Annex 3: Prioritising Pharmaceutical R&D in a Public Health Context
By Dr Warren Kaplan
March 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 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
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.
1
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Annex 3: Prioritising Pharmaceutical R&D in a Public Health Context
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 preworld 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.
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
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
2
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Annex 3: Prioritising Pharmaceutical R&D in a Public Health Context
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.
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?
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Annex 3: Prioritising Pharmaceutical R&D in a Public Health Context
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 costeffective 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 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 Research 5 (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 costeffectiveness 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:
4
Results were published as World Bank. 1993. World Development Report 1993: Investing in Health. New
York: Oxford University Press.
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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Annex 3: Prioritising Pharmaceutical R&D in a Public Health Context
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 costeffective 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.
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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Annex 3: Prioritising Pharmaceutical R&D in a Public Health Context
Figure 1 (taken from Figure 1.1 of the Ad Hoc Committee Report, p.7)
Relative shares of the burden that can and cannot be averted with existing tools
100%
Unavertable with existing interventions
Combined
efficacy of a
mix of all
available
interventions
Z
Averted with
current mix of
interventions
and population
coverage
Avertable
with existing
but
non-cost
effective
interventions
Avertable with
improved
“efficiency”
0%
0%
X
Y
Population coverage with
current mix of interventions
100%
Maximum achievable
coverage
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 criteria 7, 8 is written in only the broadest terms. This is perhaps not
Published as A Research Policy Agenda for Science and Technology to support global health
development. WHO, Geneva, 1997, WHO/RPS/ACHR/97.3.
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
6
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Annex 3: Prioritising Pharmaceutical R&D in a Public Health Context
surprising considering that the aim of this group was to provide a 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 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
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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Annex 3: Prioritising Pharmaceutical R&D in a Public Health Context
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 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
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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Annex 3: Prioritising Pharmaceutical R&D in a Public Health Context
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 Research
The 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 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.
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Annex 3: Prioritising Pharmaceutical R&D in a Public Health Context
Section 2. Conclusions of prioritisation efforts with regard to
pharmaceutical R&D
PRIORITIZATION
SCHEME
COHRD
ENHR-South Africa
ACUTE
CONDITIONS
CHRONIC
CONDITIONS
Diarrheal diseases
Vaccine Development for HiB,
Measles and pneumonia
Acute Respiratory
Infections
Effectiveness of chemotherapy
Pneumoccal vaccine trials
Infectious
Diarrhea
Rotavirus vaccine testing
C/E of rotavirus vaccine
HIV/AIDS
Vaccine Development
Vertical transmission drug
development
TB
Alternative drug delivery
systems
BCG vaccine efficiency
Diarrheal
Diseases
HIV/AIDS
Acute Respiratory
Infections
PROBLEM
INJURY /
TRAUMA/
VIOLENCE
SCORE
1713
TB
1589
NUTRITION 1501
HIV/ AIDS
1224
STD'S
1198
CANCER (ALL)
1123
DIARRHOEA 1051
RESPIRATORY
INFECTION
777
MENTAL HEALTH (EXCL.
SUBSTANCE ABUSE
685
MALARIA
57
Pneumococcal vaccine,
inexpensive, simple antibiotic
regimens
Infectious
Diarrhea
TB
Malaria
World Development
Report
COMMENTS See Also
Notes a
Respiratory
Infections
Diarrhoeal
Diseases
Rotavirus/toxigenic E. coli
vaccine, improved V. cholera
vaccine
“New, improved vaccines”
Childhood
Diseases (polio,
measles, tetanus,
diphtheria)
TB
“New and cheaper drugs”
Associated DALY loss
3.3-10
Annex 3: Prioritising Pharmaceutical R&D in a Public Health Context
PRIORITIZATION
SCHEME
ACUTE
CONDITIONS
CHRONIC
CONDITIONS
COMMENTS See Also
Notes a
(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
Diarrheal diseases: Shigella
vaccine;
Childhood
infections
Vaccine preventable childhood
infections: alternative delivery
to vaccination of very young
babies;
Pneumonia
Pneumonia: Haemophilus
vaccine, S. pneumonia vaccine
Pneumococcal
Diseases
Pneumococcal disease: Child
vaccine in low income
countries;
Resistant malaria: New vaccine
and drug candidates;
Malaria
MDR-TB
MDR-TB: Improved
formulations (Fixed dose
combinations), better, longer
acting injectibles, vaccine;
HIV/AIDS
Helminth
infestations
3.3-11
HIV/STDs: HIV vaccine,
Vaginal microbicide
Annex 3: Prioritising Pharmaceutical R&D in a Public Health Context
PRIORITIZATION
SCHEME
Advisory Committee
Global Forum for
Health Research/TDR
ACUTE
CONDITIONS
CHRONIC
CONDITIONS
Childhood diseases
Heat stable, single dose vaccine as
aerosol/oral. Slow release
microencapsulated vaccines,
Rotavirus vaccine
Infectious cancers
Monoclonal antibodies,
recombinant approaches
(antisense, gene therapy)
Cardiovascular
Diseases
New and improved drugs like
anticoagulants, new NSAIDS,
tamoxifen-like anti estrogens,
Heriditary diseases
(CF, blood disorders)
Gene therapy
Osteoporosis
Nasal form of calcitonin
Glaucoma
New drugs for glaucoma
Burns
Reduce edema via new medicines.
Lymphatic Filariasis
New drugs to manage hydrocele;
microfilaricides requiring chronic
administration treatment,
efficacy/safety of albendazole
combinations; improved drug
delivery strategies
Malaria
Better drugs, vaccine
Tuberculosis
Chagas disease
Rapidly acting drugs, better
vaccine
Drugs that sterilize/kill adult
worm
Better drugs and diagnosis
Schistosomiasis
Additional drugs
Leishmaniasis
Better drugs
Dengue
Vaccine
African
Trypanosomiasis
Lymphoma,
leukemia,
melanoma PRG
Better drugs
Onchocerciasis
National Cancer
Institute
Drugs for Neglected
Diseases Initiative
(MSF)
COMMENTS See Also
Notes a
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
Melarsoprol: becoming ineffective
in some areas
Eflornithine: Difficult to
administer
Nifurtimox: for Chagas disease but
Human African
Trypanosomiasis
3.3-12
Annex 3: Prioritising Pharmaceutical R&D in a Public Health Context
PRIORITIZATION
SCHEME
ACUTE
CONDITIONS
CHRONIC
CONDITIONS
COMMENTS See Also
Notes a
not approved in HAT
Megazol 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, welltolerated but finished injectable
product is not
available.
Visceral
Leishmaniasis
Various artemisinin-type
combinations: artesunate + S/P),
artesunate/amodiaquine,
artesunate/mefloquine fixed
combinations, artemether +
lumefantrine
artesunate +
chlorproguanil/dapsone,
artesunate + pyronaridine)
Malaria
European Initiatives
Cardiovascular
diseases (ischaemic
heart disease and
stroke)
CNS (particularly
neurodegeneration,
cognitive impairment
and autism) and
metabolic/endocrine
disorders.
Mental disorders,
schizophrenia
Research difficult or few
therapeutic alternatives
Research difficult or few
therapeutic alternatives
Non-toxic anxiolytics.
Disease-modifying drugs rather
than palliatives.
Asthma
Disease-altering drugs
Menopausal and other
hormonally determined
conditions such as
osteoporosis
New compounds to treat
Relief of intractable
pain
Few effective analgesics
Fostering Competitiveness
in Europe`s Biotechnology
Industry
Genito-urinary and
gastro-intestinal
infections, MDRTB, S. aureus
infections
Pediatric diseases
New classes of broad-acting
antibiotics
Pediatric diseases
3.3-13
Annex 3: Prioritising Pharmaceutical R&D in a Public Health Context
PRIORITIZATION
SCHEME
ACUTE
CONDITIONS
CHRONIC
CONDITIONS
COMMENTS See Also
Notes a
Neurodegenerative
diseases in CNS and
PNS
Novel therapeutic substances
Cardiovascular,
neurodegenerative or
neoplastic disorders
Identification of new targets for
innovative treatments (nitric oxide
and eicosanoid signalling).
Inherited diseases
(cystic kidney diseases,
neuromuscular,
metabolic and central
nervous system
disorders,
haemoglobinopathies
or immunodeficiencies
Improved gene delivery systems
for therapy
Diabetes, liver cirrhosis
Improved gene delivery systems
for therapy
Stem 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 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).
IOM
Prioritization 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.
DNDi
See 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:
3.3-14
Annex 3: Prioritising Pharmaceutical R&D in a Public Health Context
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).
100%
“Index of
Effectiveness”
50%
0%
Burden of Disease
Section 4. Summary and Conclusions
In spite of the variety of organizations with disparate mandates and orientations and
stakeholders, some common themes exist.
3.3-15
Annex 3: Prioritising Pharmaceutical R&D in a Public Health Context
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 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.
2.
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?
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?
3.3-16
Annex 3: Prioritising Pharmaceutical R&D in a Public Health Context
Appendix 2:
Antiviral Research
Chronic Fatigure Syndrome (CFS)
Emerging Diseases

Hantavirus and Other Emerging Threats

Evolution of Infectious Diseases
Fungal Diseases
Hepatic 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
3.3-17