic Development Tuberculosis Research Materials Tuberculosis Research Unit Tuberculosis Vaccine Development

Vaccine R&D (http://www.niaid.nih.gov/dmid/vaccines/ ) Vaccine and Treatment Evaluation Units Vaccine Production

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