E-DRUG: Priority Medicines for Europe and the World - conclusions
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[I strongly recommend E-druggers to read this landmark report - all chapters are downloadable freely at http://mednet3.who.int/prioritymeds/report/index.htm
Yesterday we presented the exec summary; today the conclusions and recommendations.
WB]
Chapter 9. Conclusions and recommendations
Introduction
The Priority Medicines for Europe and the World Project was established to determine priority needs for pharmaceutical innovation from a public health perspective and to make policy and research recommendations on these needs. Within this public health context, a key objective throughout has been the need to identify common areas of interest between Europe and the world as a whole, particularly in the area of discovering and developing new and improved medicines to combat diseases/conditions which pose a current or future threat to public health.
At present, pharmaceutical research and development (R&D) is based on a market driven incentive system relying primarily on patents and protected pricing as a prime financing mechanism. As a result, the research agenda is driven towards areas that represent market prospects and leaves certain health needs unaddressed. This Report suggests approaches that can be used to fill the gaps that result from the current system.
Since Europe can and should play a global leadership role in public health, the overall recommendations of this Report extend well beyond the specific needs of European citizens. This public health approach is consistent with Europes long tradition of social solidarity in which national health systems were established to create social safety nets for all citizens. In many developing countries, the poor are already increasingly affected by the chronic diseases that are widespread in Europe, including cardiovascular disease, diabetes, smoking-related diseases and mental diseases such as depression.
The recommendations presented in this Report are the outcome of a priority-setting exercise involving multiple stakeholders. This exercise used three different prioritization methods. In similar exercises in future, it is recommended that multiple stakeholders should again be involved and that a combination of prioritization methods reflecting different perspectives be used to achieve a similar balanced and optimal result.
Major recommendations
This Report has tried to identify the "main stakeholders" for further action. However, in highlighting specific DGs, this does not exclude other branches of the Commission and certainly not EU Member States. Indeed, it is in this spirit of hoped-for cooperation among many stakeholders that the bold vision of this Project must be realized.
Antibacterial resistance
Antibacterial resistance is a major long-term threat to public health both in Europe and worldwide. There is a risk that future generations will not be able to rely on the life-saving benefits of antibacterials presently enjoyed. Control strategies are needed which encompass:
Research and product development: New approaches are required for the prevention and treatment of bacterial infections, and support should be continued for research into new medicines. Economic incentives will be needed to address the kind of "market failure" which has arisen in Europe, where antibacterials are widely used and are relatively inexpensive. This contributes to the development of antibacterial resistance while providing insufficient financial return for manufacturers to invest in the development of new antibacterials. Patients, the public and industry all share a common interest in addressing this market failure.
7 EU regulatory authorities should allow limited release of new products for the treatment of proven drug-resistant organisms together with value-based pricing as this can provide a different kind of incentive for the industry to develop them (Member States, EMEA).
7 The EU should promote research into the development of rapid diagnostic tools as this would help prevent the misuse of antibacterials by identifying at the outset which antibacterial is needed for treatment (DG Research, Member States).
7 Targeted research into vaccines for specific infections may be a useful way to prevent the need for antibacterials and should be further supported by the EU Framework Programmes (DG Research, DG SANCO, Member States).
Surveillance: Effective surveillance of both antibacterial resistance and the use of antibacterial agents should be undertaken in Europe and worldwide.
7 The new European Centre for Disease Control and Prevention should coordinate an EU-wide surveillance system that would link antibacterial surveillance, monitoring of medicines use, and prescribing practices with the evaluation of interventions to prevent the emergence of antibacterial resistance. These interventions must include comprehensive education of medical students, doctors, and other health professionals and the public in the appropriate uses of antibacterials and the dangers associated with their misuse and overuse (DG SANCO).
Prevention: Prevention of communicable diseases and infection control is required to reduce the need for antibacterial agents (DG SANCO, Member States).
International cooperation: Close cooperation between regions and countries is required because drug-resistant organisms are "international travellers" (Member States, DG SANCO, DG Trade).
While these recommendations focus on antibacterial drugs, including those used to treat TB medicines, there is also a need to address the broader problem of antimicrobial resistance. In particular, resistance to antimalarials and HIV medicines is a major and growing problem in some countries. A similar combination of surveillance, prevention, R&D, and international cooperation will be required to address this threat.
Pandemic influenza
Pandemic influenza in the 21st century could be as devastating as the 1918-1919 epidemic was to a world recovering from the First World War. However, much could and must be done to prepare for this potential disaster. Making effective plans to address the inevitable influenza pandemic will also help countries prepare systems to deal with other threats, such as bioterrorism. Action needed includes efforts to:
' Support research on better short- and long-term vaccines, adjuvants (chemicals which increase the effectiveness of vaccines) and delivery mechanisms, and on new and improved antiviral agents. This includes analysis of incentives to manufacturers, as development of new anti-influenza medicines is at present not economically attractive (DG Research, DG SANCO).
' Ensure an increase in the uptake of existing vaccines in order to stimulate the market, build production capacity and provide annual immunity for all European citizens. Such a high level of immunity may reduce the severity of the pandemic and benefit European citizens (Member States, DG SANCO).
' Continue surveillance systems in Europe through the new European Centre for Disease Control and Prevention, and define the burden of disease in high-risk groups, including the elderly, pregnant women and children (DG SANCO).
' Conduct multi-country trials to better define the role of antiviral agents in reducing disease transmission, severe illness and mortality. (DG Research)
' Investigate through multi-country epidemiological studies the role of other existing medicines in reducing (co)morbidity and mortality (DG Research).
' Address liability, safety and regulatory issues associated with the production of a new vaccine under pandemic emergency situations (EMEA).
' Investigate the establishment of national stockpiles of antiviral agents to manage outbreaks (Member States).
Smoking and smoking cessation
In formulating the overall recommendations for this Report, consideration was given to the overwhelming evidence regarding the burdens of respiratory and cardiovascular disease that are attributable to smoking. Rates of smoking are particularly high in the new EU Member States as well as in many transitional and developing countries. While recognizing that the most effective response is the development and implementation of comprehensive and vigorous anti-smoking policies, to be pursued throughout Europe and the world, the Report also notes the evidence regarding the variable efficacy of some pharmacological aids to smoking cessation (e.g., nicotine replacement treatments and antidepressants). Some of these treatments have modest efficacy and some have limiting side-effects.
7 The EU could make a considerable contribution in this field by encouraging the development and testing of new compounds for treatment of smoking cessation (DG Research).
Promoting innovation through pricing and regulatory reforms
Efforts to shorten the medicine development process without compromising patient safety would greatly assist in promoting pharmaceutical innovation.
7 The EU should create and support a broad research agenda through which the EMEA, the national regulatory authorities, scientists, industry and the public would critically review the regulatory requirements within the medicine development process both clinical and preclinical - for their relevance, costing, and predictive value (DG Research and EMEA).
Health authorities are responsible for medicines reimbursement decisions that aim to ensure quality treatment for all patients, while reconciling this with budgetary constraints. This Report recognizes that novel approaches need to be reviewed against the background of the EU common market and the EU G-10 initiative.
7 Health and reimbursement authorities and manufacturers should agree on general principles for the valuation of future medicines (Member States and DG Research).
7 The EU Commission and national authorities should support a research agenda on the various methods of rewarding clinical performance and linking prices to national income levels. The Report maintains that these will help encourage industry to invest in the discovery of innovative medicines that address priority health care needs (DG Research).
To support the development of pharmaceutical innovation, there is a need to establish a more attractive basic research environment and to create long-term financial incentives for researchers in an effort to encourage high-quality research in basic biomedical research.
7 The EU and Member States should support the further strengthening of capacity in preclinical research to bridge the continuing gap that exists for various neglected diseases between the development of promising medicine leads and their entry into clinical trials (DG Enterprise, Member States).
7 The EU should continue to support the existing translational research on diagnostics, vaccines and pharmaceuticals that is presently being undertaken by small and medium-sized enterprises (DG Enterprise).
Detailed recommendations
List of priority diseases/conditions requiring priority medicines
The following diseases/conditions have been identified by the priority-setting exercise in this Report. The first three items on this Preliminary List are discussed above. The remaining conditions are discussed in sections on specific conditions ("Pharmaceutical gaps") and other sections that are based on broader issues.
Infections due to antibacterial resistance
Pandemic influenza
Smoking cessation
Cardiovascular disease (secondary prevention)
Diabetes
Cancer
Acute stroke
HIV/AIDS
Tuberculosis
Neglected diseases
Malaria
Alzheimer disease
Osteoarthritis
Chronic obstructive pulmonary disease
Alcohol use disorders: alcoholic liver diseases and alcohol dependency
Depression in the elderly and adolescents
Postpartum haemorrhage
Pharmaceutical gaps
The methodology of the Report is designed to identify pharmaceutical gaps, that is, those diseases of public health importance for which pharmaceutical treatments either do not exist (lack of basic scientific knowledge or market failure) or are inadequate (lack of efficacy or safety concerns or because the delivery mechanism or formulation is not appropriate for the target patient group).
For some diseases, the biology is well understood and there are many people willing and able to pay for medicines. For these diseases, there are likely to be a range of highly effective medicines available. Peptic ulcer, cardiovascular disease, HIV infections, diabetes and depression in adults are in this category.
For other diseases, there is a strong demand and willingness to pay, but effective medicines are not available because the biology is not well understood. This category includes diseases such as Alzheimer disease, osteoarthritis, certain cancers, depression in the elderly and children, and acute stroke.
Another category of diseases are those where the biology is well understood but there is a limited market for the products. This category includes malaria, tuberculosis, trypanosomiasis and leishmaniasis.
A fourth group of diseases are those where the biology is complex and there is a limited willingness to pay for the new medicine. This group includes orphan diseases and some neglected diseases such as Buruli ulcer. It also includes a number of preventable diseases such as chronic obstructive pulmonary disease (COPD) and alcoholic liver disease diseases which suffer from a public perception that because they are avoidable by changes in behaviour and lifestyle they are less worthy of support.
Although this categorization has limitations, it is a useful indicator of future investment needs. Where the market is strong and the problem is poor understanding of the basic biology, investment in basic research and in facilitating innovation by the pharmaceutical industry will be needed. Where the biology is well understood but the market is weak, public support for translational research possibly through product development public-private partnerships (PPPs) and other not-for-profit product development initiatives will be the preferred solution. Where the biology is not well understood and there is also a weak market, then biological research can be supported while market incentives are created for the pharmaceutical industry, through reducing barriers to innovation and through improving reimbursement rewards.
Cardiovascular disease (secondary prevention): In general, there is an absence of "user-friendly" formulations to ensure that high-risk patients receive optimal therapy. The Report recommends research on all aspects of the development of fixed-dose combinations (FDCs) for such patients (DG SANCO, DG Research, EMEA).
Diabetes: The pharmaceutical industry considers development of effective diabetes medications as a major goal, but there is still a need for oral agents to act in a more efficient manner within the body (i.e., faster absorption by the body, action to control blood glucose over a longer time period, fewer side-effects, paediatric formulations). The EU should create an infrastructure to facilitate diabetes clinical trials, in particular comparative clinical head-to-head trials to compare efficacy, side-effects and cost-effectiveness using full pharmaco-economic analyses (DG Research, DG SANCO).
Cancer: Both the public sector and the pharmaceutical industry have invested heavily in finding new pharmaceutical treatment options for cancer. However, many cancers are still resistant to treatment and the search for effective medicines is ongoing. The EU should expand its capacity (infrastructure and human resources) and strengthen coordination to conduct comparative Phase II/III clinical trials and continue to invest in basic research into cancer biology (DG Research).
Acute stroke: A major basic and clinical research effort is required as the current treatment of acute stroke is unsatisfactory. Most agents are not effective and they are associated with an increased risk of adverse events (DG Research, DG SANCO).
Tuberculosis: Diagnosing TB with the existing tools is a cumbersome, expensive and sometimes unsuccessful task. The EU should support research on diagnostics and vaccines as well as the pharmaceutical translational research presently being undertaken by product development PPPs and by small and medium-sized enterprises. Gaps in the regulatory process for new TB medicines can be addressed by joint negotiation of a global standard for regulatory approval of new TB medicines, institution of an automatic fast-track process for new TB medicines, and regulatory approval of surrogate markers (when available) to support medicine registration (DG Enterprise, EMEA, DG Research).
Depression in the elderly and adolescents: The biology of depression and its treatments are poorly understood in these groups. Antidepressants have been reported as efficacious in adults but they have high levels of side-effects. Lack of efficacy data and a growing number of medicine-related suicides preclude their use in young people. Recommendations for a publicly funded research agenda include efforts to improve the understanding of the biology of depression and its treatments and to initiate comparative studies of existing therapies (DG Research, EMEA, DG SANCO).
Osteoarthritis: Public funding of research into new diagnostics, biomarkers and imaging technology is needed for the management of this debilitating condition. Biomarkers are an essential area of research since they will help the medical community to determine who is likely to get arthritis, the severity and progression of disease, and the response to medicines (DG Research).
Alzheimer disease: Public funds must be directed toward finding more sensitive, reliable and valid instruments for detecting changes in normal aging and the onset of early Alzheimer disease. Surrogate markers are needed as therapeutic endpoints remain a major barrier in the clinical development of efficacious medicines to treat this disease (DG Research, Member States).
Chronic obstructive pulmonary disease (COPD): The overriding imperative in developing countries and in the expanded EU should be to reduce the prevalence and incidence of smoking. The outlook is poor in the short- and medium-term for development of new therapies to treat lung inflammation or reverse COPD. A major need is for translational research to convert basic science advances into products that can be used in clinical trials. It is recommended that the existing infrastructure of the Sixth Framework Programme Global Allergy and Asthma European Network should be expanded to create an EU-wide consortium to study COPD (DG Research, DG SANCO).
Alcoholic liver disease: All alcoholic liver diseases are preventable with appropriate public health responses involving behavioural and lifestyle changes, including pharmaceutical approaches to combat alcohol addiction. As in the case of COPD, the outlook is poor in the short- and medium-term for development of new therapies to treat liver fibrosis and other diseases/conditions related to alcohol abuse. The major need is for translational research support to convert basic science advances into products that can be used in clinical trials (DG Research, DG SANCO).
Therapeutic improvement through improved pharmaceutical delivery mechanisms
Two main conclusions arise from a review of the existing state of the art of medicine delivery mechanisms: first, there is a wide range of existing off-patent technologies that are underutilized; second, the advent of new biotechnology-derived protein/DNA-based medicines requires investment in better delivery technologies, particularly those that can withstand extremes of climate.
Fixed-dose combination products
Fixed-dose combinations (FDCs) could provide an important approach to the management of both chronic and acute diseases. Their application needs to be carefully analysed, taking into account the past problems associated with FDCs.
7 Three areas of research needed for product formulation are: the possible use of a cardiovascular FDC for the secondary prevention of heart attack and stroke; the use of FDCs of antiretroviral medicines for the treatment of HIV/AIDS in adults, pregnant women and children; and the development of FDCs of second-line TB medicines for the treatment of multidrug-resistant TB (DG Research, DG Enterprise).
7 Although there are pharmacological, regulatory and intellectual property/legal barriers to the widespread use of FDCs, these barriers can be overcome with a comprehensive strategy and cooperation between and among the private and public sectors (DG SANCO, DG Enterprise, EMEA).
7 It is recommended that the EU sponsor one or more FDC Centres of Excellence which would act as clearing houses for information about FDC therapy, coordinate field studies of FDCs, and assemble and maintain the best evidence on their development, as well as on regulatory and legal issues (DG Research).
Heat-stable formulations
Heat-stable formulations are required so that medicines used in hot and humid conditions maintain their required potency.
7 Research is needed to develop a heat-stable insulin, available for use in developing countries which lack a regular system of refrigeration. This would be a major public health advance, and would also provide important advantages for European patients who travel, even within Europe (DG SANCO, DG Enterprise, DG Research).
7 In order to reduce postpartum haemorrhage and maternal mortality throughout the world, the development of a heat-stable oxytocin that can be delivered through simple injection devices would lead to important public health gains (DG Enterprise, DG Research).
Special groups
The elderly
Medicines development for the elderly must also be improved. The altered body functions in the elderly (e.g. changing body composition and liver metabolism) may require adapted dosages. Appropriate dosing is the key to successful medicines development and dosing in the elderly is one Achilles heel of medicines innovation.
7 Specifically, there is a need for public funding to provide therapeutic formulations tailored to the special needs of the elderly in order to improve adherence, prevent the underuse of medicines and provide the best possible care (DG Research, EMEA).
Women
Women suffer from some common conditions more frequently than men, but women are often still excluded from clinical trials and other types of medical research.
7 Public-funded research is needed on the treatment of conditions or diseases uniquely affecting women.
7 The individual research programmes will vary according to the specific problem. For reproduction control and subfertility, basic and clinical research will probably be the priorities. For pregnancy and lactation (including birth defects), the creation and analysis of exposure and defect registers using pharmaco-epidemiological approaches are likely to be the methods of choice.
Children
To improve medicines development for children, there is a need to invest more in basic paediatric research, to increase the participation of children in clinical trials, and to reverse the underfunding of research on children-specific medicine formulations. There is also a need for more information on the safety and efficacy of medication use in children, especially for mental disorders, which account for a high burden of disease (for example, depression, anxiety disorders).
7 Specifically, there is an urgent need to develop paediatric formulations of antiretroviral medicines, including FDCs for children (DG Research, EMEA).
Neglected diseases
A clear case has been made in this Report that the EU should support research to address neglected diseases appearing in developing countries. To this end, it is recommended that the EU should:
7 Mobilize and sustain adequate funding for neglected diseases.
7 Encourage translational research to transform the results of basic research into useful medical applications, adapted to the needs of patients affected by neglected diseases.
7 Expand the activities of the EDCTP to include other neglected diseases as well as other phases of clinical development (Phase I, Phase IV).
7 Create a Centre for Preclinical Research to bridge the continuing gap between the development of promising medicine leads and their move into clinical trials. This Centre should complement the activities of the EDCTP.
7 Develop mechanisms to provide direct support for PPPs to develop drugs and vaccines for diseases where there is no commercial market.
Innovative responses to market deficiencies
Product development initiatives provide an innovative approach to the critical need for new interventions to combat examples of market failure, such as development of medicines for infectious diseases in developing countries. There are many PPPs but it remains to be seen whether this innovative approach will succeed in bringing products to market. The EU has displayed strategic leadership with the establishment in 2003 of the European and Developing Countries Clinical Trials partnership (EDCTP), focused on clinical trials for the medicines development process for HIV/AIDS, TB and malaria. However the pipelines for medicines for TB, malaria and neglected diseases are far from robust. If the chemical entities are not available to be tested in clinical trials, the EDCTP will be underutilized. To date, the role of the EU in supporting product development PPPs has been modest.
This Report recommends that the EU develop a leadership strategy and accompanying funding to provide selective support for translational and preclinical phases of R&D for medicines to treat various neglected infectious diseases.
7 The EU research funding process is not always user-friendly and may actively discourage applications from PPPs. Modifications to the current application process are needed (DG Research).
7 Innovative funding mechanisms should be promoted to encourage additional investigators to undertake multidisciplinary research on microbicides for the prevention of HIV transmission (DG Research).
Information technology and pharmaceutical innovation
When new medicines enter the market, often little is known about their effectiveness and safety beyond comparison to a placebo. Moreover, knowledge of adverse effects is usually limited to what has been detected in small, short-term trials and in pre-marketing toxicology studies. As a result, uncertainty about the relative cost-effectiveness of new and existing medicines hampers re-imbursement decisions by insurers. Estimates of the comparative efficiency and safety of new medicines require extremely large and expensive trials which may delay the entry of new products.
Traditional forms of post-marketing surveillance have concentrated on the detection of uncommon severe adverse reactions and provide little information on other important aspects of medicine performance. To help bridge this gap, there is considerable scope for the use of electronic medical records (EMRs) captured in automated databases, in the investigation of the relative benefits, side-effects and cost-effectiveness of new medicines. Studies of tens of thousands of recipients of new and older medicines, with routine collection of major outcomes, can be conducted relatively cheaply using existing databases. Studies can be strictly observational or can employ a randomization step (randomized epidemiology) in order to provide unbiased estimates of comparative effectiveness and safety.
As the results of these studies have implications for reimbursement decisions, governments and insurers should consider sharing their costs with pharmaceutical manufacturers. If agreement can be reached on the conduct and funding of such randomized epidemiological studies, it may be possible to reduce pre-marketing regulatory requirements and speed up the market entry of new medicines.
The introduction of EMRs has a range of other attractions including improvements in quality of care and in the efficiency of the operation of health systems. Electronic prescription and medical databases can be used to conduct Phase IV and other such pharmaco-epidemiologic studies. The European Commission is presently discussing so-called e-prescribing and other information technology (IT) approaches as part of its interest in the information society, although such an effort will require clarification and adjudication of outstanding issues relating to data privacy. The European Union has a clear competitive advantage in "e-prescribing" which should be exploited as a matter of urgency. In response to these challenges the Report makes the following recommendation:
7 Private insurers and governments should set aside a proportion of their annual budget for medicines in order to endow an organization which could provide an independent source of research into the comparative effectiveness and cost of medicines. This is particularly needed in the case of off-patent (generic) medicines where the industry sponsor is unlikely to invest in such strategies for post-marketing follow-up (Reimbursement authorities).
7 A research programme should be established by the EU to use electronic prescription and medical databases to conduct Phase IV and/or pharmaco-epidemiologic studies on comparative effectiveness. Results of these studies have implications for reimbursement decisions. Governments and insurers should consider sharing their results with pharmaceutical manufacturers (DG SANCO).
7 If agreement can be reached on the conduct and funding of randomized epidemiological studies, it may be possible to reduce pre-marketing regulatory requirements and speed up the market entry of new medicines (EMEA).
7 The full realization of the potential of EMR in monitoring medicine-related adverse effects and other health outcomes requires a significant commitment of resources, perhaps through inclusion in a technology platform (DG Research).
Increasing patient involvement in health policy
Since the public and patients are directly affected by the policies and practices that inform pharmaceutical innovation, policy-making must reflect an approach that includes public and patient involvement. The public's involvement must include, but not be limited to: providing advice on the harmonization of trial processes and confidentiality/informed consent protections for trial participants in Europe; providing input into the design and improvement of research for individual medications; membership of ethics committees; reviewing and setting medicines regulations; advising and disseminating information and encouraging involvement in clinical trials; providing insight into the design of treatment guidelines and reimbursement decisions.
7 The EU should use public funds to support suitable structures to allow patient feedback on these policies at the national and regional level (DG SANCO, DG Research).
Technology Platform for the Pharmaceutical Industry
"Technology Platforms" can be created under the provisions of Treaty Article 171. A technology platform is intended to unite stakeholders around a common vision and approach for the development of technologies and the mobilization of the necessary critical mass needed for research and innovation efforts. The mission of the proposed Sixth Framework Technology Platform for Innovative Medicines would be to enhance and accelerate the development process of medicines, in part through reinforced product development PPPs and increased support for small and medium-sized enterprises. Antibacterial resistance and pandemic influenza the focus of two major recommendations identified in this Report may be suitable priorities around which to build a common strategy for the European pharmaceutical and biotechnology industry. Both of these pose a major threat to global public health. Addressing them successfully would require the involvement of every country in the EU. Individuals, doctors and pharmacists, national ministries, professional associations, universities, research institutions, regulators and the pharmaceutical industry would all have to work together to address the common threat.
7 This Report recognizes that other Seventh Framework Programme actions can be used to address the issues of pandemic influenza and antibacterial resistance. However, the proposed Technology Platform for Innovative Medicines could mobilize sufficient human and financial resources across all sectors to address antibacterial resistance and pandemic influenza, while promoting innovation in the European pharmaceutical industry.
7 The Platform should adopt equitable access principles to ensure that people in developing countries will have access to the fruits of the innovations through, for example, reasonable pricing clauses or open access licences that would allow low-cost producers to offer the products in low-income countries.