ZonMw GGG UK Final

Proposal ZonMw Programme

Rational Pharmacotherapy

Optimising effective, safe and efficient use of medicines in health care

2 Programma Goed Gebruik Geneesmiddelen (GGG)

Contents list

Preface 31. Introduction 42. Background 6 2.1 Patient interests 2.2 Goals 2.3 Results 2.4 Context of the programme 2.5 Subject demarcation and general conditions 2.6 Programme structure3. Infrastructure 124. Research 155. Implementation 23

3 Proposal ZonMw Programme Rational Pharmacotherapy

PrefaceResearch and development is necessary to achieve progress. ZonMw (The Netherlands Organisation for Health Research and Development) funds health research and stimulates the use of acquired knowledge to improve health and healthcare in the Netherlands. ZonMw’s main commissioning organisations are the Ministry of Health, Welfare & Sport, and the Netherlands Organisation for Scientific Research.

In our view, two things are needed to improve health and healthcare in the Netherlands: knowledge, and actual use of knowledge. Aided by a range of grant programmes, ZonMw stimulates the entire innovation cycle, from fundamental research to the implementation of new treatments, preventive interventions and improvements to the structure of healthcare. In selecting grant proposals, ZonMw always looks for a combination of innovation and quality, given that this is the only way to tackle the complex challenges society faces today, and ensures that clients receive affordable care of a high standard. ZonMw unceasingly strives for the best result.

Rational use of pharmacotherapy is essential to optimise the full potential of medication. Many important research questions need to be addressed prior to, but also following the introduction of novel therapeutics. Many post-registration research questions are, understandably, addressed by the pharmaceutical industry, but it is also clear that others are left unanswered due to lack of funding possibilities.

In 2009 and 2010 ZonMw advised the Dutch Ministry of Health to provide funding for addressing these gaps in society’s knowledge of how to optimally use pharmacotherapy. These pleas included the recommendation that before research activities on a large scale can be funded, an adequate research infrastructure needs to be created. Research standards for both interventional and observational studies will require a robust infrastructure. Finally, implementation of acquired knowledge will have to become the standard in daily practice.

In order to achieve these ambitious goals, ZonMw has developed an outline for a funding programme which is presented to you here. Please note that this outline needs to be developed into a full funding programme proposal, together with the relevant stakeholders. Public-private partnership in both content and contribution is envisioned for this funding programme. This will hopefully yield a structural and fruitful collaboration between academia, private partners such as pharmaceutical companies and health care insurers, patients and government to optimise pharmacotherapy in daily practice.

Henk J. SmidDirector


1. IntroductionThe use of existing drugs can be greatly improved. An alarming number of patients do not receive the correct medication for their condition, or receive the wrong dose. Others experience unnecessary complications or side-effects. These problems affect many individual patients and aggravate the burden on the health care system which is already struggling to cope with the demands of an ageing population. There is, therefore, compelling reason to invest in ways to make pharmacotherapy with available drugs more effective, safe and efficient. More research is needed to accomplish this, as well as improved methods for the dissemination and application of new or existing knowledge.

Along with this message, contained in the report ‘Follow-up on Rational Pharmacotherapy’ (Dutch: ‘Verdieping Goed Gebruik Geneesmiddelen’), researchers, physicians and other stakeholders stated the case for a comprehensive, structural programme on rational pharmacotherapy. They voiced concern about the lack of relevant knowledge in the daily clinical use of available drugs. The report also made clear how such a programme could contribute to policy goals of the Dutch Health Department, namely, optimising safety in health care, increasing efficiency and efficacy of healthcare and alleviating the burden on health care workers in the light of a diminishing working population. The report shows that these goals are both realistic and attainable.

The current document contains a proposal for a ZonMw 1 programme ‘Goed Gebruik Geneesmiddelen’ (GGG, meaning literally: the correct use of medication, in other words ‘rational pharmacotherapy’). It is not a definitive proposal, but a general outline awaiting further choices by the financing parties. A clear decision has been made to focus on those projects which are not easily financed within the current system, and to exclude research which is the explicit responsibility of private parties. Obligatory research for registration of new medicines, for instance, will not form part of the programme, nor will the usual post marketing surveillance and other studies required by law. There will, however, be investment in an infrastructure which may also be used for these types of studies.

This proposal concerns an integrated research programme under the broad theme of rational pharmacotherapy. The programme aims to offer structural support to pharmacotherapy in daily practice. This requires a clear structure, incorporating sufficient possibility and flexibility to include projects to answer specific needs and issues which arise in daily practice. Themes relevant to policy-makers from the national government or international bodies may also be added, as well as themes which could be addressed in public-private partnerships.

The basic premise of this programme is that increasing efficacy and efficiency in pharmacotherapy enhances the quality of care, and that this results in an overall reduction of health care costs.

1 ZonMw is the Netherlands Organisation for Health Research and Development. It funds health research and stimulates the use of the knowledge developed to help improve health and healthcare in the Netherlands. More information on www.ZonMw.eu


The programme presented here can be compared to a three-storey house. The first floor offers the infrastructure. The second floor consists of all research efforts, the top floor represents the implementation of relevant knowledge.

Infrastructure is an essential prerequisite for research. In this programme, it will deliver:- Systems and tools (such as quality control systems) which enable the execution of independent

pharmacological intervention studies;- Data which can be employed in observational pharmacological research;- Conditions required optimising the use of existing data, such as harmonisation of data (using

the same terminology and structure in databases, the actual linking of data systems), transparency and accessibility of data, paying particular attention to all relevant aspects of law, ethics and social issues.

Research within the programme will lead to:- Providing answers to questions and needs arising in daily practice, and applying knowledge in

patient care;- Filling existing gaps in the evidence needed for guidelines and healthcare standards (in

collaboration with the Dutch health care quality institute, which is to be established in the near future);

- Support for policymakers in their decisions concerning medicines and pharmacotherapy, for example decisions concerning registration and reimbursement.

Implementation and application in daily practice is the ultimate goal of all efforts within the programme. Its primary aim is, after all, improved quality of care, which is in the interests of the individual patient and society as a whole. Applicable knowledge is being generated, therefore application is the final measure of success.

This means that implementation will form part and parcel of every project within the program. Furthermore, there will be initiatives leading to:- Systematic application of available knowledge on pharmacotherapy, disseminating news and

information on best practices and keeping an eye out for any gaps in the evidence;- Clustering relevant knowledge and making it accessible; this concerns both evidence already

available and knowledge emerging from new research initiatives.

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2. BackgroundRational pharmacotherapy as we define it here is about the effective, safe and efficient use of existing medication. The first report on this subject, called ‘Signalement Goed Gebruik van Geneesmiddelen’, was presented to members of the Dutch parliament on July 20, 2009. Experts from various backgrounds voiced their concern about important gaps in the available evidence, which could have severe consequences for healthcare, both in terms of efficiency and quality of care. Research on rational pharmacotherapy can improve individual patient care, and at the same time lower the overall cost of healthcare and alleviate the burden on healthcare personnel. It should, however, be borne in mind that evidence does not automatically translate into change. It is essential to pay attention to implementation issues.

GapsThe gaps in the evidence on rational pharmacotherapy have been categorised as follows:

A. Is the medicine prescribed where it is needed?B. Is the medicine prescribed in the right dosage?C. Are there other useful indications where the drug could be effective?D. Is the drug used correctly?

This first report made it clear that stimulating practice-oriented research on rational pharmacotherapy could lead to great benefits in terms of both quality and efficiency of care. This conclusion was confirmed in a follow-up study by ZonMw at the request of the Minister of Health. This report was published in the summer of 2010. The experts agreed on the potential contribution that research on rational pharmacotherapy could offer towards solving government policies challenges, especially those so-called ‘social challenges’ (policy priorities) of the Department of Health: safety in healthcare, healthcare efficiency and the reduction of the workload of healthcare workers in the light of a diminishing working population.

ConclusionsThe second report, underlining and broadening the case made in the first report, reached the following conclusions:- in order to increase the quality of day-to-day health care, there is a structural need for research

and implementation of knowledge on rational pharmacotherapy;- although there is some ongoing research, there are still major gaps in the evidence, including

areas which are highly relevant to safety, efficiency and efficacy of pharmacotherapy in the Netherlands;

- scientific research on rational pharmacotherapy is important in order to generate reliable knowledge for daily practice;

- scientific research is an international endeavour, but to implement its conclusions within the Dutch healthcare system, additional fact-finding may be necessary. Basic pharmacology can be studied anywhere, but pharmacotherapy deals with the application of this knowledge within current praxis;

- if research is attuned to the needs of daily practice, the application of its results is easier, leading to a more effective use of all available resources.

Structural independent financingIn the explorations and discussions which resulted in the first two documents on rational pharmacotherapy, a recurrent theme is the interrelation of the various problems and gaps highlighted by the experts. They repeatedly made the point that the Dutch healthcare system requires a clearly identifiable structural source of financing for projects concerning rational pharmacotherapy, so as to stimulate those areas which have until now been left behind. Independence of these financial resources is of crucial importance. Only practical relevance and scientific quality should count in the decision to accept or reject a proposal.


Some current ZonMw programmes already finance research on rational pharmacotherapy, proving that there is sufficient potential within the Dutch research community to address major issues in clinical practice. These programmes are temporary; most of their funds have already been dedicated to specific projects. They also had a limited focus on specific subjects. Research that did not match those qualifications, no matter how relevant to clinical practice, could not be financed. The need for a structural programme with a broader scope has become clear from these experiences.

Reading the two reports, one finds a recurrent plea for funding research on rational pharmacotherapy. Experts from various backgrounds and organisations stress the importance of this research, which is both necessary and expensive. It can lead to an increase in cost-effectiveness, but requires structural independent funding. One of the main areas which could benefit from structural funding is the infrastructure for independent clinical research. High-quality clinical research is being carried out in our country. The great majority of studies, however, are initiated by pharmaceutical companies. Contract research organisations (CRO’s) provide the necessary infrastructure for these studies. To answer questions concerning rational pharmacotherapy which fall outside the scope of commercial interests, an independent infrastructure for high-quality clinical research is required. Structural funding will make this possible.

Types of research in pharmacology

Depending on the subject and the available knowledge, there are several useful approaches:• Observational research; essentially a collection of (large amounts of) data in patient registries

or bio banks (the latter term refers to the storage of biological materials) that can be used in scientific analysis. Observational research can be really close to daily practice. It is an excellent way to study trends and problems in an unbiased population. Automated data analysis allows for the recognition of patterns that would otherwise escape notice. This type of research requires a good infrastructure, clear protocols on data collection, storage and analysis and, of course, good hardware and a professional organisation.

• Translational research literally translates laboratory findings into healthcare practice. More and more university medical centres in the Netherlands are focussing on this field, sometimes in collaboration with newly founded spin-off companies. This form of research requires substantial investment in facilities such as Good Manufacturing Practice (GMP) laboratories. Most translational research is aimed at the development of new treatments, which falls outside the scope of our Rational Pharmacotherapy programme. There are, however, questions which concern, for instance, the formulation of medicines for special target groups, where translational research is necessary for rational pharmacotherapy.

• Randomised Controlled Trials (RCTs) are considered the gold standard in clinical research. They deliver the highest level of evidence, provided that the study design, execution, data collection and analysis are all carried out professionally and according to the highest standards of quality. Within the pharmaceutical industry and its CROs, there is sufficient expertise to perform high-quality RCTs. In a non-commercial setting, however, there may not be as much experience in these areas. To perform independent RCTs within the framework of a Rational Pharmacotherapy programme, an independent clinical study infrastructure should be established. There is a need for hardware, qualified personnel and a well-defined set of procedures: a Good Clinical Practice (GCP) toolbox.


2.1 Patient interests

A cornerstone of the Rational Pharmacotherapy programme is the patient’s perspective. Most of the programme’s goals are derived from patient interests. This also means that patients should have a recognisable voice in prioritising the research agenda. A recent report of the Advisory Council on Health Research (Dutch: RGO) expresses the same principle (Medical products: new and needed! – which, incidentally, is not available in English). The ultimate goal of our programme is, after all, to serve the interests of the patient.

These interests have been formulated in the report ‘Follow-up on Rational Pharmacotherapy’ as follows:

• The patient requires good and effective treatment. This demands coherent research in rational pharmacotherapy, focusing for instance on gaps in the evidence concerning special groups of patients (including orphan diseases), off-label use, efficiency and efficacy, new indications, compliance and formulations. For patients with chronic diseases in particular, this is of great importance to their quality of life;

• The patient needs the treatment to be safe. This requires research on subjects such as poly pharmacy, avoidable mistakes, side-effects, special groups (for instance, children and elderly people) and formulations;

• The patient wants affordable and accessible health care. This is essentially a distribution issue, in which efficiency questions are paramount. To answer these questions, there first needs to be more evidence concerning the first two clusters of research questions.

Project proposals within the Rational Pharmacotherapy programme should be assessed independently. Parties contributing to the programme (such as governmental agencies, pharmaceutical companies, healthcare insurance companies and other commercial partners) will need to guarantee this independence. To perform relevant research and make sure the results find their way into clinical practice, efforts from all parties involved in healthcare will be needed.

2.2 Goals

The ZonMw Rational Pharmacotherapy programme has the following goals:1. Optimising effective, safe and efficient use of medications; this is accomplished by the

systematic generation, dissemination and implementation of knowledge;2. Building an infrastructure that allows for adequate and independent ways to answer questions

pertaining to rational pharmacotherapy;3. Increasing knowledge and expertise on rational pharmacotherapy in physicians, pharmacists

and the general public;4. Enhancing knowledge and expertise concerning specific groups of patients (such as children,

the elderly, pregnant women, patients with rare diseases, people of non-Dutch descent), as well as the dissemination and application of this knowledge;

5. Strengthening the scientific foundation (evidence) of guidelines and policy decisions;6. Increasing practical knowledge which contributes to healthcare efficiency;7. Increasing practical knowledge on health care safety, reduction of hospital admissions (thus

alleviating the burden on personnel), and increasing quality of care.


2.3 Results

Investing in a programme on rational pharmacotherapy would yield at least the following positive results:

Who benefits? What are the benefits?

Patient enhanced quality of life, faster recovery and decreasing loss of opportunities for work/social participation

improved safety in health care by addressing issues of under– or overtreatment

preventing side effects and interactions

keeping individual health care costs manageable

Healthcare professional

increased professional competence

act more effectively, providing better patient care

improved substantiation of pharmacotherapy, through guidelines and automated systems.

Government an (infra)structure that addresses issues relevant to policy-making

more efficient use of financial resources available for health care overall, and medicines in particular

better basis for deciding on the authorization of funds, reimbursement or financing of medicines and law-enforcement (eg on off-label use)

increasing patient safety, reduction of avoidable injury

alleviating the burden on health care workers

good healthcare for every Dutch citizen

Health insurance company

reduction of direct costs (cutting redundant drug use), reduction of indirect costs (reduction of hospitalisations and other consequences of improper drug use)

reimbursement only of medicines appropriate for the individual patient

more options for control: improved standards/guidelines

better care for the client, in particular the special client groups (elderly, children, etc.)

Pharmaceutical companies

give medicines their due, by increasing and demonstrating effective use

prevention of adverse effects associated with inappropriate use

improved knowledge of the daily use of medicines, to substantiate policy decisions (admission to market, reimbursement, etc.)

easier introduction of new drugs, as there are means to signal adverse effects.

more synergy in market introductions

Society a healthy society, with less absenteeism, more human resources and an optimum use of health care staff

the Netherlands will become an attractive country for independent high quality research on pharmacotherapy


2.4 Context of the programme

Within the NetherlandsZonMw wants the Rational Pharmacotherapy programme to contribute to the effective, safe and efficient use of existing medicines. The programme is being developed in conjunction with other initiatives with similar aims and goals initiated by other parties in our country: the Ministry of Health, client and patient organisations, sector (professional) organisations, the National Institute for the Quality of Healthcare that is being developed, reimbursement agency, Medicines Evaluation Board.

ZonMw will contribute to dissemination of knowledge, channelling of research questions and other methods to enhance synergy. This will enable optimal use of knowledge gained within the programme, in current developments within and outside of ZonMw.

Activities within the programme are relevant to policy-making in regard to medicines, such as market authorisations and decisions concerning the reimbursement or financing of specialty care products. This means that both independence and diligence are of utmost importance. When it comes to policy decisions, there are always different and sometimes differing interests at stake. The programme allows for project proposals that could not be financed otherwise.

Most importantly, the results of this programme will need to make an impact on daily practice in health care. In the assessment of project proposals, applicability will therefore be a key criterion.

InternationalRational pharmacotherapy is not, of course, an issue only in the Netherlands, and there are relevant initiatives in other countries. Communication and even collaboration with these other initiatives will contribute to the efficiency of our programme, if only through the avoidance of unnecessary duplication. Through the World Health Organisation we will connect to similar initiatives abroad, to ensure the optimal coordination of our activities.By connecting to initiatives such as EUnetHTA and ISPOR, we can tune in to a network of organisations who already have experience in financing research on pharmacotherapy, aimed at improving policy-making.

An interesting example of existing international collaboration is Priority Medicines for Children (PRIOMEDCHILD), a European initiative financed by the national research councils, aimed at research into pharmacotherapy for children. ZonMw coordinates this consortium. The main aim of PRIOMEDCHILD is to strengthen and enhance paediatric pharmacological research. One of the benefits of the consortium is the achievement of a clear overview of the various national research programmes and the exchange of expertise between the participating countries.

2.5 Subject demarcation and general conditions

The Rational Pharmacotherapy programme aims at optimising effective, safe and efficient use of existing medicines (i.e. pharmacological treatments authorised for the Dutch market). Questions surrounding the utilisation of medications in daily practice are a central theme. It can thereby imply the use of a drug:- for an indication for which the medicine has been registered;- for new indications, not yet registered (e.g. orphan diseases);- in groups of patients not included in the original registration research (e.g. children, elderly

people, pregnant women).

Pre-registration drug development research cannot be financed by this programme.

The following general conditions apply:1. Crucial to the programme is the patient, and therefore the quality of care. The programme as

well as the research that is funded will be based on this principle;


2. Research funded by the programme must contribute to optimising clinical practice, in other words, it will need to improve the use of available medicines through optimising the effect, improve the way drugs are used and/or increase cost-effectiveness;

3. Dissemination of available and new knowledge towards clinical practice is a necessary requirement for every research project within the programme. (Dissemination may take place through the usual channels: registration, financing, guidelines and healthcare standards);

4. Existing initiatives and organisations will, wherever possible, be used to enhance efficiency and avoid duplication. For example, the programme will provide the future National Institute for the Quality of Healthcare with relevant knowledge;

5. Only those projects that cannot reasonably expect to find funding elsewhere will be funded.

2.6 Programme structure

In order to achieve these goals, a structural programme that will support and promote rational pharmacotherapy in the Netherlands is needed. The programme, as proposed here, resembles a three-storey house: infrastructure, research and implementation. The driving force in research should be questions that arise in daily practice and policy-making. The integral approach of the programme allows for the creation of a more effective infrastructure for research and implementation.

This proposal is as yet preliminary, awaiting definitive decisions by those who will have to finance the programme. Both the Ministry of Health and several private parties have already indicated their interest in these proposals. The programme content can be finalised as soon as there are firm commitments.

ZonMw programmes which already contain elements of the Rational Pharmacotherapy programme, as proposed here, will be incorporated into the new programme.

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3. InfrastructureTo facilitate research on rational pharmacotherapy, a stronger infrastructure will be needed for two types of research: A. intervention studies B. observational research.

A. Infrastructure for intervention studiesMost RCTs and other drug research projects in the Netherlands are conducted on behalf of commercial parties, such as pharmaceutical companies. In these studies, all activities relating to data management and project management, quality control and quality assurance are generally in the hands of specialised contract research organisations (CROs). The costs of these activities are relatively high. The high costs and shortage of expertise outside the CRO’s represent an impediment for conducting clinical studies without industrial sponsoring.

ResultThis part of the programme focuses on the development and optimisation of facilities for independent pharmacological intervention studies such as RCTs in the Netherlands. To achieve this, independent and affordable quality control systems will be needed.

Approach The lack of an adequate infrastructure for clinical intervention research has been noted by several organisations and individuals, such as the Royal Dutch Academy of Sciences and the Federation of University medical centres. There are plans within the Central Committee on Research involving Human Subjects (known by its Dutch initials as CCMO) to develop a GCP “toolbox”. All activities concerning the infrastructure for intervention studies within the Rational Pharmacotherapy programme will be coordinated in conjunction with these parties, and with other experts in the field. Projects can be aimed at several aspects of intervention studies, such as the creation of central facilities for data management, supporting and expanding existing trial facilities, educating trial staff, etc.

B. Infrastructure for observational researchObservational research provides insight into the daily use of drugs, their effects and side-effects and complications. It also provides essential evidence which complements the outcome of registration studies. Clinical studies needed to register a new drug are performed in selected study populations, which may differ in crucial aspects from patients who receive the drug in clinical practice.The quality of observational research is determined by the accuracy with which data is collected, stored and analysed. It is important to avoid interference with the normal course of action in healthcare, and to circumvent extra burden on patients and/or healthcare professionals. In short, observational research requires a solid infrastructure which must meet strict conditions.

ResultsThis section of the Rational Pharmacotherapy programme is aimed at the creation of conditions and facilities to conduct observational pharmacological research in the Netherlands. New data will be collected and existing sources of data made accessible. Co-operation between the relevant professional groups, companies and researchers is essential to avoid duplication, and to make optimal use of all resources. The Rational Pharmacotherapy programme can stimulate the development of such synergy. Centralisation of some facilities, according to the needs of the relevant stakeholders, can enhance scientific quality using minimal financial investment.


ApproachTwo kinds of activities are needed to achieve these aims: creating the right preconditions and collecting new data.

Creating preconditionsThe most important precondition for observational research is a structure within which the available data and materials can be exchanged. The importance of this issue has been stressed in a letter from the Dutch health Minister to Parliament in response to a report from the Advisory Council on Health Research (RGO) ‘Securing the data supply’ (http://www.gezondheidsraad.nl/en/publications/securing-data-supply-availability-population-health-information-netherlands-now-and-fut). In the Netherlands, much effort is being invested into organising such networks. Thanks to these initiatives (e.g. Mondriaan project from the Top Institute Pharma, BBMRI-NL) the Dutch are prominent among pioneers worldwide in biobanking and patient registries. A considerable amount of knowledge and technology has already been developed in order to deal conscientiously with issues of privacy, safety and other legal, social and ethical aspects.

Approach: The programme will contribute to a basic structure which can be used to set up new patient registries. This structure will contain built-in guarantees for transparency, controlled public access, privacy and other patient interests. Experts and physicians who will actually collect this data will look into designing an optimal setup for data collection, dataset linkage and analysis. Wherever possible, cooperation will be established with existing initiatives, both within the Netherlands and abroad. For some diseases, there are already several competing registries, often regionally based. The Rational Pharmacotherapy programme could contribute to the harmonisation and integration of these data sets.Such a network structure for observational research will serve both private and public interests. For the realisation of this network structure public-private collaboration is desirable.

Collecting new dataPatient registries are increasingly used, both in scientific research and surveillance of effects and side effects of new drugs, following their launch. Such registries contain data on drug use, patient characteristics, clinical outcomes and other relevant aspects of the disease under study. Patient registries have been proven to provide excellent means to evaluate treatments, particularly in diseases with a variable course. The Dutch Ministry of Health plans to set up a patient registry as a precondition for the reimbursement of expensive treatments, for example in oncology. There are several patient registries in the Netherlands which function well, collecting data about diseases such as rheumatoid arthritis (DREAM), leukaemia’s and lymphomas (Hemobase en PHAROS) and cystic fibrosis (see also example Bio banks and registries). Approach: During the course of 2011, stakeholders will be consulted in order to determine for which indications patient registries may have added value in terms of improving the quality of clinical care and decision-making concerning (new) drugs. An optimal time frame for the establishment of such registries will also be determined. When actual registries are being set up, special attention will be paid to standardisation and data exchange. To facilitate exchange, it is important to know in advance which data are essential to register. Within the existing Dutch initiative (String of Pearls Initiative), a ‘minimal dataset’ has been formulated, which can act as a good starting point. Depending on the potential use of patient registries, a broader scope is needed. Not only disease-related data will need to be recorded, but also information about (co-) medication, including dosages, health care costs and quality of life. Physicians and other healthcare professionals need access to relevant subsets of the data as benchmarks for the quality of the care they provide. When this is realised, patient registries will not only be useful for the scientific results they generate, but also for their direct impact on local quality of care. An infrastructure such as this creates myriad possibilities for the study of clinical practice.


Some examples: Bio banks and registries: contributing to quality of care

Most major breakthroughs in the history of medicine have their roots in careful observation. A very observant individual physician might contribute to the solution of a medical problem, but as a rule large datasets are needed to trace relevant patterns. These facilities can be established, thanks to automated storage of both data and biological materials. In addition, new techniques are available to compute large amounts of data and perform high throughput biological analysis. During the past few years, the Netherlands has invested in bio banks within the String of Pearls Initiative and BBMRI-NL. Dedicated efforts in many hospitals have also contributed to the establishment of many patient registries.

1. A good example of the latter is the Dutch Cystic Fibrosis Registry, financed and managed by the Dutch Cystic Fibrosis Foundation (Nederlandse Cystic Fibrosis Stichting, NCFS). This registry, containing data on almost all (97%) Dutch cystic fibrosis patients, provides a number of methods by which to follow national trends and to do scientific research on several aspects of this severe genetic disorder. Clinicians may employ the registry to compare their own performance with the national average. In this way, the registry also contributes to quality of care. No data on the performance of individual centres is made public, due to the small numbers of patients, the fluctuating course of the disease and the many factors influencing it.

Cystic fibrosis is a relatively rare disease. It is therefore highly important for a Dutch registry to connect to European counterparts. European cystic fibrosis organisations already collect data on 25,000 patients, a number comparable to the cystic fibrosis registry in the United States. With numbers like these, it becomes possible to conduct additional studies amongst subgroups (for example defined by age, gender or specific genetic characteristics).

2. Several drugs for the treatment of prostate carcinoma are expected to be launched within the next few years. Registries of patients with this condition allows monitoring of the use of these new drugs and allow comparison with the current situation from the start. The establishment of patient registries would provide both healthcare professionals and authorities with relevant data on which to base their decisions and policies.

3. For many drugs no clear overview exists of all indications used in daily practice. A registry can create this overview. This allows for the identification of off-label use and may help establish and verify new indications for these drugs. Such an inventory would then provide a good foundation for studying the efficacy of the drug in a given indication. Observational studies such as these would be a great leap forward in the rational treatment of some orphan diseases, as well as in oncology, paediatrics and geriatrics.


4. ResearchThis part of the Rational Pharmacotherapy programme is dedicated to filling gaps in the evidence described in our earlier reports. Research serves three goals, which may overlap. First of all, evidence which may become the basis for new guidelines is being generated. Secondly, research will address relevant questions which may contribute to policy making by Dutch authorities (i.e. reimbursement and registration). Last but not least, questions which arise in daily practice will be answered in a way that will lead to improving quality of care.

The type of research most suited to answer a certain question depends on the question itself, as well as the available knowledge, means and opportunities. A review of the available literature will sometimes be enough to provide an answer, while in other cases observational research may help formulate the relevant research questions. Other issues warrant a randomised controlled trial, etc.

To ascertain that the results of research projects can and will be implemented in daily practice, patients and health care professionals will be consulted as part of the research proposal assessment process.

ResultsThe results of research projects carried out within the Rational Pharmacotherapy programme will lead to optimising effective, safe and efficient pharmacotherapy through practice-based solutions, careful and responsible policies relating to pharmacotherapy and a stronger evidence base for guidelines and health care standards. Quality of care for individual patients will improve. Research within the programme will be financially viable, because the results contribute to improved pharmacotherapy, decreasing the number of unnecessary consultations, hospitalisations and other interventions. Medicines will be used more effectively, thereby enhancing the patient’s quality of life.

Research within the Rational Pharmacotherapy programme will be conducted along three lines:

A. Generating evidence for guidelines and health care standardsB. Research for government agencies: input for decision-makingC Research inspired by patient needs and healthcare practice: practice-based research


A. Generating evidence for guidelines and health care standards

This section of the Rational Pharmacotherapy programme aims to gather evidence which will enhance the quality of existing guidelines and make them more suitable to select appropriate pharmacotherapy. Evidence generated within this section may also serve the development of new guidelines which will provide information on efficiency.

Guidelines are increasingly important in pharmacotherapy decision-making, on the micro level (the doctor’s consulting room), the meso level (within a hospital or group of general practitioners and pharmacists) as well as on the macro level (market authorisation, reimbursement/financing). In developing guidelines, professionals always aim for the highest level of evidence. Whenever there are gaps in the evidence, choices will be based on pragmatic considerations. Instead of a solid foundation in reviews and the meta-analysis of several high-quality RCTs, the guideline will then be based on incidental observations, clinical experience and other sources of knowledge with a high level of subjectivity. Such a pragmatic approach is of course better than nothing, as it gives clinicians a general rule of thumb to act on, but it is inappropriate to base important decisions on meso and macro levels.

There still are many disorders and categories of patients for which as yet no evidence-based guidelines or health care standards exist. In order to develop guidelines and standards where needed, additional research is often required to provide the necessary evidence.

The Dutch government plans to grant guidelines a more prominent position in the system of reimbursement and financing of medical treatment. This is possible only if guidelines also contain information on efficiency of treatments, including pharmacotherapy. In many cases, this evidence is still lacking.

Approach In this part of the program, stakeholders may pose research questions related to signalled gaps in the evidence. The assessment committee will decide whether or not the questions fit within the aims of the programme, and if the proposed research is feasible and relevant. Should this be the case, researchers interested in these questions can then submit detailed proposals for research projects. These proposals should always include a clear path which leads to embedding of the results in guidelines. The commitment of relevant stakeholders in guideline development will also need to be included in the proposal. The approach will be coordinated with the National Institute for the Quality of Healthcare, as soon as this agency has been established.


Example: A controlled trial on the contribution of Prednisolone in the treatment of Erysipelas

Erysipelas is a bacterial skin infection, often with an acute onset, caused by Streptococcus. The lesion has sharp margins, but can spread subcutaneously, sometimes affecting lymph vessels. The patient suffers acute onset fever (sometimes with cold shivers), headache, nausea and vomiting. Before the actual onset of disease, the patient often experiences general symptoms such as general malaise, fatigue and a listless feeling. Incidence of erysipelas is between 5 and 6 per 1000 inhabitants. 1,2 In a typical Dutch general practice of around 2000 patients, it is a more or less common disease. The incidence is highest in young children aged 0-14 years (incidence 13.5), declines sharply in the 14-25 years age group (incidence 2.7) and then gradually rises again with age. In people of 75 years and older, the incidence is 8.1 1. In the elderly, the lower legs are particularly affected, as circulation in the lower extremities decreases in old age.Movement is restricted due to swelling of the limbs. Patients are immobilised for several weeks, during the ten day treatment with antibiotics and 2 to 3 weeks afterwards. This often makes them dependent on home care services. The nurse will care for the skin lesion and apply bandages several times a week to decrease swelling, which aids recovery. In daily practice, it has been found that the combination of antibiotics with the inexpensive drug Prednisolone (7 days 30 mg daily) decreases recovery time by almost 50%, which allows patients to resume their activities sooner without dependence on home care services for bandage application. This finding has, however, been documented in only one controlled study which was conducted in a hospital setting 3. There is therefore currently no conclusive evidence that a short course of Prednisolone added to the usual antibiotic treatment supports recovery of patients with erysipelas in primary care. A randomised controlled trial with erysipelas patients, with rate of recovery as the main endpoint could provide this evidence. In the trial, one group of patients in primary care should receive the usual antibiotic treatment (flucloxacilline 500 mg twice daily), in the other group prednisolone (30 mg daily) will be added. An analysis of cost-effectiveness should be included. At present there are no ways to fund such a study, which could increase quality of care for the more than 75,000 Dutch erysipelas patients each year.

Based on input from Prof A.P.E. Sachs Julius Centrum Utrecht.

References:1. Okkes IM, Oskam SK, Lamberts H. Van klacht naar diagnose. Episodegegevens uit de

huisartspraktijk. Bussum: Coutinho, 1998.2 Ong RSG, De Waal MWM. RHUH-LEO basisrapport IX: databestand 2000/2001. Leiden:

LUMC Afdeling Huisartsgeneeskunde en Verpleeghuisgeneeskunde, 2002.3 Bergkvist PI, Sjöbeck K. Antibiotic and prednisolone therapy of erysipelas: a randomized,

double blind, placebo-controlled study. Scand J Infect Dis. 1997;29(4):377-82.


Example Expensive biologicals in rheumatology: lower doses may be equally effective

In the treatment of severe rheumatological disorders such as rheumatoid arthritis, Bechterew’s Disease and psoriatic arthritis, there is an increasing role for new biologicals. These new medicines such as Etanercept, Adalimumab, Infliximab, Rituximab and Abatacept are derived from antibodies and other biotechnologically produced substances. Pharmacotherapy with biologicals is effective and safe, but somewhat expensive: the costs are about €15,000 per patient per year if the drug is given at registration dose. At a higher dose, which is very common in daily practice, this price will of course be even higher 1. Data from the GIP database show that in 2008 the cost of treatment with two biologicals, Adalimumab and Etanercept already amounted to €250 million in the Netherlands. The total number of patients treated with these two drugs already exceeds 20,000. 2. The substantial gain in terms of quality of life, social participation and independence comes at a high financial price. It is therefore important to study possible ways to reduce these costs, while maintaining the beneficial effects.

During the past few years, the Sint Maartenskliniek Rheumatological Centre in the Dutch city of Nijmegen has studied dose reduction and even cessation of biologicals in patients with stable rheumatoid arthritis. The results have been quite encouraging. A study in 2002 showed that high doses of Adalimumab can be reduced by an average of 67% without loss of effect and that high doses of Infliximab can be reduced by 40%, and that this treatment can even be discontinued without loss of efficacy.3-5. The centre is currently performing a more extensive study on reduction and cessation of Infliximab on patients with stable rheumatoid arthritis. Intermediary results show significant possibilities for dose reduction, leading to a decrease in the total volume of medication and costs by tens of percentage. Elsewhere it has been shown that Rituximab is as effective at half the registration dose as at the registration dose itself.

Disease activity-driven dose adjustment has potential to limit both the costs and side-effects of drugs in future 6. Investments in clinical research needed to study and implement dose adjustment in different rheumatological diseases and with different drugs may lead to greater improvements in care while simultaneously reducing health care costs.

Based on input from Dr. F. van den Hoogen, Dr. A. den Broeder; Dr. B. van den Bemt; Dr. J van Eerd.

References:1. The frequency and effectiveness of dose increase of Adalimumab, Etanercept and Infliximab in

daily clinical practice: results of the Dutch Rheumatoid Arthritis Monitoring registry. M Blom, W Kievit, H Kuper, T Jansen , et al. Arthritis Care Res 2010

2. www.gipdatabank.nl3. Dose titration using the Disease Activity Score (DAS28) in rheumatoid arthritis patients treated

with anti-TNF. A den Broeder, M Creemers, A van Gestel, et al. Rheumatol 2002;41:638-424. Sustained effect in the majority of RA patients after lowering high dose infliximab: a

prospective dose titration study. B van den Bemt, A den Broeder, G Snijders et al. Ann Rheum Dis 2008;67:1697-701

5. Discontinuation of Infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study. Y Tanaka, T Takeuchi, T Mimori, et al. Ann Rheum Dis 2010

6. Dose de-escalation strategies and the role of therapeutic drug monitoring of biologicals in RA: evolving of new paradigms. A den Broeder, A van der Maas, B van den Bemt. Rheumatol 2010


B. Research for government agencies: input for decision-making

At several moments in the life cycle of a drug, decisions have to be made on questions concerning registration, reimbursement and financing. Most of the evidence needed to make these decisions is provided by the pharmaceutical company which markets the drug. Sometimes, however, not all evidence which might be useful for decision-making is being generated. Companies will make their own decisions, based on their assessment of potential profits, especially when there is no legal obligation to provide certain evidence. This may be the case when the drug is out of patent, when the target group is small, as in orphan indications, and of course whenever, because of competition issues, information is considered sensitive. A head-on comparison between competing drugs, for instance, is only very rarely financed by pharmaceutical companies. In short, gaps exist in evidence needed for rational decision making, which are not likely to be plugged by existing regulations and/or structures. Independently financed research is necessary to provide a better foundation for drug policy in the Netherlands.Several experts, including representatives of the Medicines Evaluation Board propose that independent research should contribute to improved pharmacotherapy by including new evidence on drugs already on the market in the registration text (SmPC text). This text is the cornerstone of all rational prescription policies. Should this suggestion become reality, the SmPC text will be constantly upgraded according to expert evaluation of available evidence. The document would then closely reflect the life cycle of a drug and provide better support for physicians and pharmacists prescribing and delivering drugs.

Approach Decision-making bodies can propose research questions relevant to their decision making process. The assessment committee will then decide if these questions fit within the aims of the Rational Pharmacotherapy programme and whether the proposed research is feasible and relevant. Research groups may then submit detailed proposals for projects to tackle these questions.

Example: Evaluation period for expensive medication

Although essential for optimal quality of care, expensive specialty care products impose financial pressure on hospital budgets in the Netherlands. To ensure access to all necessary expensive drugs, the Ministry of Health has set special policy rules. These provide for temporary and conditional financing; during a set period, the drugs will be financed, on condition that this time period is used for additional research into cost-effectiveness and the contribution of this drug to the health and quality of life of patients. In principle, this research will be done by (commercial) stakeholders. Should the stakeholders be unable to fund that research, however, such as in the case of some orphan indications, ZonMw can provide funding. The programme also offers funding for research deemed essential to decision-making by healthcare professionals, i.e. research which falls outside the remit of the pharmaceutical company marketing the drug. Working towards a good balance between the interests of the patient (accessibility of effective medicines even if they are expensive) and the interests of society (a restraint on unbridled financing of expensive drugs without added value).


Example: Registration of old drugs for new indications

Drugs long out of patent, or even no longer regularly available on the market, may sometimes appear to be useful for a new indication. A well-known example is the stimulant Dexamphetamine. Although no longer regularly available in the Netherlands, it is the treatment of second choice for children and adults with Attention Deficit Hyperactivity Disorder (ADHD). According to the Dutch pharmacopoeia (“Farmacotherapeutisch Kompas”): “In the multidisciplinary ADHD guideline, should there be insufficient effect from methylphenidate, dexamphetamine (off-label) is the next drug of choice.” and “The amphetamines are no longer on the market in the Netherlands as a preparation. Dexamphetamine is, however, being prescribed off-label in a pharmacy preparation.”

Such drugs will not be commercially attractive to pharmaceutical companies, as they are no longer patent-protected. It is highly unlikely, therefore, that companies will invest in registration studies on such drugs. From the evidence-based pharmacotherapy perceptive, however, it would be desirable to conduct these studies. As it is, these drugs are being prescribed based on clinical experience, but their effect is never validated according to the highest level of evidence. Were this to happen, the next step could be registration, for example, by a company producing generic preparations or even by a profession. Increasing the evidence base and potentially gaining registration would be in line with the new drug law (Geneesmiddelenwet, article 68) which aims to reduce use of off-label drugs, or at least provide the necessary evidence for such use.


C. Research inspired by patients needs and healthcare practice: practice-based research

The ongoing process of improving daily practice in health care implies a structural need for independent research on rational pharmacotherapy. Knowledge emerging from this research will eventually form part of guidelines and health care standards, but it serves primarily to underpin everyday professional conduct in pharmacotherapy. More knowledge is required on rare and new indications, exceptional (age-related) groups of patients, compliance, targeted pharmacotherapy, formulations and poly pharmacy. An overview of all these gaps in evidence can be found in the report ‘Follow-up on Rational Pharmacotherapy’. Part of the necessary research will address areas where there is a backlog (for example drugs which were registered before there was a legal obligation to do research in younger age groups), but there will always be a need for new knowledge on rational pharmacotherapy. Patients and professionals themselves are best suited to decide which questions are most urgent. That is why there is a bottom-up approach for this part of the programme.

ApproachThere will be open calls for proposals from researchers. Patients and patient organisations can also submit proposals, alone or along with researchers. An important criterion for funding will be applicability and feasibility. The end-user of the study must be involved in study design. The advantage of an open call approach is that proposals will be practice-based, with the highest potential for real innovation. If there is a need for some degree of guidance using themes or issues, professionals and patients will need to be consulted to select themes which reflect the most urgent issues in clinical practice.

Example Compliance: seeking new solutions for an old problem

One of the biggest problems in pharmacotherapy is the fact that most patients do not take their medication exactly as prescribed. This may be due to complex considerations such as, for instance, when patients deliberately ignore prescriptions to avoid side-effects. Researchers are exploring how changing the doctor-patient relationship could contribute to improved compliance. In some general practices, a new model is emerging in which patients, GP, nurse and other professionals function as a team. When treating chronic ailments and risk factors (blood pressure, cholesterol, etc) especially, such an approach may lead to interesting improvements.

There is also the fact that people simply forget to take their medicine. Easy technical solutions can contribute to significant improvements in compliance. In patients who have to take antipsychotic medication for instance, it has been shown that texting their mobile phone helps improve compliance, both in taking their medication and showing up at therapy sessions. Compliance can be notoriously low in patients with psychotic disorders, partly due to their cognitive disabilities. Texting and other technological solutions may also help patients with other (chronic) disorders, especially when the problem is patients forgetting to take their medication.


Example: Genetic differences influence drug effect and optimal dosage

Reports are regularly published which show that some groups of patients do not receive effective treatment because of their genetic makeup. In 2010, for instance, it was demonstrated that in some patients, the regular dose of proton pump inhibitors failed to protect them from the effects of gastric acid because of a genetic variant of the enzymes in their liver, leading to a rapid degradation of the drug. Another example is Clopidogrel, a platelet inhibitor used in the prevention of stroke, which is much more rapidly metabolised by some people. These patients also need a higher dose of the drug for it to be effective. The danger here is that lack of effect may become evident only when it is too late. Studies will need to show whether it is useful to determine the genetic make-up of every patient treated with Clopidogrel, in order to detect those patients who require a higher dose.

Example: Excipients need attention

Most pharmacological research focuses on the active substance. Excipients, once authorised, receive very little attention. This may pose a problem when drugs are used off-label. Prof. dr. Bert Leufkens, chairman of the Medicines Evaluation Board mentions a poignant example. The corticosteroid drug Prednisolone Sodium succinate is available as a generic preparation and as the proprietary preparation Di-Adreson-F Aquosum®. In oncology, this drug is sometimes administered intrathecally. Di-Adreson-F Aquosum® contains no excipients, so this is a safe off-label application of this drug. The generic preparations, however, often contain sodium-EDTA, which may cause severe complications with intrathecal use.

Excipients can also be the cause of severe problems in vulnerable groups, such as patients in a neonatology intensive care unit. This is the focus of a project within the European PRIOMEDCHILD programme. A group of neonatologists will use innovative techniques such as blood spot analysis to measure exposure to excipients. They will also study the pharmacokinetics of excipients in their very young patients. Such a dataset can become crucially important once the effects of excipients on newborn babies are known in greater detail. This European project also helps to take an inventory of all the various preparations used in neonatology, so that sometimes safer preparations containing fewer excipients can be imported from other countries.


5. ImplementationUseful knowledge and interventions proven to be successful often fail to be applied in practice. Both professionals and authorities sometimes need the proverbial gentle push. Implementation almost always takes more effort than most people expect. ZonMw values the importance of implementation of results from its programmes and projects. Applicability and application are important leitmotifs throughout the organisation. However, implementation itself is also an area of expertise for which often other well-established institutions exist. In the field of (rational) pharmacotherapy, several organisations do an excellent job implementing available evidence and knowledge. Whenever necessary, they can assist in implementing results from research projects within the Rational Pharmacotherapy programme. These efforts will be integrated in the projects themselves, and will be necessary preconditions for the funding of research projects.

The part of the Rational Pharmacotherapy programme dedicated to implementation is aimed at - identifying and flagging up bottlenecks in the implementation of existing evidence;- education and vocational training;- facilitating transfer of knowledge to both professionals and patients.

ResultsThe Rational Pharmacotherapy programme represents adjoining of forces, in which expertise, knowledge and experience come together. This also means that bottlenecks in implementation will come into sharper focus. The programme will contribute to signalling and solving these problems, either directly or through other parties. It will provide a structure for the dissemination of knowledge on rational pharmacotherapy, for example, through a network or a portal in cooperation with relevant organisations in the field. Such a structure will bring knowledge and initiatives together, creating synergy. Another way to disseminate knowledge of new developments in pharmacotherapy is through projects aimed at education and vocational training for physicians and other health care professionals and users.

ApproachThe programme efforts on implementation will be filled in following consultation of other parties involved. Wherever possible, existing structures and efforts will be used.

ZonMw is The Netherlands Organisation for Health Research and Development.

Progress requires research and development. ZonMw funds health research and stimulates use of the knowlegde to help improve health and healthcare.

ZonMw’s main commissioning organisations are the Ministry of Health, Welfare and Sport and the Nederlands Organisation for Scientific Research.

For further information on this proposal for a ZonMw Rational Pharmacotherapy programme you can get in touch with the secretary by means of

e-mail [email protected] or phone +31 (0)70 349 52 82.

Text: Pieter van Megchelen

Editorial office: Benien Vingerhoed-van Aken, Saco de Visser, Hannah Dijkhuis, Louri ’t Hart, Marja Westra, Denise Ryan

Photography: Dreamstime

Design: Boulogne Jonkers, Zoetermeer

March 2011

The Netherlands Organisation for Health and Development

Laan van Nieuw Oost-Indië 334P.O. Box 932452509 AE The HagueThe NetherlandsPhone +31 (0)70 349 51 11Fax +31 (0)70 349 51 [email protected]

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