high level pharmaceutical forum 2005 – 2008 final report · 10/2/2008 · january 2006 to july...

High Level Pharmaceutical Forum 2005 – 2008

Final Report

Final Conclusions and Recommendations of the Pharmaceutical Forum 2

High Level Pharmaceutical Forum 2005-2008

Introduction to the process Three years have now passed since Vice-President Verheugen and former Commissioner Kyprianou jointly set up the Pharmaceutical Forum in 2005, in order to find relevant solutions to public health considerations regarding pharmaceuticals, while ensuring the competitiveness of the industry and the sustainability of the national health-care systems. Background In its Conclusions on Medical Products and Public Health of 2000, the Council of Ministers underlined the importance of identifying innovative medicines with significant added therapeutic value to attain both industrial and public health sector goals. In this spirit, a High Level Group on Innovation and Provision of Medicines (called “G10 Medicines”) was set up by the Commission to take a fresh look at the problems facing the pharmaceutical sector. The G10 Group presented its report in May 2002 in which it set out 14 wide-ranging recommendations. In 2003, the European Commission published the Communication1 “a stronger European-based pharmaceutical industry for the benefit of the patient – a call for action” in response to the G10 Group’s Recommendations. In order to tackle some of these recommendations, the Commission created the Pharmaceutical Forum in 2005 to take the process forward around three key themes: information to patients on pharmaceuticals; pricing policy; and relative effectiveness. Mandate The process was set up to bring the European Commission, Member States, representatives of the European Parliament and a wide range of stakeholders together to take forward, collectively, the challenges relating to the: information to patients on pharmaceuticals; pricing and reimbursement policy; and relative effectiveness assessment. These three themes were identified from a total of 14 recommendations from the so-called G10 Group in its report of May 2002. The other recommendations have been or are being addressed by the Commission, in particular as part of the review of pharmaceutical legislation, research programmes and support to patient groups. Deliverables Concrete recommendations and tools have been produced during the work of the Pharmaceutical Forum in these three challenging issues. Apart from the recommendations presented in this report, it has to be acknowledged that a major deliverable has been the process itself. Bringing the Member States, EFTA, the Commission, representatives of the European Parliament, the industry and major stakeholders

1 Communication from the Commission to the Council, the European Parliament, the economic and social Committee and the Committee of

the regions “a stronger European-based pharmaceutical industry for the benefit of the patient – a call for action”, (COM (2003) 383).


from the public health sector - various parties having potentially divergent interests was as such a challenge. The second deliverable is of course the adoption of conclusions backed by recommendations for direct implementation and/or further improvement resulting from the discussions in the working groups. The last deliverable is that discussions over the last three years have provided direction for future work under the mandate of the new European Parliament and the new Commission. In the meantime, 2009 will be a year of implementation and reflection. Membership The Pharmaceutical Forum was composed of the European Commission, the 27 Member States, three representatives from the European Parliament nominated in their personal capacities, EFTA representatives and key stakeholders from the public and private sectors: - European Patients Forum - EPF - Standing Committee of European Doctors - CPME - Pharmaceutical Group of the European Union - PGEU - Association Internationale de la Mutualité - AIM - European Social Insurance Platform - ESIP - European Federation of Pharmaceutical Industries & Associations - EFPIA - European Generic medicines Association - EGA - European Self-Medication Industry - AESGP - European Association for Bioindustries - EuropaBio - European Association of Full-Line Wholesalers - GIRP A number of other stakeholders were also invited as observers for certain specific discussions. The secretariat of the Pharmaceutical Forum was provided by the European Commission's services in Directorates General Enterprise & Industry and Health & Consumers. Timetable The launch of the Pharmaceutical Forum initiative by the European Commission was officially announced to the Members on 19 October 2005, following discussions in the Health Council on 3 June 2005. Regular meetings of the three working groups and the Steering Committee took place from January 2006 to July 2008. The High Level Pharmaceutical Forum met on 29 September 2006, 26 June 2007 and 2 October 2008. The Pharmaceutical Forum initiative was officially concluded on 2 October 2008. Working methods The Pharmaceutical Forum was a high-level political platform for discussion supported by a Steering Committee and three expert working groups.


High Level Pharmaceutical Forum The Forum was the overall political driver of the process. The main role of the Forum was to provide strategic direction and political momentum for the initiative. It was also designed as a platform for discussion on competitiveness and related public health issues. The Forum was chaired jointly by Vice-President Verheugen and former Commissioner Kyprianou, followed by Commissioner Vassiliou. Members were Ministers from each Member State, EFTA, three representatives from the European Parliament and senior representatives of stakeholder members of the Pharmaceutical Forum. Steering Committee The Steering Committee gave the strategic guidance needed between the High Level Forum meetings and provided operational guidance to the Working Groups. It was also responsible for ensuring the flow of information between the Pharmaceutical Forum and the Working Groups. The Steering Committee consisted of seven Member States (selected from the EU Presidencies during the Forum process), representation of the European Parliament, and a senior representative from ten key stakeholder organisations. The Committee was chaired jointly by Directorate Generals Health & Consumers and Enterprise & Industry.

Working Groups Three expert Working Groups supported the work of the Forum and the Steering Committee. The task of the Working Groups was to provide the ideas to make progress on information to patients, pricing policies and relative effectiveness assessments.

The Working Groups were composed of representatives of the Member States, EFTA and stakeholders. Working Groups were chaired jointly by Directorate Generals Enterprise & Industry and by Health & Consumers.

Working Group on Information to Patients Working Group on Pricing and Reimbursement Working Group on Relative Effectiveness


Final Conclusions and Recommendations of the High Level Pharmaceutical Forum

On 2nd October 2008, the High Level Pharmaceutical Forum agreed on the following final Conclusions2 and Recommendations3. The High Level Pharmaceutical Forum:

1. Was launched with the overall aim of exchanging best practice and examining efficiency gains within a European high level platform, as a way of contributing to ensuring patient access to medicines within a sustainable healthcare budget, and recalls its initial mandate to discuss the competitiveness of the European pharmaceutical industry and related public health considerations, with a specific focus on information to patients on disease and treatment options, relative effectiveness assessments and pricing and reimbursement of medicinal products.

2. Acknowledges that the three-year process has strengthened the understanding of the

positions and concerns of all parties and demonstrated the added value of working together in a consensus -based manner, leading to the adoption of strategic recommendations and priorities for future joint work.

3. Welcomes the political momentum gained in the field of public health and

competitiveness of the industry and, more precisely in the three themes of the mandate, which was built on mutual understanding among the interested parties and common diagnosis for the core issues. The continuous exchange of experiences established new networks among experts and enhanced the knowledge within national authorities and relevant stakeholders. The added value of this cooperation has lead to the adoption of strategic recommendations and priorities for future joint-actions to be initiated within the three key themes.

4. Endorses the recommendations made in the specific themes of information to

patients, relative effectiveness and pricing and reimbursement. 5. Emphasises the fundamental role and responsibility of each Member of the Forum

in actively taking forward the agreed recommendations and reporting on their efforts. 6. Invites the Commission to facilitate the reporting from the Members and to engage in

a reflection process in 2009 to identify the remaining challenges in these fields.

2 In line with the competences as enshrined in the EC Treaty, the final Conclusions and Recommendations of the Pharmaceutical Foru m are

of a non-binding nature. Their implementations should reflect the overall objectives of the Pharmaceutical Forum and, therefore, contribute to the good usage of pharmaceuticals and efficiency of national healthcare systems.

3 The recommendations provide guidance to address challenges as identified in the final Conclusions from the High Level Pharmaceutical Forum. The recommendations are the result of discussions, brainstorming and exchanges of practices in the different working groups set up under the Forum. The recommendations provide concrete implementing actions, addressed to the European Commission, interested stakeholders and the Member States themselves. All the recommendations are subject to the European and national legal provisions.


Information to Patients The High Level Pharmaceutical Forum:

7. Is aware that patients and citizens increasingly expect quality information, particularly when related to their health, and recognises the urgent challenge to invest in high quality and accessible information on diseases and treatment options considering the shared responsibility of all engaged parties and the importance of empowered patients and citizens in general.

8. Recognises the role of national authorities to make the best information available

and stresses the added value of common principles, European methodologies and specific requirements for information development. The Forum welcomes in this respect the recommendations put forward, notably the quality principles for health information, the core elements for information material, and the enhanced access to information in healthcare settings for the dissemination of information to patients.

9. Recognises the benefit of mobilising the knowledge and resources from different

partners towards the generation of information and strongly calls all actors engaged in the field of information to patients to take into account the outcomes of the Pharmaceutical Forum for use in developing approaches and actions. Notes the role of existing partnerships and other collaborative approaches, bearing in mind that healthcare professionals and competent authorities remain primary sources of information on medicinal products and takes note of the Council Conclusion of 10 June 2008.4

10. Invites sound cooperation fostered by the wealth of national initiatives and

recommends the Commission and the Members to consider all aspects related to the launch of a European information library of existing high quality information to patients. The Forum invites the Commission and the Member States to consider developing formal strategies to improve health information to ensure coherent approaches both at national and at European level.

11. Stresses the need to enhance health literacy as a policy at EU and Member State

levels. Recommends that future EU policy on information to patients on diseases and treatments should move towards new approaches in a coordinated manner, built on dialogue with stakeholders, promoting health literacy and health information in the broadest sense.

Recommendation 1: Enhance quality of information 1.1 The Forum recognises that the mandate of the Pharmaceutical Forum is part of a broader health information context, as identified by a number of important elements which Member States and the Commission should commit themselves to taking into consideration when developing work in this field.

4 Council Conclusions on the Communication from the Commission to the European Parliament and the Council concerning the report on

current practices with regard to provisions of information to patients on medicinal products, in accordance with Article 88a of Directive 2001/83, as amended by Directive 2004/27/EC on the Community code relating to medicinal products for human use.


1.2 All the relevant players, including national competent authorities, the Commission, public health stakeholders and industry5, should ensure high quality information and thereafter should commit themselves to implementing and using the core quality principles and their methodology of use for the development of information, and to identifying poor quality information. 1.3 The Forum recognises the added value for patients and citizens of providing information on medical conditions jointly with information on treatment options. All the relevant players should ensure that the identified key elements for information to patients on medical conditions and treatment options are taken into consideration when information to patients is produced, assessed and improved. 1.4 The Commission should consider using the EU Health Portal to raise the visibility of good information sources and ensure that all principles developed by the Forum are applied. Member States and stakeholders, with the assistance of the Commission, should commit themselves to continuing to share information about new initiatives regarding information that are in line with the principles. 1.5 The Commission together with the Member States and the relevant stakeholders should consider developing a common approach to quality assurance of information. 1.6 The ban on advertising of prescription medicines to the general public should continue. Recommendation 2: Increase accessibility and dissemination of Information 2.1 Member States, stakeholders and the Commission should accelerate their engagement toward generation of information to citizens in effective communication formats (electronic and non-electronic means), taking account of local traditions, healthcare systems and languages. To initiate the process, Member States, stakeholders and the Commission are invited to implementing the specific recommendations identified to increase accessibility and dissemination of health information in the various healthcare settings. 2.2 The Commission should commit itself to making visible the best practices identified in the Member States and to promoting cooperation between the Member States and the relevant stakeholders to further exchange experiences. 2.3 The European Medicines Agency should continue, and be financially enabled to continue, its efforts in improving the database on medicinal products authorised in the EU as foreseen in Article 57, 1(l) of Regulation (EC) No 726/2004 and its cooperation with Member States and stakeholders with regard to information on medicinal products.

5 AIM expresses some reserve concerning the involvement of industry in providing information to patients


Recommendation 3: Generation of information by making the best use of all actors 3.1 Member States, the Commission and other stakeholders should take note of existing partnerships and collaborations between the various parties that mobilise knowledge and resources for producing and disseminating information to patients. 3.2 Member States, the Commission and other stakeholders should exchange information about the different approaches existing across Europe in the choice of partners, structures and responsibilities. They should also consider whether further collaborations could be created. 3.3 Where such partnerships and collaborations are set up, Member States and stakeholders should commit themselves to respecting the minimum ethical requirements of i) transparency, ii) disclosure of financial and other support and iii) definition of responsibilities as identified in the Forum process. 3.4 The Commission should raise the visibility of existing partnerships and collaborations, for instance by using the EU Health Portal6, which respect the ethical guidance and produce information in line with the core quality principles. Recommendation 4: Continued momentum on Information to patients 4.1 The members of the Pharmaceutical Forum are invited to disseminate the outcomes of the Forum to all interested parties and citizens, e.g. through workshops. 4.2 Member States and the relevant stakeholders are expected to ensure that the recommendations are followed up at national level. Member States and the Commission in cooperation with the relevant stakeholders should within the next two years undertake a first review of what exists, and what has been created and/or improved following the recommendations from the Pharmaceutical Forum in the field of information to patients. 4.3 Further cooperation and sharing of experiences at EU level is needed, and thus the Commission should set up a process building on the Information to Patients working group to evaluate the direct outcomes and follow-up of the Pharmaceutical Forum.

Relative Effectiveness The High Level Pharmaceutical Forum: 12. Recalls that the evaluation and the decision making process leading to decisions on

the pricing and reimbursement of pharmaceutical products lie with the national competent authorities.

13. Acknowledges the distinction between the scientific assessment of the relative

effectiveness of medicinal products and health-economic assessments of their costs and benefits. Endorses the aim of relative effectiveness assessment to compare

6 The health portal is accessible at http://ec.europa.eu/health-eu/index_en.htm


healthcare interventions in daily practice and classifying them according to their added therapeutic value.

14. Acknowledges, in this respect the importance for Member States of exchanging

information on their respective relative effectiveness assessment criteria, systems and activities in order to i) consolidate the scientific evidence on relative effectiveness by collecting data, processes and conclusions reached at national level, for purposes of comparison, where appropriate, ii) facilitate the work of the pricing and reimbursement authorities by providing them with consolidated scientific evidence, and iii) inform health-care professionals and patients on the most effective medicines.

15. Endorses the working definitions on efficacy, relative efficacy, effectiveness and

relative effectiveness which will serve as a common understanding for future exchange of information between all parties involved and calls on Member States to take these definitions into account when developing and implementing systems of relative effectiveness assessment.

16. Endorses the good practice principles7 for relative effectiveness assessment that will

set the scene for the scope of future work and invites Member States to take them into account in developing and implementing systems of relative effectiveness assessment.

17. Welcomes the check-list8 on the use of the agreed principles, which could be used

as a basis for a future toolbox for all interested parties involved. 18. Welcomes the significant added value of the first set of information gathered in

Member States on data availability and needs and on the methodologies used to conduct relative effectiveness assessments for medicinal products sampled. Welcomes the conclusions and recommendations9 reached, as regards i) the need to improve data availability on relative effectiveness throughout the product life cycle10, notably post-market data and ii) the need to address barriers of all kinds, including legal ones, that can prevent Member States and stakeholders from exchanging data.

19. Acknowledges the fact that more substantial work remains to be done as regards: i)

the development of methods for the transferability of such data and ii) the need to consider how information in the European Public Assessment Report and the National Public Assessment Report, as foreseen in Article 13(3) of Regulation (EC) No 726/2004 and Article 28 of Directive 2001/83/EC, can further contribute to relative effectiveness assessment.

20. Welcomes, in this respect the important added value of the mapping exercise of

existing networks involved with relative effectiveness assessment at European level which could take these recommendations forward. Notes that the mapping exercise concludes that this objective would be achieved more effectively by an existing network rather than by setting up a new one.

7 See annex 8 See annex 9 See annex 10 AIM and ESIP recall that the major conclusion of the exercise on the availability of data was that there are not enough data to assess

relative effectiveness at the time this first needs to be done and even later on. Exploring ways to generate the data needed to make relative effectiveness assessments on a sounder scientific basis should be done.


21. Considers that the Commission, in consultation with the Members of the Forum,

should look together with the relevant networks at how they could take forward the work that needs doing, distinguishing as appropriate, between policy-related and scientific actions.

Recommendation 5: Implement agreed good practice principles for Relative Effectiveness assessments 5.1 Member States and stakeholders - the pharmaceutical industry, social insurers, health care professionals and patients' organisations- are encouraged to adopt the agreed working definitions11 on efficacy, relative efficacy, effectiveness and relative effectiveness and to use them in the scientific literature and reports of all kinds. The use of these common definitions will ensure a common understanding of the work done at national level and will facilitate the exchange of information between all parties involved. 5.2 Member States and stakeholders are encouraged to implement the agreed best practice principles12 for relative effectiveness assessment and to regularly communicate and exchange information on their adoption, where appropriate. Such implementation should also ensure medicines receive fast access to market and appropriate reward13. Recommendation 6: Promote the exchange of information on relative effectiveness assessments in order to improve the data availability and transferability 6.1 Member States and stakeholders are encouraged to regularly exchange information in order to achieve the objectives set out in the conclusions, namely: i) to consolidate the scientific evidence on relative effectiveness by collecting data, processes and conclusions reached at national level, for purposes of comparison, where appropriate, ii) to facilitate the work of the pricing and reimbursement authorities by providing them with this consolidated scientific evidence, focusing on their priority areas and iii) to inform health-care professionals and patients on the most effective drugs. This exchange should also aim to identify any barriers, whether scientific, technical or legal, that prevents all the parties involved from circulating the information easily. 6.2 In particular this exchange of scientific evidence should focus on the need to: i) improve the understanding of the scientific evidence generated that can be used for relative effectiveness by sharing best-practice in terms of data requirements and processes; ii) increase the understanding among those involved in relative effectiveness assessments of the possibilities and limitations in the generation of data that can be used for relative effectiveness assessments during and after the granting of marketing authorisation; iii) explore better avenues for dialogue between assessing bodies and/or decision-makers and the marketing authorisation holder to address point i); 11 See annex 12 See annex 13 AIM and ESIP highlight that this last sentence was suggested by some members of the Steering Committee and not agreed upon in the

working group. Further the issues of market access and reward for innovation were topics of the working group on pricing not relative effectiveness and should therefore not be included in the recommendations of the working group on relative effectiveness.


iv) strengthen the methodological quality and rigour of relative effectiveness assessments and identify any scope for common approaches in certain areas of assessment, as appropriate; v) inform health-care professionals and patients on the most effective medicines 6.3 National authorities and companies should also consider ways of having early dialogue during product development to improve the generation of appropriate data as far as possible. 6.4 Member States, with the involvement of the European Medicines Agency, should continue their efforts to consider how European Public Assessment Report and the National Public Assessment Report can further contribute to relative effectiveness assessments. 6.5 In an effort to streamline the exchange of such information and to ensure effective EU-wide coverage of relative effectiveness assessments, Member States and the Commission should identify how existing networks could be involved and any support that might be needed. Member States and the Commission should also address the issue of the involvement of stakeholders, while observing the above agreed principles.

Pricing and Reimbursement The High Level Pharmaceutical Forum:

22. Welcomes the development of a shared understanding that pricing and

reimbursement policies need to balance (1) timely and equitable access to pharmaceuticals for patients all in the EU, (2) control of pharmaceutical expenditure for Member States, and (3) reward for valuable innovation within a competitive and dynamic market that also encourages Research & Development.

23. Welcomes the identification, analyses and development of options addressing more

specifically access issues like orphan medicines and small national markets. The Pharmaceutical Forum considers that patients in the EU should have equitable access to medicines. It therefore invites all Member States, all stakeholders and the European Commission to effectively ensure an equitable access by taking up the suggested options forward.

24. Recognizes the development of common knowledge on what kind of innovation is

expected and valued as well as on how value assessments can translate into pricing and reimbursement decisions. The Pharmaceutical Forum considers that clear and common expectations, together with consistent pricing and reimbursement decisions, can motivate the development of highly needed medicines. It therefore invites all Member States, stakeholders and the European Commission to collaborate towards these two goals.

25. Recognizes the development of several knowledge initiatives related to pricing and

reimbursement and to the control of pharmaceutical expenditure. The Pharmaceutical Forum considers it necessary that pricing and reimbursement policies and practices are based on good knowledge, including data, facts and experiences exchanged between different Member States and stakeholders. It therefore invites all


Member States, stakeholders and the European Commission to further develop a joint knowledge basis.

Recommendation 7: Access to medicines for EU citizens 7.1 Member State authorities and stakeholders of the Pharmaceutical Forum should strengthen their efforts in ensuring timely access to valuable innovations and in ensuring access to medicines for all citizens. Member States should do so following the requirements laid down in the Transparency Directive (89/105/EEC). 7.2 Member State authorities and stakeholders of the Pharmaceutical Forum should strengthen their efforts in ensuring sustainable availability and delivery of medicines to all EU Member States, in particular to small national markets. They are therefore called upon to take up the appropriate ideas developed in the Working Group Pricing and in other relevant fora. This should be done in parallel and in collaboration with regulatory efforts, taking into account the work of the Heads of Medicines Agencies14. 7.3 Member State authorities, stakeholders and the Commission should strengthen their efforts to ensure access to orphan medicines in all EU Member States. They are therefore called upon to take up the appropriate ideas developed in the Working Group Pricing regarding i) early dialogue on research and development, ii) exchange of knowledge on the scientific assessment of the clinical added value, iii) specific pricing & reimbursement mechanisms and iv) increased awareness on orphan diseases. Recommendation 8: Expect, Identify and Reward Valuable Innovation 8.1 Member States are called upon to set clear and common expectations on what innovation they consider valuable and would reward. This will give companies a clear direction on healthcare priorities and indications on the evidence needed by authorities, while bringing authorities clarity on the mid- to long-term budget needs. Companies are called upon to deliver the innovative medicines that society needs. Cooperation with patient organisations should also be encouraged. 8.2 National pricing and reimbursement policies should reflect and recognize these expectations and give a consistent reward to benefits considered valuable. 8.3 National systems on pricing and reimbursement should therefore be well aligned with systems that assess the value of medicines. Recommendation 9: Optimal use of resources 9.1 Optimal use of national budgets should take into account patients’ needs. 9.2 National pricing and reimbursement policies should ensure an efficient use of price control, a consistent package of supply- and demand-side measures and the right environment 14 See the Report of the task force of the Heads of Medicines Agencies MG, “Availability of Human Medicinal Products – 2007”

http://www.hma.eu/uploads/media/Availability_medicines_HMAMG_TF_Report.pdf


for price competition. Member States should secure the principle that a Member State authority to regulate prices in the EU should extend only to those medicines purchased by, or reimbursed by, the State. Full competition should be allowed for medicines not reimbursed by State systems or medicines sold into private markets. 9.3 National pricing and reimbursement practices should take account of experiences in other Member States. The mutual exchange of knowledge and experiences should be continued and fostered. 9.4 Further knowledge and experience should be gathered and exchanged regarding tendering, conditional pricing / risk sharing and utilisation of generic medicines. Recommendation 10: Continued momentum on Pricing and Reimbursement 10.1 Member States, the Commission and relevant stakeholders are called upon to take into account the above recommendations in policy developments. Member States and the Commission, in cooperation with relevant stakeholders, should within the next 2 years undertake a first review of progress following the recommendations from the Pharmaceutical Forum in the field of pricing and reimbursement. 10.2 Further cooperation and exchange of experiences at EU level is needed. The Commission, in cooperation with Member States, is called upon to build on and bridge the work of the Pricing and Reimbursement Working Group and the Relative Effectiveness Working Group in order to evaluate the direct outcomes and follow up of the Pharmaceutical Forum.


Annex:

Pharmaceutical Forum Reference Documents

The reference documents are the result of discussions, brainstorming and exchanges of practices in the different working groups set up under the Forum.

1. Information to Patients

- Overview of practices on access of health information in health care settings - Recommendations to enhance access to information using health care settings - Core quality criteria and a Methodology for use of the core quality criteria - Diabetes information example package - Summary of research: equipping patients to distinguish good quality health

information - Key elements for information to patients - Overview and explanatory document on different partnerships providing

information to patients - Ethical guidance with regard to partnerships - Wider Health Information – looking at the future

2. Relative Effectiveness Assessments

- Core principles on relative effectiveness assessments - Study on the availability of date to conduct relative effectiveness assessments - Overview of exiting networks and recommendations for the development of

networking and collaboration on relative effectiveness assessments

3. Pricing and Reimbursement

- Guiding principles for good practices implementing a pricing and reimbursement policy

- Ensuring access to medicines in small national markets in Europe - Improving access to orphan medicines for all affected EU citizens - Characterisation of the value of innovative medicines - From assessing innovative value of pharmaceuticals to pricing and reimbursement

decisions - Risk sharing practices and conditional pricing of pharmaceutical - The Toolbox exercise


Reference Documents To lend support to the high level discussions that resulted in the strategic recommendations, the members of the Forum exchanged considerable national experience and conducted various analyses of existing practices. This pool of knowledge resulted in numerous reference documents for the High Level Pharmaceutical Forum in the field of Information to Patients, Pricing and Reimbursement and Relative Effectiveness. The reference documents were developed on the basis of information provided by the members of the Forum, although none of them should be considered as exhaustive. All the elements developed by the Forum should be given due consideration by all authorities, stakeholders and individuals engaged in the fields of Information to Patients, Pricing and Reimbursement and Relative Effectiveness. The competitiveness of the pharmaceutical industry and related public health issues should also be improved, with better use made of the principles, methodologies, recommendations and other reference documents created within the Pharmaceutical Forum. All the documents will be available on the European Commission website15. In addition, the core documents will be published for the members of the High Level Group with the Conclusions of the Pharmaceutical Forum. List of Reference Documents - Reference Documents on Information to Patients (page16) - Reference Documents on Relative Effectiveness Assessments (page 54) - Reference Documents on Pricing and Reimbursement (page 82)

15 The webpage containing the outcomes of the Pharmaceutical Forum is accessible at http://ec.europa.eu/pharmaforum


Reference Documents on Information to Patients The Information to Patients Working Group has developed and agreed on a number of documents which should be further disseminated. The documents will be clearly referenced and made available on the European Commission website16. 1. Recommendations to enhance access to information on diseases and treatment options in healthcare settings and examples of good and innovative practices (page 18) The recommendations will help all relevant actors to enhance access and dissemination of healthcare information in the three healthcare settings: general practices, community pharmacies and hospitals. As a complement, a set of examples of good and innovative practices in several Member States have been collected and are made available on the Commission website to provide reference to existing practices. 2. Core Quality Principles on information to patients and detailed practical methodology of use (page 23 and page 25) Core quality principles on information to patients were identified as a basis for developing quality health information on diseases and related issues to patients. The quality principles were submitted to public consultation, the results of which are published on the Commission website. A methodology of use of the core quality principles will make them easier to implement. 3. The key elements for core information on disease and treatment and the diabetes package example (page32) The key elements for core information on diseases and treatment options intends to list in detail what ideally should constitute health information for patients and, more generally, citizens. A specific example of an information package on diabetes was designed as the basis for identification of the key elements of core information. Both the diabetes example package and the results of the public consultation are available on the Commission website. 4. Summary of research on patients tools to distinguish good health information quality. The summary research, based on published studies, covers two aspects. Firstly, the summary provides some examples of patients needs in different population groups and propose in an information "tool-box" some actions to tackle the problems. Secondly, the summary sets out some tools to help consumers find relevant information on the internet, including the so called D.A.R.T.S17 tools. This summary is only published on the European Commission website.

16 The webpage containing the outcomes of the Pharmaceutical Forum is accessible at http://ec.europa.eu/pharmaforum 17 D.A.R.T.S refers to Date, Author, References, Type and Sponsor.


5. Introduction to Public Private Partnerships and other Collaborative Approaches Delivering Information to Patients on Diseases and Treatment Options in Europe illustrated by an overview of existing initiatives (page 38) This document provides a summary of existing collaborations and partnerships in Europe delivering information to patients. It highlights the existing possibilities for setting up national initiatives with diverse stakeholders, and gives an idea of the multiple models already in existence. An overview table providing key information on some of the existing initiatives is annexed to the document. 6. Ethical guidance as to collaborations and public private partnership among partnering organisations (page 47) The ethical guidance aims at helping create and improve collaborations and partnerships, to ensure that relations between the various categories of partners are responsible and meaningful. 7. Wider Health Aspects (page 51) Discussions within the Pharmaceutical Forum on information to patients are recognised as being part of a wider health information context that can be further expanded in the future. This document sets out a number of issues in this wider context, linking information, for example, to patients and health literacy.


Recommendations to enhance access to information on diseases and treatment options in healthcare settings 1. Introduction The main objective of this paper is to set out recommendations to Member States, Stakeholders and the European Commission which could assist in enhancing the access to information to patients on diseases and treatment options in healthcare settings, taking into account the healthcare systems in the Member States and the national organization for elaborating and disseminating information to patients. This document focuses on access and dissemination of healthcare information in the three healthcare settings of general practices, community pharmacies and hospitals, as identified by the High Level Pharmaceutical Forum. Other settings where information to patients on diseases and treatment options are or could be accessible are therefore not within the remit of this paper, but could be considered in a future exercise. The recommendations in this document are based on the fact that information to patients needs to be addressed in the wider context of healthcare systems and policies. They are also based on the assumption that high quality information to patients on diseases and treatment options is validated against the quality criteria approved by the Forum18 and should be made available in all Member States. The recommendations target Member States, stakeholders such as healthcare professionals and healthcare institutions and the European Commission. Overall, this document is intended to contribute towards better informed patients by recognizing that patient access to information on diseases and treatment options and its discussion with healthcare professionals enable patients to: § Enhance their ability to make informed decisions about optimal disease management

and prevention in full partnership with health care professionals; § Optimise health outcomes through improved treatment concordance19 based on the

belief that the more patients are informed, the better they understand their treatment and in particular how medicines must be taken;

§ Make more effective and rational use of the therapies that are available; § Increase their awareness of benefits and risks of medicines and the importance of

reporting and managing possible side effects and adverse reactions; § Improve patients’ quality of life by adopting preventive measures, seeking earlier

diagnosis, recovering faster from illness, avoiding hospitalisation and invasive surgery where possible, and enabling patients to continue their normal daily routines.

It is important to note that patient access to information on diseases and treatment options in itself should not be seen as the end point but rather part of a process. This information process must not be dissociated from an underlying interactive communication process between the patient and his/her healthcare professional(s). Additionally, it should not be dissociated from an underlying learning process on how to best respond to patients’ and carers’ information

18 Objective and Unbiased; Patient Oriented; Evidence-Based; Up-to-Date; Reliable; Understandable; Accessible; Transparent; Relevant;

Consistent with Statutory Information. 19 Concordance describes an agreement between a patient and a healthcare professional about whether, when, and how medicines are to be

taken. Concordance therefore refers to the creation of an agreement that respects the beliefs and wishes of the patient, and not to compliance – the following of instructions.


needs, taking due account of their individual expertise, beliefs, concerns and available resources. In certain situations, such as with severe diseases or elderly people, the assistance of health professionals and social workers should be considered in order to guarantee the adoptive skills of the patient at the time of information exchange. In view of the above-mentioned principles, a strategy towards better informed and thus better educated patients, which can ensure patient safety, and lead to the most cost-effective use of medicines and treatment options while ensuring optimal therapeutic benefits should include: § Developing health literacy20; § Facilitating access to high-quality and validated information within different

healthcare settings and through signposting practices (e.g. to patients and consumers organisations, community groups, independent and certified websites and call centres);

§ Raising awareness of what patients should expect from healthcare professionals and what questions they should ask or seek answers to within the consultation process with healthcare professionals;

§ Promoting the information flow between the different health settings and teamwork in order to provide consistent messages;

§ Promoting the human contact between patients and health professionals where verbal information, complemented with tailored written and nonverbal information can be provided.

2. Barriers identified in healthcare settings In order to propose a set of relevant recommendations, an analysis of barriers to access information in healthcare settings was undertaken21. The key barriers identified as common to the three healthcare settings are as follows:

Barriers involving the Healthcare setting

Barriers involving the Healthcare Professional

Barriers involving the Patient

Ø Inappropriate or insufficient communication between healthcare settings Ø Duplication and lack

of consistency of messages passed on to the patient and to different healthcare professionals Ø Inaccessibility to

patient health records Ø Reliance on general

standards without auditing their appropriateness and implementation to specific situations

Ø Communication skills Ø Time available Ø Lack of patient-

friendly information available to healthcare professionals Ø Patronising or

judgemental attitudes towards the patient or carer Ø Working pressure/

productivity demands

Ø Health literacy Ø Time available Ø State of mind Ø Confidentiality Lack of information/too much information22

20 Health literacy is the degree to which individuals have the capacity to obtain, process, and understand basic health information and

services needed to make appropriate health decisions. 21 This refers to the different examples from pharmacies, hospitals and general practices as published on the European Commission website.


Ø Level of privacy 3. General recommendations The Pharmaceutical Forum recommends Member States, relevant Stakeholders and the European Commission: § To recognise the added value of providing information to patients on diseases and

treatment options in friendly and patient-centred healthcare settings, such as general practices, pharmacies and hospitals;

§ To encourage investment in organisations’ capacity-building initiatives to improve Health Literacy;

§ To promote the integration of information to patients aspects in health professionals' education and the development of continuous training in communication skills;

§ To support the development of collaborative care approaches23 within different institutions and among health professionals;

§ To facilitate the deployment of relevant tools, such as integrated ICT systems and electronic health records.

3.1 Key areas for action for Member States § Undertake regular and exhaustive reviews of what exists at national level, to make

sure to target initiatives on the real demands of patients. § Consider development and use of healthcare performance indicators (hcpi) and

development of tools to measure the quality of information provision and its effectiveness.24

§ Select priorities areas to target, using where relevant information gained from hcpi. § Consider national annual campaigns for the provision of key information, e.g. vaccine

immunisation, nutrition, sun protection. § Support development of national health information policies and programmes with an

active participation of organisations representing citizens and patients as well as different health professionals and healthcare settings.

§ Develop collaborative care approaches within different institutions and among health professionals by considering joint educational initiatives.

§ Promote the education and training of health professionals in communication skills; § Establish effective electronic tools, such as databases of updated information, and

communication tools, such as integrated ICT systems and electronic health records. § Invest in organisations’ capacity-building initiatives towards improving Health

Literacy. 3.2 Key areas for action for relevant Stakeholders § Map education needs and communicate them to the relevant competent authorities. § Promote implementation of best practices in the provision of information to patients in

healthcare settings. § Encourage multidisciplinary and collaborative care among health professionals. § Stimulate the use of modern technology by health professionals and patients. § Collaborate in initiatives to tackle Health Illiteracy.

22 AIM and ESIP considers that lack of access to patients own records is a barrier to access information. 23 Collaborative care is an integrated approach to care management. This type of approach is an ongoing collaboration among a variety of

health service providers, patients, their families and caregivers, and the community, with patients as both the focal point and full partner in the overall effort.

24 AIM and ESIP does not agree to include the use of hcpi in this document.


3.3 Key areas for action for the European Commission § Encourage investment in organisations’ capacity-building initiatives towards

improving Health Literacy in the Member States. § Facilitate the exchange of knowledge, evidence and good practice in the provision of

information in different healthcare settings.

4. Practical solutions as already existing in some Member States, and exemplified in the input from stakeholders and Member States Considering that a number of good and innovative25 initiatives responding to some of the challenges identified above already exist in the Members States, a number of practical solutions of interest have been extracted from the document "Overview of practices on access to and dissemination of health information in health care settings”. The selected examples26 are not exhaustive and further examples of initiatives can be found in this overview. The sources and nature of the information should be considered together with the ways of dissemination.

Member States Stakeholders involved in healthcare settings Ø Joint education programmes Ø Databases Ø Public portals, such as national

web-portals on hospitals Ø “Information prescriptions” Ø National campaign with

information packages to Healthcare professionals

Ø “Questions about your medicines” campaigns

Ø …

Ø Patient information leaflets, regularly updated, available in hardcopy and possibly in electronic format ready to print with disease and health-related information (1)

Ø Electronic templates with core information which can then be tailored to the individual patient by the health professional and printed out(2)

Ø More privacy through the creation of more isolated counselling areas, and more emphasis on information counselling(3)

Ø Call centres(4) Ø Windows displays and posters(5) Ø Technological tools(6)

- On-site TV channel with video content27; - Audio solutions and web-pages - Touch screens/waiting areas with

computer access, health contents and printer

Ø … Examples: (1) Development of patient leaflets in Danish pharmacies, and patient handbook for safer hospital stay under the chapter on Hospitals in the overview. (2) Finnish pharmacy information system. (3) Counselling session in Swedish pharmacies, internal health communicators in Swedish hospitals, and group sessions and personalised treatment calendars in Spanish hospitals.

25 France and AIM do not agree on the wording "good and innovative" in this sentence. 26 France states that it is necessary to conduct an impact study before advocating an extension of the examples given in the box. 27 AIM could have concerns with this example depending on the source.


(4) Swedish pharmacy call centre and Finnish and Icelandic GPs call services, for instance, to get "educated guessed" from local health services. (5) Posters in connection with campaigns, e.g. French pharmacies, in GPs' waiting (rooms see Spanish example). (6) Hospital webpages in France and Belgium, TVs in waiting area GP Ireland and Austria, self-service waiting area in Portuguese pharmacies with displays, computer access and printers, use of SMS in a Portuguese hospital, "TV health channel" in France with practical information for people going to hospitals. 5. Future challenges28 The implementation of some of the recommendations to enhance access to information on diseases and treatment options in healthcare settings identified above for stakeholders, Member States and the European Commission will need commitment from all the different players. The Pharmaceutical Forum therefore suggests that the Commission considerers the establishment of a group dedicated to Information to Patients under the coordination of the Commission, where Member States, Stakeholders and the Commission could engage in future steps. In a first instance, such group could focus on exchanging experiences and practices in relation to building capacity for patients’/citizens health literacy to optimise their communication/understanding capacities in healthcare settings. It should also look at encouraging the development of health professionals’ communication skills towards the patients. This could possibly lead to an EU-funded project.

28 AIM considers that point 5 goes beyond access to information in healthcare settings.


Core quality principles for patient information on diseases and treatment options High quality information must meet the criteria set out in these principles and should also have a clear process for compliance/certification. Information provided by a Member State and/or the European Commission should be done without restricting or replacing other sources. Objective and unbiased Information is objective when it is based on facts and not influenced by prejudices or personal perceptions. Information is unbiased when it is impartial, non-directive and balanced. These two definitions do not relate to the source of information which is a separate issue (see the ‘Transparent’ principle). Patient-oriented Information provided should be patient-centred taking into account patients’ needs and expectations in order to empower patients. Patients should be involved in the production and dissemination of information on diseases and treatment options wherever possible. Evidence-based The evidence base for any information resource needs to be clearly stated, including making clear the level of evidence. Information should be verifiable, based on comparisons and backed up by scientific peer review where possible. Up-to-date Information should be kept up-to-date and the date of publication should be included. Reliable Information needs to be factually correct and not misleading. Information should be scientifically valid and reflect latest knowledge. Understandable Information provided should be comprehensible for a patient/citizen. Accessible Information should be easily accessible via different mechanisms for example, through written documents, websites of certified official bodies etc. Information should also be accessible to people with disabilities. Transparent Informed choice requires transparency. That entails transparency of what is known as well as what is not known. Funding, sources of information, evidence for that source and transparency when there is known controversy about a particular treatment, for example, all need to be made clear. Relevant Information should include issues of relevance and importance to patients’ decision-making e.g. including adverse effects. Impact on quality of life and the consequences of the disease on


contribution of the patient to society/the work place are important elements of information on disease. Consistent with Statutory Information Information not regulated by statute should, nevertheless, be consistent with the legal requirements of European law (e.g. must not be designed to promote a prescription only medicine, reflecting the prohibition of direct to consumer advertising of prescription only medicines, must not be misleading etc.) and should refer, where appropriate, to statutory information approved through the process of regulation.


Methodology of use of the core quality principles on information to patients On 26 June 2007 the Pharmaceutical Forum agreed on a set of core quality principles on information to patients on diseases and treatment options:

- objective and unbiased - patient-oriented - evidence-based - up to date - reliable - understandable - accessible - transparent - relevant and appropriate - consistent with statutory information

On the request of the Pharmaceutical Forum, a methodology of use has been developed to facilitate the implementation of the core quality principles on information to patients on diseases and treatment options. The overarching goal of developing a methodology of use of the core quality principles on information to patients is to set out quality requirements for information material on diseases and treatments to prevent any promotional orientation of the information and ensuring the confidence of patients on the high quality of the information. Thereafter, the main purpose of the methodology in its application is to assist Member States and Stakeholders to develop good quality information and to help patients29 distinguish high quality information from poor quality information. The methodology of use should not undermine national control system that exists but rather contribute to support evaluations by national competent authority. The clear and reproducible criteria for each of the quality principles should be fulfilled to ensure the distinction between promotional data and good quality information. This general methodology applies to all kind of information and has the two overall practical objectives of: • Establishing a guiding framework ensuring the respect and use of the quality principles

for providers of information; • Support the Member States and/ or other organisations, as well as patients and healthcare

professionals when assessing the quality of information. It has been developed in the format of a checklist under which all the essential points of the list should be fulfilled.

29 AIM and ESIP considers that this methodology is intended for information providers and would be very difficult to be used by patients and

citizens.


Checklist ensuring the application of Core Quality Principles for Information to Patient30

1. Objective and Unbiased Information is objective when it is based on facts and not influenced by prejudices or personal perceptions. Information is unbiased when it is impartial, non-directive and balanced. These two definitions do not relate to the source of information which is a separate issue (see the ‘Transparent’ principle).

• Information should be comprehensive, complete, impartial, non-directive and balanced.31

• Information should rely on exhaustive sources of information covering the total of evidence which should be made public32.

• A publication should be peer-reviewed and approved by an independent editorial board with proven scientific expertise, with representatives from professional organisations and/or patient and consumer groups.33

• A publication should respond to the need of patients and have its aims stated at the beginning of the publication.

• It should be indicated when there are only symptomatic treatments available. • It should be indicated when products are being studied in clinical trials or made

available under compassionate use programmes34. Patients should be referred to EUDRACT, the EMEA database, for further information on clinical trials.

• It should always be indicated which choices of treatment exist, even if a full account of alternatives has not been presented in the publication35.

• It should be indicated how the treatment fits into therapeutic strategies • Information on how each treatment is administered, how it acts on the body and what

are the consequences for every day life should be included as well as the benefits and risks.

• Information on pharmaceutical treatments should contribute to the good use of medicines

30 The quality principles and their corresponding texts in italic as listed below were endorsed by the Pharmaceutical Forum on 26 June 2007,

see http://ec.europa.eu/enterprise/phabiocom/docs/pf_20070626_progr_report.pdf . 31 AIM suggest further criteria: The wording and language should be neutral and non-directive and does not see words that appeal to the

emotions, fear, creating a need, unrealistic hope or promises so that decisions are made in accordance with the patients’ own values. 32 AIM and ESIP suggests further wording: (including results of positive and negative studies). AIM added that: Information on (on-going)

clinical trials should be made available through the EMEA database on clinical trials (EUDRA CT). 33 ESIP does not agree to characterise the participants. 34 ESIP and AIM do not agree to the reference to compassionate use programmes as these are not validated information. 35 AIM and ESIP suggests to replace this criteria by: For diseases, validated treatments should be equally well described (benefits, harms,

risks…) along with information on prevention.


• The denomination of the pharmaceutical treatments should include the class names and the names of the active ingredients. References to brand names depend on EU and national legislation.36

2. Patient-Oriented and Understandable Information provided should be patient-centred taking into account patients’ needs and expectations in order to empower patients. Patients should be involved in the production and dissemination of information on diseases and treatment options wherever possible. Information provided should be comprehensible for a patient/citizen.

• The language should be clear, easy to read and appropriate for patients. • If technical terms are used, there should be an explanation or a glossary at the end of

the publication. • There should be some kind of notice that the publication is designed to support, not

replace, the relationship between patient and health professionals. • There should be an opportunity for feed-back, asking questions or reporting any

problems with the publication. • Patient groups should be involved in information production from the onset or

consulted prior to publication whenever possible to ensure the relevance of the information and to test the readability and if the message is understandable to the general public.

• The publication should commence with an overview indicating what it is about, what it covers and who it is meant for.

• The language and layout of the publication should make the information reader - friendly and facilitate the search for specific information.

36 France, AIM and ESIP do not agree to include a reference to brand names.


3. Evidence-Based The evidence base for any information resource needs to be clearly stated, including making clear the level of evidence. Information should be verifiable, based on comparisons and backed up by scientific peer review where possible37.

• The content is based on rigorous and systematic evidence • The information is developed following a systematic method which aims to minimise

bias and maintain neutrality. • Evidence-based communication techniques should be used to meet the goals of

informing, supporting and empowering patients and consumers. • A main statement, “fact” or recommendation38 should be accompanied by a level of

evidence.39 • Information on evidence should be understandable to the general public and not being

directive. • The lack of evidence, contradictory evidence, or uncertainty as well as potential

benefits and risks should be clearly stated. 4. Up to Date Information should be kept up-to-date and the date of publication should be included.

• The date of publication or last revision and the dates of the main sources of evidence used and reported in the publication should be stated.

• The date of the next planned update should be also stated when possible. • Information should be kept up-to date to remain evidence-based.

37 France does not agree to the wording "where possible because it is in contradiction with point 2 and point 5. 38 AIM and ESIP do not agree with the inclusion of "recommendation” in this criteria as information should maintain neutrality. 39 AIM and ESIP wants to add "According to the methodology of evidence-based-medicines".


5. Reliable Information needs to be factually correct and not misleading. Information should be scientifically valid and reflect latest knowledge.

• Information needs referencing to make it clear where the evidence for the information

has come from. - A main statement, “fact” or recommendation40 should be accompanied by a

reference to the source of the publication. It should not be used out of its context. - A source of evidence should be listed in a bibliography or reference list at the end

of the publication. • Method and quality review by an independent editorial board on the accuracy of the

content and the structure of the publication should be put in place. • A quality assurance system for the research and selection of information and for the

editorial review should be respected.

6. Accessible Information should be easily accessible via different mechanisms for example, through written documents, websites of certified official bodies etc. Information should also be accessible to people with disabilities.

• Information material41 should be easily accessible to patients and citizens • Sufficient supply and dissemination of material should be ensured (e.g. through

pharmacies, general practices and hospitals)42. • Opportunities to make information accessible to people with disabilities should be put

in place. • Additional official43 and/or non-commercial sources of high-quality information and

contact for support should be listed at the end of the publication under headings such as “Useful addresses” and “Further reading”.

• The reader should be encouraged to ask for further clarification or to discuss the content of the publication with a health professional.

40 AIM and ESIP do not agree with the inclusion of "recommendation" as information should maintain neutrality. 41 AIM wants to have "independent, validated, high quality information material" added to this criteria. 42 ESIP does not agree with this criteria. 43 AIM wants to have "validated additional official" added to this criteria.


7. Transparent Informed choice requires transparency. That entails transparency of what is known as well as what is not known. Funding, sources of information, evidence for that source and transparency when there is known controversy about a particular treatment, for example, all need to be made clear.

• Existing controversy about particular elements in the information should be indicated. • The publication should disclose information or a reference on where to find

information44 on the following elements: - Name, mission, structure and financial background of the organisation publishing

the material - Sources of funding for the material and possible conflicts of interest of the sponsor - Names, qualifications and possible conflicts of interest of all authors. - Names, qualifications and possible conflicts of interest of the editorial board

review and disclosure of the process and quality assurance. - Method, process and respected quality principles for the submitted information

• Origin of the information should be indicated. 8. Relevant Information should include issues of relevance and importance to patients’ decision-making e.g. including adverse effects. Impact on quality of life and the consequences of the disease on contribution of the patient to society/the work place are important elements of information on disease.

• The information provided on a certain disease should be relevant to the patient’s needs and circumstances, especially healthy lifestyle, prevention, treatment options, benefits and risks.45.

• Information should be neutral and non-directive. • The publication should not make recommendations that are unrealistic or contain

assumptions or language that may be considered inappropriate or offensive. • The inclusion of comparative information on the different treatment options should be

evidence-based and relevant to patients.

44 ESIP is of the opinion that to achieve full "transparency" the information should be included directly in the publication so the reader should

not have to look for it. 45 AIM wants to include reference to comparative information.


• The reader should be made aware that more specific and tailored information to his/her individual situation could be obtained by consulting a health professional.

9. Consistent with Statutory Information Information not regulated by statute should, nevertheless, be consistent with the legal requirements of European law (e.g. must not be designed to promote a prescription only medicine, reflecting the prohibition of direct to consumer advertising of prescription only medicines, must not be misleading etc.) and should refer, where appropriate, to statutory information approved through the process of regulation.

• The information material shall be compliant with national and European legislation. • The information delivered shall be compliant with the legal requirements of

information on medicinal products. As for information on medicinal products, information should be in conformity with approved summaries of product characteristics and patient information leaflets and it should not contradict or go beyond the key elements specified in them.

• Copyright laws must be observed. As for the special requirements internet information calls for, we refer to the report on the implementation of an Austrian health portal, which provides an extensive and feasible methodology for this purpose.46

46 France does not agree to have a reference to the Austrian report in this document. France finds that the quality criteria and other specific

criteria for information disseminated by internet have to be added as such in this methodology of use of the core quality principle and there should not be a reference to this Austrian report that has still to be discussed.


Key elements of information to patients on diseases and treatment options 1. Context This guidance template has been prepared in the framework of the EU High Level Pharmaceutical Forum Working Group on Information to Patients47. At the request of the Pharmaceutical Forum, the working group identified what could be the key elements for European level core information that could provide a basis for a wide range of information material. The development of a list of key elements of information to patients on diseases and treatment options builds on the public consultation by the European Commission on a first model information package on diabetes48. The public consultation revealed a universal acknowledgement of the value of framing what would be a comprehensive information package in different disease areas that covers all issues relevant to patients. A member of the Pharmaceutical Forum, the European Patients Forum, undertook a consultative work with its membership in relation to a framework of the key elements that would constitute a comprehensive information package for patients in different disease areas. This was developed using ‘case study’ examples from different disease areas at European and national level. For the examples selected, an all-embracing approach had been adopted to information including a variety of health-related quality of life, prevention, lifestyle, treatment, therapies, disease management, social and peer support, patient education and reimbursement options.49 2. Objectives The document key elements of information to patients on diseases and treatment options intends to list in detail what should constitute ideally the key elements of health information developed for patients and citizens. The list should constitute a reference template for drafting and development of information material and could also be used as a basis for assessing, benchmarking, improving and completing existing materials. This proposal attempts to reflect implicitly the ‘quality principles’50 in relation to information to patients that were adopted at the High Level Pharmaceutical Forum meeting in June 2007. It is important to reiterate, however, that the delivery of information to patients should be adapted to different situations. Information needs to be disease-specific, very often age and

47 http://ec.europa.eu/enterprise/phabiocom/comp_pf_en.htm 48 A public consultation on the diabetes information package pilot project developed by the Pharmaceutical Forum Information to Patient

Working Group took place in spring 2007, http://ec.europa.eu/enterprise/phabiocom/comp_pf_consult_2007.htm 49 Consultation of the European Patients Forum to its membership November and December 2006 http://www.eu-

patient.eu/news/attached_documents/EPF_reference_doc_itp.pdf 50 Core Quality Principles for Patient Information on Diseases and Treatment Options, Progress Report, 2nd Pharmaceutical Forum , 26 June

2007 , Annex B, http://ec.europa.eu/enterprise/phabiocom/docs/pf_20070626_progr_report.pdf


gender group-specific and, most importantly, accessible to the individual patient, in his or her cultural context. 3. Instructions for use Any information provider, even when providing information on a specific issue only, such as prevention, should understand that patients have various information needs. This ideal template aims to cover all the information needs that the provider should consider. The first column describes the key elements of information and is illustrated with guiding topics on what the key information might cover. While aiming to be comprehensive, the template cannot cover all disease-specific issues and does not necessarily show the order in which information should be presented. 4. Key Elements of Information to patients on diseases and treatment options The document key elements of information to patients on diseases and treatment options intends to list in details what should constitute ideally the key aspects of health information developed towards patients and citizens. It comprises a list of what constitute the key elements for information illustrated with the main topics they should cover. The content in the list of the key elements and their specifications is not exhaustive and should be adapted according to the diseases and the targeted group of the publication and the material itself.


Introduction to the Information material Background information

§ Objective of the publication § Context of the publication § Purpose of the information § Target audience

Disease

Repartition of the disease § Prevalence - Different age groups - Gender differences

§ Incidence - Different age groups - Gender differences

Diagnosis

§ Early signs § Tests § Accuracy

Pathology § Disease mechanism Causes § Inherited/Genetic disease

§ Environment § Lifestyle § Other

Symptoms

§ Description of the symptoms § Causes of symptoms § Occurrence of symptoms § Exacerbations

Development of the disease

§ Natural course/lifecycle of the disease § Severity § Disease at different stages of life

- Foetus, childhood - Adolescence - Adulthood - Pregnancy - Old age - End of life

§ Changes of cure or regression Co-morbidities Misconceptions Uncertainties Essentials on what we do not know


Living with the disease Coping with the disease • Quality of Life (health related QoL)

• In different settings - everyday life - day-care - education - home - work - travelling

• At different ages/ stages in the life continuum

• Disease and gender • Psychological factors

- Self-esteem - Relationships: love & sex, work

mates, friends, family - Communicating about the

disease (to others) • Disability-adjusted life years

(DALY) Compliance/concordance/adherence51 • Issues on managing chronic disease

• Taking part in decisions about treatment

• Following the treatment regime - Motivation - Reporting exacerbations - Changes in the treatment

• Benefits and risks of adherence, compliance/non-compliance

Availability Information on whether the medicines are placed on the market; availability of other treatments

Price/Reimbursement52 • Reimbursement status • Price status

Prospects for future development53 • Prevention • Treatments • Opportunities to be involved as a

patient54 Navigating care and support services / Patient resources

• Government • Private • Health insurance • Healthcare settings

- general practice - hospital

51 AIM suggests moving the elements to the part of patient empowerment. 52 AIM suggests including global cost of the treatment, global costs for patients to live with the disease. 53 ESIP questions this point and makes it clear that they disagree with any invitations to patients to join clinical trials. 54 France and AIM do not agree with this point.


- pharmacy - others

• Patient organisation - membership - services (help lines, education,

rehabilitation, peer support) Information for carers • Support

• Coping Prevention (as defined by WHO) • Primary prevention

• Secondary prevention Lifestyle and environment Medications 1. What can be treated

2. State of the art of treatment options55 • Class name and name of active

ingredient (INN) (brand name if possible under national/EU legislation)56

Treatment goal and medicine mechanisms (how they act)

• Indications • Contraindication • Effectiveness • Safety

- Benefits - Risks

• Side-effects • Dosage and interval • Interactions with other medicines

and treatments • Evidence-based comparison of

medications 3. Future treatment prospects57

Other treatments58 What non pharmaceutical treatments options are existing

Rehabilitation Follow-up in the convalescence period • Clinical examinations

• Tests • Lifestyle

55 Sweden wants to include environment aspects under that topic. 56 France, ESIP, AIM and Austria do not agree to the reference to brand name. 57 AIM does not support this as they consider that it could probably be used for the promotion of not validated information 58 AIM wants to include comparative information on treatment options.


Where to find more information

References Background information on the publication Author/s Publisher/s Contact information Funding of the publication Date of publication

59 AIM wants to add "official treatment guidelines"

Treatment guidelines59 Other non-commercial sources of information

• National Competent Authorities • Patients organisation • Health professionals • Health insurance organisations • Other initiatives


Introduction to Public-Private Partnerships and other Collaborative Approaches Delivering Information to Patients on Diseases and Treatment Options in Europe

The purpose of this document is to provide an idea of different models of existing collaborations and partnerships in Europe delivering information to patients on medical conditions and treatment options, considering the possible partners, structures, process, outcomes and funding. Its main objective is to clarify the existing possibilities in setting up initiatives with parties from different sectors and how each partner can contribute to the realisation of the projects. The report does not intend to evaluate the success of any initiative or to assess the information provided to the public. All the projects mentioned in this document were submitted by members of the Pharmaceutical Forum while conducting an analysis of practical implementation of partnerships/collaboration for information package at national level. An overview table mapping out the main characteristics (structure and membership; roles and responsibilities of the partners; budget and sources of financing; outcome; impact) of partnerships/collaborations submitted by the Members of the Pharmaceutical Forum is annexed to this report. For the purpose of this report, the concepts of partnerships and collaborations are understood in the broadest sense. There is indeed not one single approach in building partnerships with the objective of developing and providing information on diseases and treatment options to citizens and patients. The pre-condition for including partnerships or collaborations in this report was the decision of different actors to gather expertise and resources in a single project aiming at informing patients. The experience has shown how diverse and complementary existing approaches can be. Considering the different possibilities from the structures and outcomes of the partnerships, a number of examples were selected in the overview table to illustrate the diversity. The initiatives listed should constitute experiences of interest when developing future cooperation between different partners. Who are the partners? There are many kinds of partnerships in the Member States. The general principle is that parties launch joint projects when there is interest in sharing experiences, resources and knowledge. The variety of approaches presented to the working group has shown that initiatives can involve multiple possibilities of public-private collaborations and public-public collaborations. Examples of private-private collaborations also exist in some Member States. For the Medicine Information Project, a public-private partnership in the UK, NHS Direct online, is the provider of information on conditions and treatment options. In addition, there is the Medicine Guide, independently authored by health experts and subsidised by individual companies, which is directly interlinked with NHS Direct online. Interested parties such as industry, patient organisations, the UK Department of Health and healthcare professionals jointly supervise this initiative. The Medicine and Reason project in Austria is another example of a public-private partnership where the Minister of Health is not involved directly but where the association of Austrian social security institutions, an independent


administration, is working with the Medical Chamber, the Chamber of Pharmacists, the Chamber of Commerce and the Austrian pharmaceutical industry association. Public-public partnerships also exist in Europe. For instance, individual Swedish county councils launched Health Care Direct, a website and phone advice service on health services disease information and treatments in Sweden. Actors representing different activities and different interests share expertises and resources for specific initiatives resulting in further information to patients on diseases, treatments and health topics. How are partners involved in the projects? The roles and responsibilities of the partners are very diverse. In some initiatives, partners are involved only as resource providers, i.e. providing funding or knowledge. Orphanet, for example, is a government service headed by INSERM, the French Institute for Health and Medical Research. For some of its ad hoc projects, such as the provision of information on orphan drugs and on clinical trials, the private sector is involved by providing financial support. Partners might also contribute by providing initial information, to be used as a basis for the end product. This is the case, for example, with FASS.se, where the pharmaceutical industry provides information on pharmaceutical products – package leaflets, SPC, etc. to the national medical product register. In other projects, partners provide factual content on health/disease topics. In other initiatives, parties are involved at a later stage in the production of information. In a number of cases, independent experts are in charge of the drafting of information and stakeholders, including patient organisations, healthcare professionals and sometimes industry, are involved through being consulted on the text. This is the case with "Informed Health Online" (Gesundheitsinformation.de) in Germany, for instance. Finally, all partners can also be at the core of projects, being deeply involved throughout all stages of the development of the projects. This kind of involvement can be organised in different ways, e.g. within the board of trustees (Informed Health Online), or within a Steering Committee (Informatum in Denmark and Medicine and Reason). What are the possible outcomes of partnerships? Most of the initiatives on information to patients on diseases and treatment options that were mentioned to the Pharmaceutical Forum focus on electronic information. A number of websites created by partnerships which disseminate information on diseases and/or pharmaceutical treatments already exist in the UK, Germany, Sweden and Denmark. Other possible non-electronic outcomes of collaborations are flyers, drug guides, guidelines, fact sheets, newsletters and phone advice.


What about validation? From these examples, it seems that a common trend exist regarding the validation process of information. In general, initiatives have clearly defined validation systems in place. As part of the process, there are usually two key safeguard mechanisms. Firstly, the draft material is presented to independent expert groups for a first review. Afterwards, as a final condition before publishing, the text is usually sent for validation by a review group, usually composed by stakeholders. The liability of the sources of information is of major importance. How are the outcomes disseminated? It should be mentioned that initiatives resulting from collaborations between different parties are sometimes directly linked to or even integrated within public authorities’ websites. This is the case in the UK, with NHS Direct Online, and in Germany with the website of the German Institute for Quality and Efficiency in Healthcare. Other initiatives are separately promoted, such as FASS.se or Orphanet. Dissemination of the outcomes can also be carried out by specific members of the partnership. For Medicine and Reason, flyers are distributed by three of their funding members (the Main Association of Austrian Social Security Institutions via its Health Care Institutions, the Medical Chamber and the Chamber of Pharmacists) in healthcare settings, while, in parallel, all members have included the project on their websites. Impact 60 Considering the different aims of the initiatives, the impacts of the collaborations mentioned to the Information to Patient Working Group are variable. Some initiatives can reach many citizens, illustrating the increasing need for information by patients. The Swedish FASS.se has 4 million visitors a month, of which 40% are patients or citizens. Orphanet has 20 000 daily users from 150 countries of which 33% are patients. In addition to the extensive use of certain initiatives, the degree of satisfaction among users is also found to be high. 88% of users of the Medicines Information Project found the information to be of use, and 85% found the information to be trustworthy. Financing Funding of the projects can be either public or private. In the Medicine and Reason project, for example, the costs are shared equally by all four members (Austrian pharmaceutical industry association and the Chamber of Commerce are regarded as one member). The financing systems of initiatives also vary. Indeed, the running of the initiatives can depend on annual contributions (Informed Health Online/Gesundheitsinformation.de), sponsorship of ad hoc projects (Orphanet), or even fees from pharmaceutical companies per product mentioned (FASS.se).

60 The figures used in the report were provided by members of the Pharmaceutical Forum and are only indicative.


Overview of Existing Collaborations / Public Private Partnerships in the field of Information to Patients61 62

Name – Member State Structure and membership (link to legal basis and mandate if publicly available)

Role and responsibilities of the partners

Budget and sources of financing

Outcomes

Impact • Number of users/Frequency of

use • Level of trust/number of

complaints • Other

Medicines Information Project UK

Partnership including government, MHRA, NHS, pharmaceutical industry, patients, HC professionals Details on the website

Supervisory remit for the project, giving it overall direction and setting priorities

• Funding for development of the NHS Direct Online content about medical conditions and treatment options, provided by NHS Direct Online.

• Funding for individual Medicine Guides provided by the pharmaceutical industry

• The funding model is based on a fee per product and contribution to development and management costs based on companies’ turnover.

Medicine guide: guide about individual medicines with links to/from information about condition and treatment options published on NHS Direct Online

• website

• Approaching 500000 pages download per month

• Survey about the information: 88% usefulness, 85% trust

• Direct electronic interaction with NHS direct and the Health encyclopaedia

Medicine and Reason Austria

Partnership between main association of Austrian social security institutions, industry/Chamber of Commerce, medical chamber, pharmacist chamber. (Guideline for procedure, external quality assurance of abidance by this procedure)

• Members of the Steering Committee and of all other boards (expert group, implementation, evaluation)

• After a first draft being developed by experts, stakeholders are consulted through roundtables

€ 73 000 p.a. 25% paid by each partner

Flyers on disease and treatments for patients disseminated free of charge to Healthcare settings and in addition accessible on internet, and guidelines for general practitioners

• 9 guidelines and flyers available (Jan. 2008)

• website

• last printed edition: 260 000 flyers and 18 000 guidelines

• support for general practitioners and patients

• provision of state-of-the-art and evidence based therapies at an economically reasonable price

• interdisciplinary approach

61 This overview is not exhaustive or exclusive. 62 AIM and ESIP stresses that this overview should not aim to provide the basis for a recommendation for the establishment of collaborations or public private partnerships.


FASS.se Sweden

Pharmaceutical industry association involved in certain collaborations contributing to the website - Swedish Association of Local Authorities and Regions: Supply and development of information to the Swedish health care - Medical Products Agency, the Pharmaceutical Benefits Board and the National Corporation of Pharmacies : National Medical Products Register - Uppsala University: interactions and descriptive texts on certain topics - National Poisons Information Centre: overdose treatment - Swedish Environmental Research Institute: Validation of environmental classification - Stockholm county: Development of environmental classification

• Product information supplied by pharmaceutical companies.

• Other information by independent authors.

Individual pharmaceutical companies

Website: • Patient FASS text on authorized

medicines in Sweden • 300 diseases and their treatments,

40 topics covering general aspects of use

• information about patient organisations

• R &D information for more than 60 diseases

• Access to ongoing and completed clinical trials

• Environmental classification • Pregnancy and lactation

classification Accessibility for disabled people: Braille, text to voice, large font printouts and automatic translation of medical terms in SmPC and similar documents My Fass: to store patients medications. Rapid alert function available to disseminate information on product information updates. Medicines compendium: Patient-FASS is biannual publication

Website • 4 million visitors/mth with

40% visitors from general public/patients.

• Information distributed electronically to various information systems within the Swedish health care, pharmacies, etc.

• Off-line to PDA • Access from mobile phones • Information structured for

electronic transmission and supports medical decision systems

• Main provider of information on medicines in Sweden

• Cross- reference to several public sites

Patient-FASS: 35 000 copies

Sjukvårdsrådgivningen (Health Care Direct) Sweden

Partnership between county councils

Managed by a management board and editorial board. 85 employees working on the text.

Financed by the county councils with an annual budget of € 28 500 000

• Website with 1350 topics about diseases and drugs

• Phone advice

• 80 000 website visitors/mth • 3.5 millions phone advices


Medical Products Agency Sweden

Partnership with the health care, industry, and user organisations

Medical Products Agency: responsible for the production of information Other partners: advice and authorship

Website for the public on drugs and diseases

5200 website visitors / month

Partnership with the Swedish Medical Association

Medical Products Agency: production joint authorship

Included in the ordinary budget of MPA

Drug guide: 460-page book for the public on drugs and diseases

15 000 copies sold

Informed Health Online Gesundheitsinformation.de Germany

German Institute for Quality and Efficiency in Health Care cooperates with stakeholders in the final stage of the development of the information. Legal basis: Section 139a and 139b of Social Security Code Book V (SGB V)

• Board of trustees (health professionals, patients, community and industry)

• Researchers in charge of the first drafts which scope and messages will be submitted for approval. Consultations are organised with Health Ministry and board of trustees; Test readers as a final stage

Non-government Foundation established by legislation, which is financed by statutory health insurance contributions and funding from the Ministry

Website on diseases and treatments • Over 1 000 topics by 2012 • German and English • website

• Multiple international cooperation, including adoption of the patient information by NHS Direct and HAS

Infomatum Denmark

Partnership including government, pharmaceutical industry and organisations: Ministry of Health and Prevention, Industry Association for Generic Medicines, Medical Association, Association of the Pharmaceutical Industry, Medicines Agency, Pharmacy Association, Regions and Association of Parallel Importers Information on the website: http://www.infomatum.dk/

• Steering committee is responsible for 1. Impartial and knowledge based presentations on medicines and the most suitable use in patient treatment and 2. chooses members for the board of directors/executive committee

• Executive committee selects a steering group with representative of all the partners

• Owned by DADL (Danish Medical Association) and DLI (Danish Medicinal Products Information) which have an annual turnover of DKK 45 million

• The publishing establishment is financed by the pharmaceutical firms which are members of the industrial organisations represented in the steering group

Guidelines for practitioners of medicines

Objectives: - To improve the existing level of knowledge on medicines and strengthen the decision-making in connection with choice of treatment - To ensuring that patients get a treatment of high technical skill

• Website • Book • Offline PDA


Directorate of Health Iceland

Government agency headed by the Medical Director of Health. One function is to advise the Minister of Health and Government bodies, health professionals and the public on matters concerning health and health care services. Information about the structure on the website.

• A clinical guidelines unit cooperates with other clinical guidelines providers, nationally and abroad, among them the Landspitali University Hospital. The unit makes use of foreign clinical guidelines and adapts them to Icelandic circumstances.

• The DH unit of professionals chooses material for website information for the public on health and diseases.

Funded by the State Website: • Clinical guidelines for

professionals (the most frequently visited pages on the DH website).

• Information for the public on health and diseases with links to validated websites in English and in Icelandic.

Website: • 46 000 page impressions/month • 7000 visitors/ month

Orphanet

• Consortium of 37 national partners

• Independent national Orphanet teams with scientific advisory board and consortium agreement.

• Central coordination by the French team.

• Ad hoc cooperation with private and/or public organisations

• French team in charge of information on diseases written by experts and peer-reviewed; and of coordination with national teams to collect data on services at national level.

• The scientific advisory boards advise the local teams and validates the national information.

• Partners involvement depending on the project - Financial support - Data sharing from

industry, clinicians and patients organisations.

• Core budget: Minister of Health of France, INSERM (National Institute of Health and Medical research) and European Commission

• Sponsor financing specific projects: Industry organisation, patient organisation and insurances.

• Information mostly electronic: 1. Orpha.net: Website

- Database of information on rare diseases (5806 diseases) with direct link to a health encyclopaedia

- Database of information on orphan drugs (45 orphan drugs in Europe, 530 European designations, 591 clinical trials)

- Specific information per diseases with reference to: specialised clinics, diagnostics test, research activities including clinical trials and patients organisations

2. OrphaNews: Newsletter bi-monthly • Languages: English, French,

Spanish, German, Portuguese and Italian

• 20 000 daily users from 150 countries. Users: 33% patients and they entourage, 33% Doctors, 18% other health professionals

• 96% satisfaction of Orphanet users

List of websites:

1. Medicines Information Project: http://medguides.medicines.org.uk 2. Medicine and Reason: http://www.sozialversicherung.at 3. Fass.se: http://www.fass.se 4. Sjukvårdsrådgivningen: http://www.sjukvardsradgivningen.se 5. Medical Products Agency (Läkemedelsverket):

http://www.lakemedelsverket.se 6. Informed Health Online:

http://www.informedhealthonline.com/Gesundheitsinformation.de 7. Infomatum: http://www.medicin.dk 8. Directorate of Health / Iceland : http://www.landlaeknir.is 9. Orphanet : http://www.orpha.net/


Ethical guidance as to collaborations and public-private partnerships among partnering organisations for generating and delivering information to patients on diseases and treatment options.63 Preliminary Remarks 1. To support creation and improvement of existing public-private-partnerships or other collaborative approaches for generating and delivering information to patients on diseases and treatment options, the Information to Patients Working Group of the High Level Pharmaceutical Forum has mandated a number of its members to draft a methodology within work area 3 “Practical Implementation of the Partnership for Information Package at the National Level”. 2. As a first step, it was proposed to work on ethical guidance necessary for the realisation of new collaborations or to consolidate existing partnerships among partners of any nature. Indeed, ethical guidance should be considered as a tool and thus, respected by all the partners in order to ensure that relationships between partners in a collaborative initiative take place in an ethical and transparent manner for the success of the initiatives. 3. Certain Member States or organisations have already their own ethical guidance applicable for such collaborations/partnerships. The ethical principles and rules listed in this document should not been seen as "reinventing the wheel", or as an exhaustive list, but rather as general guidance providing the main ethical elements for collaborations and partnerships generating and delivering information to patients on diseases and treatment options. 4. In this document, organisations and partners cover all possible organisations interested in being involved in collaborations and partnerships for generating and delivering information to patients on diseases and treatment options. 5. Any collaboration or partnership should respect in full the existing EU ban on direct-to-consumer advertising of prescription-only medicines. Introduction The purpose of this ethical guidance is to ensure that partnership models and other collaborative approaches for generating and delivering information to patients on diseases and treatment options between any categories of partners take place in a responsible and meaningful manner. This kind of collaboration for the common good should reduce the duplication of effort by allowing to combine diverse strengths and resources and promoting greater effectiveness in tackling priorities. Furthermore, the relations and the outcomes of collaborations should also be conducted in such a manner that the parties’ independence from one another is not jeopardised or questioned from either legal or ethical standpoints.

63 AIM and ESIP would like to recall their serious reservations about the establishment of public-private partnerships in the context of

information to patients as expressed to the members of the Forum on 20 June 2007.


Considering the essential role of ethical aspects in any collaboration, an approach relying on three principles is proposed for the application of the ethical guidance for collaborations or partnerships in the field of information to patients. A - Ethical Principles The following three ethical principles64 should serve as a reference for all collaborations in this context:

1. Transparency 2. Disclosure of financial and other support 3. Definition of responsibilities

B - Ethical rules Ethical rules have been developed to provide a common understanding of the implementation and application of ethical principles in any collaborative approach or partnership. Rule 1: Transparency 1.1 Collaboration between partnering organisations should be set down in written agreements. 1.2 The written agreements should state the name of the initiative, the list of the partnering organisations, a description of the initiative and its objectives, the financial plan including the total amount of the initiative, the repartition and origins of direct and indirect funding, and the time frame of the initiative, and it should clearly state the roles, the rights and the obligations of each party. Information regarding the finances and funding of the partners and their interests in the field of activity of the partnership should also be stated. 1.3 Written agreements between organisations, contracts and any other internal documents should be publicly disclosed and be kept available to third parties via their home pages on the Internet and/or on request. 1.4 Openness relates to all agreements, whether ongoing, concluded or regarding future initiatives. Rule 2: Disclosure of financial and other supports 2.1 Financial or other support should only be given to the specified collaborative initiatives or activities developed under written agreement as mentioned in point 1.2. None of the partners should supply financial funds or other supports which are not transparent, unrestricted or compromise the independence of other partners. 2.2 Any financial support should be evident from the written agreement made between the parties with precisions on the amounts and sources. Additional financial or other support required for a collaboration should be submitted to all the partnering

64 AIM and ESIP wants a fourth ethical principle – "None of the partners should have commercial interest in the field of activity of the

partnership."


organisations signatory to the original written agreement and added to the public information domain (1.3). Rule 3: Definition of responsibilities65 3.1 The basis for collaboration is that it should be in the interest of all parties66, with equitable and genuine mutual benefits to each organisation and with a balanced level of responsibilities. Collaboration should be jointly planned and implemented in a manner agreed by the parties. Responsibilities and mandates of all the partners should be formally written, adopted by all the partners and made publicly available. This should always take place openly and in a manner transparent to the public. Furthermore, it should always be clearly evident from any informational material that this is a collaborative initiative, with reference to further information as mentioned in point 1.2, so that the recipient understands who or which parties are behind the material. 3.2 Each partner should ensure mutual respect for each other's role. Reciprocity in the relationship should be non-commercial in the interest of all and none of the partners should seek to influence the initiative in a manner favourable to their own interests. 3.3 The respect of the ethical guidance, of the planning and the right implementation of the initiative is a common responsibility of all partners. C – Respect of the ethical guidance67 68 Enforcement of national and EU legislation is always the responsibility of the national competent authorities. Additional control mechanisms could be set up with regards to ensuring the application of the written agreement establishing the collaborative approach or partnership.69 In particular, it is suggested that self-regulatory mechanisms should be setup within the public-private-partnership or collaborations to ensure the respect and the right application of the ethical guidance by all partners. Prior to the launch of the project, structures, control procedures and appropriate penalties should be fixed and agreed by all the partners to ensure the identification and the condemnation of any violation of the ethical guidance. In the case of violation of the ethical requirements, the public-private-partnership will be responsible, through its self-regulatory mechanisms, for the enforcement of sanctions. A co-regulatory body (including competent authority and stakeholders) can be responsible for the enforcement of sanctions in the case of complaints against a decision of the public-private-partnership and for severe violations of the ethical requirements, or this can be handled through legal actions by the respective judicial authorities.70

65 France wants to add a reference to the liability of the information source and the need for conformity with Article 88 of Directive

2001/81/EC as amended by Directive 2004/27/EC. 66 AIM and ESIP want to include "non-commercial" interest. 67 France does not agree with this paragraph. France thinks that this paragraph reflects the view of the Commission, as expressed in

the recent public consultation on the key ideas of a legal proposal on information to patients launched the 5 February 2008. France considers necessary to wait for the result of this consultation before concluding on this proposition.

68 Germany agrees in principle with the common approach in this chapter as long as the concept ‘private public partnership’ is not considered as a legal binding instrument. In so far Germany support the corresponding reservation of France in footnote 5

69 ESIP claims that if the partnership is founded under private lay these mechanisms will have only limited effect. 70 AIM, ESIP and Austria do not support the suggestions of auto-control mechanisms and co-regulatory bodies as they are very

sceptic about their efficacy.


Non compliance with EU legislation and national legal obligations is subject to sanctions enforced by the relevant national competent authorities.


Wider Health Information – Topics for the future The discussions within the Pharmaceutical Forum on information to patients about treatment and treatment options resulted in recognition of the importance of wider health information considerations, linking information to patients and health literacy issues. The members pinpointed 6 topics that could be expanded on in the future:

1. The importance of having a sound evidence base 2. Further work on information communication technology 3. Issues relating to "Health Literacy" 4. Issues relating to education and communication skills of patients and

professionals 5. Continuous support for health mainstreaming (Health in all policies) and

information to patients 6. Keeping the momentum of the work done under the Pharmaceutical Forum

The selected items are not intended to be exhaustive or exclusive. 1. The importance of having a sound evidence base There is a need for a comprehensive overview and good mapping exercises of the ‘state of the art’ on Information to Patients across the EU Member States, including innovation and good practice.

Further research and analysis on identified gaps and opportunities in relation to Information to Patients might be explored, for example, through the Framework Programme on Research and Development. The possible focus of such research could include socio-economic/health equity issues, harnessing the potential of ICT, health literacy, communication skills, etc.

2. Further work on information communication technology There is an intrinsic link between information communication technology and information to patients. Several initiatives are already in progress as part of DG INFSO's work and through the e-health stakeholders group. However, further initiatives could be explored in the future, as outlined below:

ü An ‘Information to Patients’ Virtual Network could be set up and linked with the

EU Health Portal. This virtual network could include links to existing ITP material that meets the quality criteria, pilot projects and innovations at national level.

ü There could be investment in the development of a web-based application, such as ‘My health space’ and a European Virtual Library could be created. The latter could be housed within the EU Health Portal.

ü The EUDRAPHARM database could be strengthened with opportunities for direct access by patients and health-care providers.

ü Ways of identifying good websites could be explored.


3. Issues relating to "Health Literacy" The importance of increasing "Health Literacy"71 amongst citizens is widely recognised and could be embedded as a policy and programme priority at EU and Member States level.

To expand on the issue of health literacy, further research on the subject is necessary. Ideas put forward in this respect cover targeted research that explores and evaluates:

o the concept of health literacy and its role in healthcare and health outcomes, o patients’ challenges in navigating the health care system, which will enrich

the understanding of health literacy, o the cost of health illiteracy, and o links and data collection on health literacy and inequality across Europe.

Research that identifies good practice and dissemination strategies could also be part of the research agenda in this respect. At EU level, the EU Health Literacy Project72 is ongoing. This work could become more comprehensive, and include all Member States and patient organisations at EU and/or national level.

Patient groups could explore how ‘patients rights’ instruments can be used effectively to promote health literacy, particularly among disadvantaged and marginalised groups. 4. Issues relating to education and communication skills of patients and professionals (Productive dialogue)

The importance of healthcare professionals in relation to information to patients has been highlighted throughout the Forum process. As regards to the role of healthcare professionals, possible initiatives could include the following: ü An EU capacity-building programme that could address education and training

for health care professionals in communication skills and shared decision-making and draws on current good practice in this area. ‘Patient experts’ could be involved in this work.

ü Patient organisations could carry out quality health literacy programmes with

patients. This should include the active participation of different healthcare professionals.

ü Under the issue of education, patients’ own stories and anecdotes regarding their patients’ journey should be recognised as a key resource.

71. Health literacy can be defined as the degree to which individuals have the capacity to obtain, process, and understand basic health

information and services needed to make appropriate health decisions. 72 Through the Public Health Programme, the Commission is financing a project that will provide a comprehensive snapshot of the

present situation in the Member States. The project aims at developing an European Health Literacy Survey. It is lead by the German Landesinstitut für den Öffentlichen Gesundheitsdienst and has been selected for funding in 2007.


5. Continuous support for health mainstreaming (Health in all policies) and information to patients “Health in all policies”, including European policies in the fields of education, social affairs, information society, etc., will often have an ‘information to patients’ component. Working to ensure a continuous focus on this issue is an important task. One idea might be to strengthen the communication on ‘Health in all Policies’ developments to patients and the public in general and work towards strengthening the health component of the Structural Funds.

6. Keeping the momentum of the work done under the Pharmaceutical Forum

As identified in the recommendations of the Forum, the momentum of information to patients should be maintained. Structures to both implement and monitor the efforts made could be set up at EU and national level. Information on developments at national level should be shared among the members of the Forum. How to set up the structures necessary to facilitate the further sharing of experiences needs to be developed.


Reference Documents relative effectiveness

The Relative Effectiveness Working Group developed and agreed on a number of documents which should be further disseminated. The documents will be clearly referenced and made available on the European Commission website73. 1. Core principles on relative effectiveness (page 55 ) The core principles on relative effectiveness assessments set out certain general principles of public administration that could be relevant for developing national systems and help to encourage of exchange of information, methodologies and experiences between the relevant national authorities. 2. Availability of data to conduct relative effectiveness assessments (page 65 ) The document provides a survey of the current processes on data availability during relative effectiveness assessments at national level. It highlights a number of key findings and best practices. Lastly the document contains some possible recommendations for the future. 3. Development of networking and collaboration (page 75 ) Practically all Member States communicate through bilateral or multilateral forms of collaboration on the issue of relative effectiveness assessments. This document identifies the most relevant networks and puts forward certain recommendations for networking at the European level on this topic.



Core principles on relative effectiveness

1. Executive summary

1.1. Context and objectives

In 2002, the G10 High-Level Group on innovation and provision of medicines recommended that the Commission (Recommendation No 7) should "organise a European reflection to explore how Member States can improve ways of sharing information and data requirements to achieve greater certainty and reliability for all stakeholders, even if the decisions they take may differ. The objective is to foster the development of health technology assessment (HTA), including clinical and cost effectiveness, in the Member States and the EU; to improve the value of HTA, to share national experiences and data while recognising that relative evaluations should remain a responsibility of Member States".

The Pharmaceutical Forum was set up in 2005 to address this and other issues raised by the G10, in particular on information to patients and pricing and reimbursement of drugs.

The objective of the relative effectiveness working group is to help Member States to apply relative effectiveness systems in an effort to manage pharmaceutical costs and provide fair reward for innovation. Relative effectiveness assessment systems are relatively new for many Member States and can be rather complex. The Working Group has combined the experience of various Member States and other stakeholders in order to support further development in this important field.

The decision to develop core principles in particular to support relative effectiveness assessment was taken by the Pharmaceutical Forum on 26 June 2007. Its progress reports quotes: "The Pharmaceutical Forum requests that further consensus on principles for relative effectiveness assessment be developed by exploring good practices in the Member States and by developing a toolbox and principles to provide support on areas such as robust methodologies or mechanisms to best use data, coordination of requests to industry, establishing training or other measures."

The action plan implementing this recommendation assigns the working group the objective of working towards a European consensus on general principles and good practices when performing relative effectiveness assessments. A set of European principles will be drawn up in order to establish good practices for relative effectiveness assessments. As a practical approach, the working group will consider developing a toolbox to provide support on how best to use data in relative effectiveness assessments."

1.2. Deliverables of the working group

There are two key deliverables:

The first deliverable is a set of “good practice” principles that Member States can draw on as they develop their own systems for relative effectiveness assessment.

The attached principles draw on the real-life experience of Member States and stakeholders in relative effectiveness assessment or related fields of activity.

It was not intended that the principles should specify individual points of good practice in detail, but rather that they should provide a “good practice” framework on which


Member States can draw to inform and support their own endeavours in this field. The principles were discussed and amended at a full meeting of the Working Group, and adopted as a consensus position.

The second deliverable is a checklist developed to support Member States in the practical application of the agreed principles.

The attached checklist is based on the real-life experience of Member States. The purpose of the checklist is to operationalise the principles and to support Member States in their implementation of the principles.

1.3. Implementing actions

The good practice principles agreed by the working group can deliver a number of benefits.

Firstly, the principles can provide Member States with a resource to draw on when developing their own assessment systems. The draft checklist will be a help in this respect.

Secondly, a common agreed framework on good practice principles will allow the Member States to share relevant data and experience in this area.

Thirdly, dialogue between Member States and key stakeholders will be improved when the terminology and definitions are based on common agreements.

Follow-up actions:

– It will be useful to have feedback from Member States on how the principles and the checklist are used.

– Such feedback might be channelled through the network set up under Work Package 3.

– It has not been possible to create a “toolbox” in the current situation where Member States are at various stages in their development of relative effectiveness assessment. This toolbox could be developed as part of a further network.


2. Good practice principles for relative effectiveness assessment

The aim of relative effectiveness (here-after RE) assessment is to compare healthcare interventions in practice in order to classify them according to their practical therapeutic value74. Differences between the objectives and priorities of different national healthcare systems may create differences in the way in which healthcare interventions will be valued relative to one another. In the EU context, this means that a relative effectiveness assessment is most likely to be meaningful at the national (local healthcare) level. However there is considerable 75 value of stimulating exchange of information, methodologies and experiences between the relevant national authorities. The first step in assessing relative effectiveness is an assessment of relative efficacy. Working definitions of these terms have been developed in the course of the full Working Group’s deliberations (see here-after).

While the rules and processes within a given healthcare system should be established by discussion among the local stakeholders concerned, some classical principles of public administration are likely to be generally relevant. The working group suggest the following principles for the Pharmaceutical Forum to endorse, for non-binding use as appropriate in Member States.

1. Individual Member States may use RE assessments for different purposes. Decisions on the detailed operation of RE assessments, including methods and relevant stakeholders76, are most appropriately made at a national level.

2. RE assessment processes, selection of products to be assessed, working methodologies and quality assurance processes should be transparent to all parties and evidence-based.

3 Relevant stakeholders should be able to contribute to the development of assessment methodologies. The purpose of RE assessment and the organisation(s) responsible for its conduct should be clearly identified.

4. RE assessment processes should remain separate from product market authorisation procedures (though this does not mean that they are necessarily performed by different organisations).

5. RE assessment processes should be time-framed, and should minimise or avoid causing unnecessary procedural delays consistent with any associated Transparency Directive requirements where applicable.

6. RE assessments should be capable of addressing transparently uncertainty in the evidence base, and the methodological challenge of translating evidence on relative efficacy and other appropriate available data into conclusions on relative effectiveness.

7. The sources of evidence which are to form the relevant RE input should be specifically discussed among the identified key stakeholders, who should each be able to submit evidence or argumentation for appraisal.

74 EFPIA quotes: "The aim of RE assessment is to compare healthcare interventions in practice in order to determine their practical

therapeutic value". 75 EFPIA suggests deleting the adjective "considerable". 76 Relevant stakeholders include patients and health professional organisations, the pharmaceutical industry and social insurers.


8. RE assessment should include comparison with the most appropriate healthcare interventions. Such comparison should build on the results of active controlled clinical trials, where available.

9. When concluded, outcomes should be communicated in a clear and timely manner to all interested parties. Communication by means of publishing the supporting evaluation on a publicly accessible website is strongly encouraged.

10. RE assessments should be capable of subsequent revision and updating as the evidence base develops.

11. RE assessments should aim to identify areas in which the evidence base on an intervention could most usefully be developed in the future.

Working Definitions Efficacy: is the extent to which an intervention does more good than harm under ideal circumstances. Relative efficacy: can be defined as the extent to which an intervention does more good than harm, under ideal circumstances, compared to one or more alternative interventions. Effectiveness is the extent to which an intervention does more good than harm when provided under the usual circumstances of health care practice. Relative effectiveness can be defined as the extent to which an intervention does more good than harm compared to one or more intervention alternatives for achieving the desired results when provided under the usual circumstances of health care practice.


3. Checklist for use of the principles

3.1. Introduction

This checklist has been developed as a technical tool for authorities and stakeholders to use, as appropriate, when developing and conducting RE assessments. It should be revised and updated to reflect developments. The purpose of the checklist is to provide Member States with a framework for evaluating their relative effectiveness assessment as well as their national relative effectiveness assessment systems, and especially how they fit in with the core principles agreed by the Member States. The checklist can be used in different ways to improve relative effectiveness assessment: § National bodies responsible for relative effectiveness assessments can simply fill

in the checklist as a form of self-evaluation. § National bodies can collect views from the relevant stakeholders. § The checklist can also be used by national bodies for cross-national comparisons

of national relative assessment systems and individual assessments. The checklist consists of 22 key items. Items 1-14 relate to national RE assessment systems and items 15-22 to the assessment of specific pharmaceuticals. The scores from different items can be added together to give the total score, which can be seen as providing a general indication of quality. The Appraisal of Guidelines for Research and Evaluation (AGREE) was used to draw up the checklist (AGREE Collaboration 2001, www.agreecollaboration.org). Response scale Each item is rated on a 4-point scale ranging from 4 “Strongly Agree” to 1 “Strongly disagree” with two mid-points: 3 Agree and 2 Disagree.

- If the person conducting the evaluation is confident that the criterion has been fully met, then he or she should answer “Strongly Agree”.

- If he or she is confident that the criterion has not been met at all or if there is no information available, then the answer should be “Strongly Disagree”.

- If he or she is unsure that the criterion has been met, for example, because the information is unclear or because only some aspects meet the criterion, then the answer should be “Agree” or “Disagree”, depending on the extent to which he or she thinks the issue has been addressed.

3. 2. Content of the checklist

NATIONAL RELATIVE EFFECTIVENESS ASSESSMENT SYSTEMS Purpose and responsibilities 1. The purpose of RE assessments is specifically described. Strongly Agree Strongly Disagree Comments: 2. The organisation(s) responsible for its conduct is clearly identified. Strongly Agree Strongly Disagree Comments: Transparency 3. RE assessment processes are transparent to all parties. Strongly Agree Strongly Disagree Comments: 4. RE selection of products to be assessed are transparent to all parties. Strongly Agree Strongly Disagree Comments: 5. RE working methodologies are transparent to all parties. Strongly Agree Strongly Disagree


Comments: 6. RE quality assurance processes are transparent to all parties. Strongly Agree Strongly Disagree Comments: Evidence-base 7. RE assessments are evidence-based. Strongly Agree Strongly Disagree Comments: Stakeholders 8. The relevant stakeholders are able to contribute to the development of assessment

methodologies. Strongly Agree Strongly Disagree Comments: 9. The sources of evidence that form the relevant RE input have been specifically

discussed between the key stakeholders. Strongly Agree Strongly Disagree Comments: 10. The key stakeholders are able to submit evidence or arguments for appraisals. Strongly Agree Strongly Disagree


Comments: Processes 11. RE assessment processes are separate from product market authorisation procedures. Strongly Agree Strongly Disagree Comments: 12. RE assessment processes are time-framed. Strongly Agree Strongly Disagree Comments: 13. RE assessment processes minimise or avoid causing any unnecessary procedural

delays and are consistent with any associated Transparency Directive requirements (timing, appeals, etc.), where applicable.

Strongly Agree Strongly Disagree Comments: 14. The national assessment body has established contacts with other national or

international agencies to exchange views, methodologies and information. Strongly Agree Strongly Disagree Comments:


RELATIVE EFFECTIVENESS ASSESSMENTS OF SPECIFIC PHARMACEUTICALS Quality of assessment 15. The RE assessment is capable of addressing uncertainty in the evidence base

transparently. Strongly Agree Strongly Disagree Comments: 16. The RE assessment is capable of addressing uncertainty in the methodological

challenges transparently. Strongly Agree Strongly Disagree Comments: 17. The RE assessment includes comparison with the most appropriate healthcare interventions. Such comparison should build on the results of active controlled clinical trials, where available. Strongly Agree Strongly Disagree Comments: Communication 18. Outcomes of the RE assessment are communicated clearly and in good time to all interested parties. Communication by means of publishing the supporting evaluation on a publicly accessible website is strongly encouraged. Strongly Agree Strongly Disagree Comments:


19. Outcomes of the RE assessment are published on a publicly accessible website. Strongly Agree Strongly Disagree Comments: Other aspects 20. RE assessment is capable of subsequent revision and updating as the evidence base develops. Strongly Agree Strongly Disagree Comments: 21. RE assessment identifies areas in which the evidence base on an intervention could most usefully be developed in the future. Strongly Agree Strongly Disagree Comments: 22. RE assessment includes input from other national or international agencies on the same or closely related projects. Strongly Agree Strongly Disagree Comments:


Data availability to conduct on relative effectiveness assessments



In 2002, the G10 High-Level Group on innovation and provision of medicines recommended that the Commission (Recommendation No 7) should "organise a European reflection to explore how Member States can improve ways of sharing information and data requirements to achieve greater certainty and reliability for all stakeholders, even if the decisions they take may differ. The objective is to foster the development of health technology assessment (HTA), including clinical and cost effectiveness, in the Member States and the EU; to improve the value of HTA, to share national experiences and data while recognising that relative evaluations should remain a responsibility of Member States".

The Pharmaceutical Forum was set up in 2005 to address this and other issues raised by the G10, in particular on information to patients and pricing and reimbursement of drugs.

The objective of the relative effectiveness working group is to help Member States to apply relative effectiveness systems in an effort to manage pharmaceutical costs and provide a fair reward for innovation. Relative effectiveness assessment systems are relatively new for many Member States and can be rather complex. Nevertheless, relative effectiveness is promising as it helps to identify the most valuable medicines, in terms of both clinical efficiency and cost-effectiveness. The Working Group has combined the experience of different Member States and other stakeholders in order to support further development in this important field.

The decision to develop core principles in particular to support relative effectiveness assessment was taken by the Pharmaceutical Forum on 26 June 2007. It quotes in its progress report: "The Pharmaceutical Forum encourages the relevant authorities and companies to explore ways to communicate and collaborate prior to the market authorisation decision as well as after it in maximising availability and best use of data relevant to relative effectiveness assessment."

In particular, "The Pharmaceutical Forum requests the working group also to explore different ways of encouraging the production of additional relevant data, such as:

• Identifying data sets (including the possibility to have appropriate comparators) that can be helpful for relative effectiveness assessments;

• Working towards consensus on good practices for concept design and analysis on what kind of new study types/study designs would be needed to improve the information available about products in real-life use;

• Elaborating on methods for the transferability of data on relative effectiveness assessments between Member States;

• Providing Member States with options for encouraging the production of more relevant data or alternative routes for producing additional data;

• Considering (with the involvement of the European Medicines Agency) how EPARs and NPARs could make a better contribution to relative effectiveness assessments;

• Recognising the value of innovation building on the work of the working group on pricing.”


The action plan implementing this recommendation of the progress report assigns the working group the objective to developing:

- agreed terms of reference for real-life example test cases

- a toolbox on ways to improve the use of relative effectiveness data. This would also make it possible to develop methods for the transferability of data on relative effectiveness assessments between Member States.

The aim is to show how relative effectiveness assessments are carried out in the Member States by using specific products or groups of products and looking at what data are used in decision-making on relative effectiveness assessment, focusing on two main phases of a product’s life:

1.) Before market authorisation (MA) (“MA data”)

2.) After market authorisation has been granted and the decision on price and reimbursement is taken (“Access to market data”)

Moreover, the issue of updating relative effectiveness on the basis of data from the use of products in practice will need to be considered. The ways the assessment outcomes are used in healthcare settings (for example, in relation to decisions made by hospitals to take medicines in their treatment protocols and in clinical decision-making) could also be looked at.

In addition to the evaluation of the availability and use of data based on real-life examples, the work package will also address horizontal issues such as early dialogue between national authorities and companies. In particular, the possibility of reporting on new products in the pipeline by way of a “horizon scanning” mechanism would be looked at in this context.

Secondly, collaboration between national authorities and other stakeholders involved in creating relative effectiveness assessment data will be addressed throughout the work package. This will illustrate the current practices on collaboration and identify areas for improvement to generate, share and use data at all stages, i.e. before and after market authorisation.

Thirdly, new methodologies and scientific principles from other related areas such as health technology assessment could be included in the search for existing tools and methods that can be incorporated into relative effectiveness assessments. This could result in a toolbox to provide support for robust methodologies and mechanisms.

To ensure the objectivity of the work, the issue of which organisations could carry out the work should be considered. Existing forms of collaboration between organisations with analytical capacities to address key aspects could be used. In particular, the working group should consider whether an existing European network on assessing technologies in relation to the scientific aspects of relative effectiveness assessment could be asked to carry out this work.

The Commission will draw up terms of reference for discussion by the working group in order to provide a platform for this area of work. After approval by the working group, both the Member States and the industry will be invited to provide potential products as show cases.


Finally, an additional area in work package 2 will look at how to make better use of EPARs and NPARS for relative effectiveness assessments.


The main deliverable is a survey on data availability and current evaluation and reimbursement processes in national relative effectiveness assessment systems. Details are given in Section 2.

1.3. Issues that are in the mandate but have not been addressed by the working group so far:

The following aspects of the 2nd progress report have not yet been addressed:

• Working towards consensus on good practices for concept design and analysis on what kind of new study types/study designs would be needed to improve the information available about products in real-life use;

• Developing methods for the transferability of data on relative effectiveness assessments between Member States;

• Providing Member States with options for encouraging the production of more relevant data or alternative routes for producing additional data;

• Considering (with the involvement of the European Medicines Agency) how EPARs and NPARs could make a better contribution to relative effectiveness assessments;

• Recognising the value of innovation, building on the work of the working group on pricing.


2. Survey conducted by Austria

2.1. Objectives

The primary aim was to explore the availability of data for the assessment of relative effectiveness, while the secondary aim was to learn more about the relative effectiveness evaluation processes and the overall reimbursement decision processes that these evaluations are embedded in.

2.2. Methods

The relevant bodies that conduct the clinical evaluations for the purpose of reimbursement decisions were identified in all 27 Member States (here-after MS). The parties responsible for these evaluations were contacted and interviewed. For this purpose, five sample medicinal products77 were chosen by the working group (here-after WG). After the interviews the protocols were sent back to the interviewees for reconfirmation (this process was still ongoing at the time of the the printing of this document).78 The final report will be made available once interview protocols are reconfirmed. The Efficacy and Effectiveness definitions from Work Package1 were used.79

2.3. Findings – based on the results of the interviews

2.3.1. No clear cut between efficacy and effectiveness concepts and uses

Four important points regarding the original definitions of efficacy and effectiveness emerge from the interviews:

(1) The data on effectiveness showed there is no clear consensus as to whether clinical trials yield efficacy or effectiveness information. All data on drugs yield information that is somewhere on an efficacy/effectiveness spectrum (see graph in Annex A). As a general rule, conventional clinical trials tend more to the efficacy side of the spectrum. The term effectiveness is used differently, in a way that is not captured by the WG definition. While some interviewees use it to describe what is actually happening in real life (and as such always theoretical to a certain extent), others use it exclusively to describe clinical trials that are as far as possible to the effectiveness side of the spectrum. This, in their opinion, gives the best estimate of what happens in real life. There is no clear consensus on this among MS.

77 Omalizumab (Xolair), Clopidogrel (Plavix), Sildenafil (Revatio), Trastuzumab (Herceptin), Desloratadin (Aerius) 78 At the time of the adoption of the final Conclusions of the Pharmaceutical Forum, 22 interviews had been conducted. Of these, 2 were incomplete and 4 only answered in writing; thus yielding 16 (or 20) complete interviews. Of the other 5, 4 were scheduled but have not yet been conducted and 1 were still unclear. Also, the 3 EFTA Members of the Working Group volunteered to be interviewed, but this had been postponed due to time constraints. 79 Efficacy is the extent to which an intervention does more good than harm under ideal circumstances.

Relative efficacy can be defined as the extent to which an intervention does more good than harm, under ideal circumstances, compared to one or more alternative interventions.

Effectiveness is the extent to which an intervention does more good than harm when provided under the usual circumstances of healthcare practice.

Relative effectiveness can be defined as the extent to which an intervention does more good than harm compared to one or more alternative interventions for achieving the desired results when provided under the usual circumstances of healthcare practice.


(2) If there is relative efficacy and relative effectiveness, their non–relative equivalents must also exist. The term relative only makes sense in the setting of clinical trials. When evidence is created in clinical trials a new drug can either be compared to a placebo (this is non-relative efficacy), to any drug (suboptimal) or to the best possible alternative drug (optimal).80 However, it needs to be borne in mind that different MS may have different views on what is the “best alternative therapy”. When “more or better relative effectiveness data” are demanded the word relative refers to trials that have the best possible alternative drug as a comparator. If this is not the case comparisons are indirect and have to be made either through value judgment or by modelling. These indirect comparisons are not preferred by many MS.

(3) At the time of a primary reimbursement decision there are often no effectiveness data available, beyond what can be assumed from phase III clinical trials. In contrast, the same data on efficacy are available in all MS. Because of different reimbursement application times the number of studies or volume of efficacy data available may vary. In practice, these differences tend to be small.

(4) In general, information on effectiveness can be based on effectiveness data alone or on a combination of efficacy data and some form of extrapolation of the same efficacy data (e.g. modelling).

The interviews revealed four possible approaches. It has to be highlighted that not all approaches are endorsed by all MS. Some MS insist on clinical trials as the only reliable source for information. In particular, approaches 3 and 4 below (i.e. modelling and the use of other sources of data) are not accepted by all MS.

As a general rule, the level of acceptance decreases from top to bottom in the following list.

(1) Better clinical trials (large pragmatic trials/effectiveness trials) yield data that tend more to the effectiveness side of the spectrum, and can be conducted.

(2) Efficacy is evaluated in lieu of effectiveness81 or effectiveness is extrapolated from efficacy data without modelling. The latter process normally includes a high degree of value judgment, as explained further below.82

(3) Relative effectiveness is produced through modelling as an integral part of cost-effectiveness studies. MS that accept economic modelling (e.g. cost-effectiveness studies) generally have economic studies that are custom-made for them.83

(4) Other types of data (real-life/post-marketing information, such as observational studies, registries and medical claims data) can be used to assess relative effectiveness.

80 When two drugs are compared to a placebo only, and not to each other, it remains unclear how they compare to each other. This is because differences between the two drugs can always be due to differences in the underlying study populations, and not to the drugs themselves. It is thus mostly preferable to compare drugs directly with one another. In theory, comparisons against placebos should be very rare, as using placebo-controlled trials conflicts with the Declaration of Helsinki wherever effective treatment is available. However, in reality placebo-controlled trials are often accepted by market authorisation agencies. This is further complicated by the fact that some regulatory agencies, most prominently the FDA, actually endorse or even ask for placebo-controlled trials in some circumstances. 81 This approach is based on the idea that in the absence of effectiveness data, efficacy data are the best estimator of effectiveness. 82 In these cases the exact same data are assessed that have been assessed for market authorisation. It is clear that different outcomes can only be obtained if the value judgments differ. However, this makes sense, as the basis for a reimbursement decision is different from a market authorisation decision. This argument is not shared by Spain. 83 However, when effectiveness is modelled, the accuracy of the results also improves, as the quality of the underlying clinical trials improves. Thus, clinical trials that tend more to the effectiveness side of the spectrum yield better information on relative effectiveness for all MS, whether they endorse modelling or otherwise.


There was an overwhelming response in the interviews that there is very often a lack of studies with the relevant comparator. The main outcome measures are often also wrong, inclusion criteria unrealistic and the observed time period is too short to yield relevant data on effectiveness. The main reason is that these studies are generally still conducted for the purpose of obtaining market authorisation, and not for reimbursement decisions. It should be noted that these studies are generally conducted after detailed discussions with regulatory authorities, including formal procedures for scientific advice from the EMEA.

2.3.2. Importance of effectiveness assessments within the overall process of pricing and reimbursement decisions

Relative effectiveness assessments are an important but not the only factor in a reimbursement decision. To understand the differences in relative effectiveness assessments in the EU it has to be understood how reimbursement decisions are taken in general.

Health policy decisions cannot be taken in the absence of value judgments.84 Also, these interviews show that, in almost all MS, reimbursement decision processes are two-step procedures:

Step one is the analysis of evidence as a scientific basis for the decision and step two is the actual decision-making, which always includes some degree of value judgment.85

While the degree of clarity regarding this distinction is quite varied and tends to be on the low side, in principle all MS reimbursement decisions include some degree of value judgement and are not based on analytical evidence alone.

In the first step, evidence is assessed as systematically and as objectively as possible. In the second step, the available evidence is critically appraised, which includes a certain degree of value judgment. Depending on the MS, more or less value judgment might be involved. Mostly, analysis of evidence is in the form of a written report while the value judgment part is made by a committee, which takes a vote on the basis of that report. This vote might be either a final decision or a preliminary recommendation that needs further approval.

Step 1: Analysis of evidence (assessment report/dossier)

An assessment of relative effectiveness is an important part of such reports in most MS. As a prerequisite to understanding this point, it should be noted that in many MS the process under scrutiny by the WG is not actually called relative effectiveness officially, but something like clinical evaluation, therapeutic (value) evaluation or medical evaluation. Irrespective of the name, this process evaluates the theoretical benefits and harms of drugs without economic considerations.

In reality, assessment reports for reimbursement consist in almost all MS of at least the following two parts:86

1) Clinical evaluation

2) Economic evaluation

84 See Reflections On Science, Judgment, And Value In Evidence-Based Decision Making: A Conversation With David Eddy. Health Affairs - Web exclusive. DOI 10.1377/hlthaff.26.4.w500 85 This should not be confused with formal decision-taking, which is mostly done in a third step by a minister of health or a social insurance executive. If this step is included it is often quite formal. However, in theses cases the second step is then not decision-taking in the legal sense but a decision to give a recommendation, which nevertheless involves a high degree of value judgment. 86 In some MS these reports also contain other parts, typically some sort of public health or societal perspective or other.


The issue is that in some Member States (e.g. France and Italy) what is understood as relative effectiveness is only 1) while in other MS (e.g. UK, Ireland and Sweden – list not exhaustive) relative effectiveness consists of 1) and parts of 2). Relative effectiveness is estimated (i.e. modelled) in some MS as part of cost-effectiveness studies.87

In some Member States, both steps are performed separately, and may be done by different organisations, whereas in others this is part of a single process.

It is logical that for MS doing the latter it is harder to disentangle the economic evaluation from the clinical therapeutic evaluation.88 For some MS it is possible but it would be difficult. And in some MS (e.g. France) the clinical evaluation is already quite clearly separated from the economic evaluation. This is the exception rather than the rule, however.

Step 2: Value judgment (committee/board)

These decision or recommendation committees responsible for the final decision on pricing and reimbursement can be formed very differently in the MS. Some rely on internal members; others staff them with external members. Sometimes there are purely medical experts with or without economists on these committees, but in some MS there are also other members, including lay people, patients, stakeholders (e.g. industry), social insurance personnel, political representatives and even priests and philosophers.

Clarification: The above gives rise to a number of issues. Firstly, these reports/assessments of evidence are often not stand-alone documents. In practice, their conclusions are in part dictated by the committee votes. Thus, it can be difficult to separate the analysis of evidence from the value judgment part. These votes are also often taken in combination for both the clinical and the economic evaluation. Thus, in some MS it is difficult in practice to isolate the evaluation of clinical effectiveness as a distinct outcome from the overall evaluation, which includes economic considerations. Some MS do however make a clear distinction between relative effectiveness and economic evaluation.

That said, while the overall evaluation processes, and the value judgments in particular, can differ somewhat among MS, the data available on efficacy are almost always the same and even the final decision to put on a reimbursement list tends to be relatively standard throughout the EU.

The following factors might cause local variations:

– As noted earlier, in MS where cost-effectiveness studies are accepted these tend to be custom-made for the respective MS and their healthcare systems. Thus, both the result and the subsequent decisions can differ.

– The level of control that reimbursement decision-taking bodies have over prescription practice varies enormously throughout the EU.89 As this tends to be taken into account

87 True data on effectiveness are very hard to find but effectiveness information is needed for realistic cost calculations. Thus, effectiveness information is often modelled as an integral part of cost-effectiveness studies. It is a common misunderstanding that cost-effectiveness studies are mainly about costs. In general, cost-effectiveness studies consist of two parts, one that models effectiveness and a second part that calculates the costs. 88 However, this should not be confused with price negotiations, which are in principle separate from economic evaluations (see specific findings in point 4) 89 The level of control ranges from almost no control to very tight control over physician prescription habits. An alternative approach to prescription control is a price-volume agreement.


for decision-taking (mostly at value judgment level), identical data can lead to different results in different MS.

– Some Member States advance the argument that they use budget impact analysis to justify negative reimbursement decisions. However, some MS explicitly refrain from the concept of budget impact for their reimbursement decisions.

2.3.3. Interpretation of information flows from market authorisation agencies to reimbursement decision bodies

Depending on the legal situation regarding the exchange of information between MAA and reimbursement agencies, the information on efficacy is in varying degrees of detail. This is particularly important for MS that rely more on the assessment of efficacy than on modelling through cost-effectiveness studies.

In some MS it is one agency that makes both assessments. In those MS there is a free flow of information. In others these are distinct agencies but exchange of confidential information is at least possible or even mandated by law. In a final category, the transfer of confidential market authorisation information to the reimbursement decision body is deemed illegal.

This might be due to differences in national law, mostly due to diverging interpretation of European Law in this context. Clarification might be useful even if, for some MS, the issue of exchanging confidential information is not of primary importance.90

2.3.4. Insights on economic evaluations91

As noted above, some MS do not accept cost-effectiveness studies92 or only attach minor importance to them, while in other MS cost-effectiveness studies or other economic evaluation methods are a core feature of both: relative effectiveness evaluations and the overall reimbursement decisions.

In MS where cost-effectiveness studies are not accepted or are of minor importance, economic evaluations are based either on price comparisons or on budget impact analysis alone.

Economic evaluations need to be differentiated from price negotiations. While price negotiations feed back into the results of cost-effectiveness studies and budget impact analysis and vice versa, the price of a product is only one of many important variables in an economic analysis.

90 This difference is also rooted in the wide variation in the level of trust that reimbursement decision bodies have in the decisions of the market authorisation agencies. 91 It was agreed to ask interviewees to provide voluntary information on economic assessments so as to improve the link between the work of the Relative Effectiveness working group and the Pricing and Reimbursement working group. 92 Cost-effectiveness studies are the best known but not the only economic evaluations that are based on modelling. The most prominent other types of studies in this field are cost-benefit analyses.


2.4. Conclusions and possible recommendations

It can be seen quite clearly from the interviews that with such a complex issue and such diversity of decision-making processes, there cannot be one single solution. Thus, it was proposed in the interviews that some MS might work together in groups in an effort to advance the issue and improve collaboration. Identifying clusters of interested member states that share common elements in their processes will enhance EU-level cooperation. The first conclusion from the interviews is that data are mainly on efficacy and not enough data are available on effectiveness and relative effectiveness. Thus, all MS, irrespective of whether they accept modelling or not, would benefit from clinical trials that tend more to the effectiveness side of the spectrum. However, it must always be discussed whether effectiveness trials – which also lack in internal validity – can reasonably be expected in the drug development programme.93 While prolonging observation times might come at too high a price (longer waiting time for new drugs), using the right comparator, relevant outcome measures and realistic inclusion criteria is something that would lead to better decisions. If studies were to be designed along these lines they would yield data that tend more to the effectiveness side than to the efficacy side. However, to achieve this, it would need to be made mandatory for companies. Whether this is realistic is debatable.94 One way to improve the quality of data for decisions on RE is for the competent authorities and other players to give advice to companies during the development process. In the meantime, the second conclusion is that the most divisive approach is the cost-effectiveness one. Indeed, the specificities make it difficult to benchmark with other approaches. That does not mean that they should not form part of clinical evaluation. In theory, non-acceptance of cost-effectiveness is not per se a denial of modelling. It is theoretically possible to model relative effectiveness outside of cost-effectiveness studies. But while there is some initiative on this at EMEA level, this is still a very uncommon approach and further research is needed. Cooperation might be easier for MS that endorse the cost-effectiveness approach. It has been mentioned that improved methodology and high quality guidelines that are approved by all stakeholders would enhance the quality and thus usefulness of these studies. The third conclusion is that it might be scientifically relevant for interested MS to share and exchange information on relative effectiveness assessments and economic evaluations at EU level. Clinical evaluations would also not need to be conducted in multiplication throughout the EU. The legal situation regarding the exchange of information should be clarified.95 To enhance trust, it needs to be made clear that the actual decision rests with the MS. One way of reinforcing this trust is by ensuring that, despite similar outcomes of relative effectiveness assessments, different MS will still be able to come to different reimbursement decisions based on either differences in value judgment or for budgetary or other reasons, such as differences in the objectives and priorities of the different national healthcare systems.

93 For EFPIA, "it is often more appropriate to conduct these studies post-approval to confirm effectiveness in real-life situations". This statement is not shared by other members. 94 Spain does not agree with this. 95 Spain does not agree with this.


The fourth conclusion is that a clear distinction between the assessment of all available evidence and value judgments that lead to a decision would improve the transparency of the decision-making process.. However, transparency should not be understood as being in conflict with value judgments, which are necessary for these decisions. The fifth conclusion is that clarification is needed of the EU legal situation on the issue of transferring market authorisation data and information to the reimbursement decision agency.

2.6. Annex A:96

96 Spain commented on this graph: this table should be discussed further. “No comparator” should not be part of absolute efficacy, and “medical claims data and post-marketing study with no comparator” should not be part of absolute effectiveness, among others.


Development of networking and collaboration



In 2002, the G10 High-Level Group on innovation and provision of medicines recommended that the Commission (Recommendation No 7) should "organise a European reflection to explore how Member States can improve ways of sharing information and data requirements to achieve greater certainty and reliability for all stakeholders, even if the decisions they take may differ. The objective is to foster the development of health technology assessment (here-after HTA), including clinical and cost effectiveness, in the Member States and the EU; to improve the value of HTA, to share national experiences and data while recognising that relative evaluations should remain a responsibility of Member States".

The Pharmaceutical Forum was set up in 2005 to address this and other issues raised by the G10, notably on information to patients and pricing and reimbursement of drugs.

The objective of the relative effectiveness (here-after RE) working group is to help Member States to apply relative effectiveness assessments in an effort to manage pharmaceutical costs and provide a fair reward for innovation. Relative effectiveness assessments are relatively new for many Member States and can be rather complex. Nevertheless, relative effectiveness assessment is promising as it helps to identify the most valuable medicines, be it in terms of clinical efficiency or cost-effectiveness. The Working Group has combined the experience of different Member States and other stakeholders in order to support further development in this important field.

The decision to develop ideas and thinking in relation to networks to support relative effectiveness assessment was taken by the Pharmaceutical Forum of 26 June 2007. The Forum’s progress report quotes: "Strengthening networks among relative effectiveness assessment authorities and relevant stakeholders across Europe and considering mechanisms to help share data, provide support and develop common principles at European level"

In particular, "The Pharmaceutical Forum supports the aim of sharing data on relative effectiveness assessment at European level and developing sustainable collaboration and networks between the competent authorities of the Member States and other stakeholders, and requests specific proposals for ways of achieving this."

Collaboration between national authorities and other stakeholders involved in creating relative effectiveness assessment data will be addressed throughout the work package. This will highlight current collaboration practices and identify areas for improvement to generate, share and use data at all stages, i.e. before and after the market authorisation process.

Relative effectiveness assessments are ultimately performed in order to improve the quality of care by promoting rational use of medicines. All EU Member States are currently carrying out relative effectiveness assessments and each Member State carries out its own assessments.


The key objectives of the work package are to consider and make a recommendation as to whether a new European network is needed in the area of relative effectiveness assessment. Regardless of this recommendation, a number of proposals and learning points for existing and planned networks to consider will be developed.


There are two key deliverables:

The first deliverable is a survey of current networks on relative effectiveness assessment, with contributions from the contact persons and members. Details are given in Section 2.1.

The second deliverable is a set of recommendations on requirements for existing and future networks: The details are given in Section 3.2

1.3. Implementing actions

Ensure proper progress of a network to improve the consistency of relative effectiveness at European level, with special focus on principles and data availability.

2. Deliverables in detail

Summary of the questionnaire conducted by Sweden

Practically all Member States communicate through bilateral or multilateral collaboration. The most relevant of these forms of collaboration or networks for the purpose of relative effectiveness are: AGREE collaboration, EUNetHTA, Guidelines International Network (G-I-N), Medical Evaluation Committee (MEDEV), Networking of the Competent Authorities for Pricing and Reimbursement of Pharmaceuticals (“Slovenian Presidency initiative”), Nordic collaboration on medicines, Nordic PharmacoEpidemiological Network (NorPEN), PPRI, European Patients' Forum, Transparency committee, UK-Germany-France – collaboration, Working Group on Relative Effectiveness Assessment. It is important to know more about the networks so as to have a full picture of activities at European level and also because these networks evolve and take on different tasks at different times. Table 1 contains a brief description of the different networks.


Table 1.

Network Purpose AGREE collaboration Improving the quality and effectiveness of

clinical practice guidelines by establishing a shared framework for their development, reporting and assessment

EUNetHTA Establishing an effective and sustainable European Network for Health Technology Assessment that informs policy decisions

Guidelines International Network (G-I-N) Promoting systematic development of clinical practice guidelines

Medical Evaluation Committee (MEDEV) Exchanging experience in the evaluation of drugs

Networking of the Competent Authorities for Pricing and Reimbursement of Pharmaceuticals (“Slovenian Presidency initiative”)

Identifying and discussing high-level issues in the field of pricing and reimbursement of pharmaceuticals

Nordic collaboration on medicines Exchanging experience in the evaluation of reimbursed drugs

Nordic PharmacoEpidemiological Network (NorPEN),

Pharmacoepidemiology

PPRI Information-sharing initiative on burning issues of pharmaceutical policies from a public health perspective

European Patients' Forum Collaboration of patients’ associations Transparency committee EU institution dealing with the transparency

directive UK-Germany-France – collaboration Exchanging experience in the evaluation of

drugs Working Group on Relative Effectiveness Assessment

Working group under the Pharmaceutical Forum (will end in 2008)

For this reason, the Secretariat and Sweden contacted these networks with a brief survey. The aim was to map existing networks and also, if possible, to learn something from their experience. The survey was web-based and contained two parts. Part a) was completed by a single representative of the network and described briefly the purpose and organisation of the network. Part b) was evaluative and was supposed to be completed by as many individual members of the networks as possible. It consisted of a few questions such as “How useful do you think the network has been for you?”. Unfortunately, there were rather few respondents to part b) of the questionnaire (30). This limits the extrapolation of the findings, but a few trends can be outlined nevertheless. • Most networks that were studied are new. In fact, only one was more than three years old.

• Generally, the respondents were satisfied with the network that they participated in.

• Only two problems were mentioned more than once by respondents:


o Limited resources – e.g. participants’ time and funding.

o A lack of structured communication tools and/or a database for communication exchange and a “blackboard” or web-based system rather than just e-mail. Only one network uses a “wiki” tool.

• Contrary to expectations, language problems were not mentioned at all. The choice of the language was not investigated.

• There is mostly informal participation from patient organisations and generally no participation from industry, which has (rarely/not) been invited to participate.

• Seven of the eight networks that responded had activities related to relative effectiveness assessment.

• About half of the networks have specific funding and about half have an administration in place for the network.

• Participants often quoted their increased access to reliable contacts in other organisations as the most pertinent added value of participating in networks.

• Other benefits that were mentioned included exchange of information, harmonisation of methodology and identifying and solving common problems.

Relative effectiveness assessments are often carried out using data that have been developed for use in the market authorisation process for a pharmaceutical. Nonetheless, the national regulatory agencies and the EMEA are currently not involved to any great extent in the networks and forms of collaborations discussed here.

To conclude, the key objectives for a network (or networks) to meet the demands set out by the Forum include:

a) regular exchange of information on methodologies used; b) regular exchange of available data; c) regular exchange on the conclusions reached regarding the relative effectiveness of the drugs assessed; d) implementing work areas 1 and 2; e) having appropriate stakeholder participation; f) reviewing implementation of best practice principles across Member States.

These requirements point to two distinct levels, or work streams, for networks: one directed towards political considerations and policy-making, and the other technical, involving, for example, exchanging assessments. Not all members in the WG put the same emphasis on which is the more important for networking at European level.

The WG and the Forum should also consider the mandate of the network and the possibilities for influencing the network.


Taking this into account, the discussion on 12 June 2008 centred on which of the existing networks could best address these objectives. In this respect, two networks were short-listed for discussion: the SL network and MEDEV. As can be seen from Table 1 above, the other networks are dealing with tasks well outside the field of relative effectiveness or have limited geographical coverage. As so discussed on 12 June 2008, neither of these groups involves industry. The proposal to make these groups the basis of a future network needs to be reconciled with the stated goal of wider stakeholder participation.

The Slovenian network focuses mainly on policy issues relating to pricing and reimbursement, with the option of including RE. It has a clear mandate from the Competent Authorities of the Member States. At this point, meetings are envisioned to take place about twice a year and involve high-level officials from the Competent Authorities. This network does not formally involve industry or other stakeholders.

MEDEV deals explicitly with the RE of pharmaceuticals and is engaged in the exchange of assessments (among other things). Membership and communication is informal. This network does not involve the R&D-based industry.

The membership issue was also discussed. There seems to be a general understanding that only the competent authorities of the MS can be part of certain processes in the networks, but stakeholder involvement is in principle desirable and beneficial. It should therefore be encouraged.

3. Recommendation for networking at European level

3.1. Background

As noted earlier, there are two distinct levels of cooperation in networks: one directed towards policy/strategy and the other technical/scientific, involving, for example, exchanging assessments. Not all members in the WG put the same emphasis on which is the more important for networking at European level. The traditional tasks of networks that would apply at both levels include promoting exchanges of ideas, giving access to contacts in other organisations and building trust. Apart from these “generic” benefits, other specific tasks that, in the opinion of the WG, should be pursued within networks include:

• Policy/strategy network

o learning from the success or failure of other organisations’ policies and strategies,

o joint problem solving,

o harmonisation of methodology, policy or strategy, if appropriate,

o being a speaking partner for stakeholders.

• Technical/scientific network

o sharing and exchanging assessments of RE with the dual purpose of improving the quality of the individual assessments and learning from each other,


o maintaining a clearinghouse for RE assessments (similar to what exists, for example, for guidelines and HTA reports). For this to work, language issues and funding need to be resolved,

o exchanging information (and possibly coordination to avoid duplication?) on post-launch studies of RE.

3.2. Recommendations

(1) The Working Group has identified two networks that could potentially function as networks between the Competent Authorities: the Slovenian Network (the network of competent authorities on pricing and reimbursement) and MEDEV97.

(2) It is not necessary for just one network to be identified. The WG believes that the Slovenian initiative network has in some ways an appropriate membership basis in the Competent Authorities and already focuses on policy/strategy issues. However, at this point the network puts too little emphasis on RE assessments. MEDEV, on the other hand, is ideally suited as a network for technical/scientific issues but is perhaps too informal.

(3) The WG suggests that no new networks should be initiated by the Forum at this point in time. Rather than creating a new network, it makes more sense to invest more in the networks that have already been established.

(4) The existing networks seem to suffer from a lack of resources. This concerns funding, but probably more importantly than that, participants’ ability to allocate time to the activities of the network. A second area where investment would be beneficial is in efficient communication tools.

(5) There is a need to consider the issue of participation/cooperative arrangements with stakeholders and regulatory agency

(a) It is strongly recommended to include both regulatory agencies and EMEA, in some form, in networks that deal with issues related to relative effectiveness.

(b) Appropriate participation of the relevant stakeholders in the network/s is encouraged.98

(6) The sharing of relevant data and experience between Competent Authorities and dialogue between the Competent Authorities and key stakeholders can be improved when terminology and definitions are based on common agreements. The WG therefore suggests that networks, where applicable, should adopt the definitions and common agreed framework on good practice principles set out by this WG and the WG on Pricing.

97 The Steering Committee acknowledged on 2 July 2008 the fact that the EUnetHTA could also be a relevant candidate for taking forward

the scientific recommendations 98 EPF made the following statement: "The membership of networks will be agreed with the consultation of different stakeholders based on the purpose and functions of the network and efforts will be made to ensure the inclusiveness of the relevant stakeholders.” As mentioned in the draft final report, relevant stakeholders for the purposes of the work of this working group are: the pharmaceutical industry, social insurers, healthcare professionals (and scientific societies) and patient organisations (point requested by AIM)


(7) There is a need to consider in the post Forum phase the legal obstacles to deeper collaboration in some Member States, in particular relating to exchange of information. Member States are encouraged to look at how and if this problem can be solved.


Reference Documents pricing and reimbursement

The Pricing and Reimbursement Working Group has developed and agreed on a number of documents which should be further disseminated. The documents were finalized and adopted within the Working Group, usually following a preparation by a taskforce of participants from the group. The documents will be clearly referenced and made available on the European Commission website99. 1. Guiding principles for good practices implementing a pricing and reimbursement policy (page 84) With decisions on pricing and reimbursement of pharmaceuticals, Member States aim to achieve 3 overall objectives of (1) finding the optimal use of resources to maintain a sustainable financing of healthcare, (2) ensuring access to medicines for patients and (3) rewarding valuable innovation. Each Member State has its specific approach for balancing these 3 overall objectives.

The guiding principles and ideas in the document aim to help Member States obtain such a balance, through implementation of national pricing and reimbursement practices.

2. Ensuring availability to medicines in small national markets in Europe (page 88) The issue of sustainable availability and delivery of medicines is in particular important for the smaller national markets, where some important medicines are not available. The production and supply of medicines is usually undertaken by economic operators (manufacturers, wholesalers and pharmacists) that are driven by economic incentives. This paper aims to understand these economic factors, and bring forward some potential solutions to ensure availability of supply. It should be noted that a parallel and separate effort is ongoing from a regulatory perspective, driven by the Heads of Medicines Agencies. 3. Improving access to orphan medicines for all affected EU citizens (page 93) Orphan medicines amplify the common tensions in the field of pricing and reimbursement: assessing and rewarding innovation is difficult, budget optimisation is challenged and access for patients is limited in several countries. In spite of many policy initiatives increasing the number of newly developed orphan medicines, many of these are not available for all EU citizens.

This paper aims to identify the main bottlenecks not only related to (1) development, but also to (2) assessment, to (3) pricing and reimbursement practices by companies and by national authorities and to (4) awareness raising. Consequently this paper puts forward some ideas that should be seriously explored in order to ensure timely and equitable access for all EU citizens to orphan medicines.



4. Characterisation of the value of innovative medicines (page 100) This report is a bottom-up exercise, based on discussions and collection of views from the relevant Member State authorities on how to recognise, assess and reward valuable innovative medicines. However, it does not aim to identify and implement an EU-wide definition of “valuable innovation”.

This exercise identifies some common ground between individual Member States, in addition to setting out more different and optional views on what constitutes valuable innovation. This exercise covers valuable innovation in 3 main areas: (1) therapeutic/clinical benefits regarding the disease, (2) quality-of-life benefits for the patient and (3) broader socio-economic benefits.

5. From assessing innovative value of pharmaceuticals to pricing and reimbursement decisions (page 104) This paper aims to clarify how some European Member States use assessments of innovative medicines in their pricing and reimbursement decisions. Such decisions drive the expenditure for the authorities as well as the revenue for companies, the basic incentive for further research and development. Hence this paper aims to understand the mechanics behind the incentive for companies to risk investing in R&D.

This information is valuable (1) for countries that in their pricing/reimbursement decisions refer to prices in Member States that assesses innovative medicines, to ensure an understanding of the rationale behind the reference price. Moreover, (2) it will benefit Member States that search for experiences and good practices to develop their own value-based pricing systems and (3) for pharmaceutical companies that need to know what revenue can be expected for the value of their medicines.

6. The Toolbox exercise (page 110) Member States increasingly look to the same range of practices to balance budgets with access and reward for innovation. Nevertheless there is need for more evidence of the benefits and risks of different practices. This increases the interest of the Member State participants in sharing their experiences and evidence on different practices. The aim of the toolbox exercise is therefore, for six selected practices, to collect expertise from Member States and stakeholders and to provide answers to questions like: real benefit(s), potential risks and interferences with other practices, driving factors of such risks or successes, practical set-up.

7. Risk-Sharing practices and Conditional Pricing of pharmaceuticals (page 125) An increasing number of Member States have set-up risk sharing practices and conditional pricing and reimbursement practices. These practices allow competent authorities and pharmaceutical companies to build clinical experience on medicines which might normally not be eligible for reimbursement.

Such practices allow at the same time budget-control and the identification and reward of valuable innovative medicines. Furthermore, they provide access for patients to highly innovative treatments. This paper describes how these practices are set-up in different Member States and draw some common findings.


Guiding principles for good practices implementing a pricing and reimbursement policy The decisions on cost of healthcare and pharmaceuticals are a national responsibility, It has appeared in the Working Group that with decisions on pricing and reimbursement of pharmaceuticals, Member States aim to achieve 3 overall objectives of (1) optimal use of resources to maintain sustainable financing of healthcare, (2) access to medicines for patients and (3) reward for valuable innovation. Each Member State has its specific approach for guaranteeing these 3 overall objectives. Member States shall ensure that any national measure to control the prices of medicinal products or to restrict the range of medicinal products covered by their national health insurance systems complies with the requirements of Directive 89/105/EEC and the Treaty. This EU legal framework requests in particular that pricing and reimbursement decisions are made in a transparent manner. The following toolbox principles will allow good implementation of pricing and reimbursement practices and are meant to offer guidance and facilitate the sharing of information and assessments. They are not binding rules.

Access for patients Ensure timely access to valuable innovation. The Transparency Directive defines deadlines that have to be respected in taking pricing and reimbursement decisions. In standard cases, a request for a pricing and reimbursement decision should come with proof of benefit upfront, based on good clinical trials delivered by the applicant, whenever possible in a comparative set-up with a standard treatment. In some cases, when a full assessment is to be made for a new breakthrough medicine with a value not yet certain or difficult to prove, these deadlines might be a constraint in spite of good clinical trials. In these cases more evidence needs to be gathered after a medicine has been put on the market. In such cases, and in particular where it concerns life-threatening situations for which no alternative treatment exists, national authorities and companies could take a first pricing and reimbursement decision with conditional on gathering more information in order to review this decision. Such decisions allow patients to gain early access to potentially valuable medicines and innovative companies to get an earlier reward for investment in R&D. In the meantime necessary data can be collected within well-designed outcome research studies. These pricing and reimbursement decisions should come with a mutual commitment to a risk-sharing contract between companies and authorities. This commitment has to come upfront given that it is difficult to withdraw a medicine from reimbursement. Such a contract lays out the expected benefits of a new medicine, the criteria to assess these benefits, the data needed and methods/capabilities to do these assessments as well as the overall timeframes. On the financial side, the contract can define prices, reimbursement levels and restrictions of utilisation during the temporary period, as well as the financial consequences once new proof of benefit is available (for example leading to price or reimbursement changes –upwards or downwards-, changes in utilisation, premiums or payback). Provide affordable medicines. Medicines should be equally accessible at an affordable cost to all concerned patients. Generic medicines provide an opportunity to obtain similar treatments at lower costs for patients and payers, while liberating budgets for financing new innovative medicines. Promoting generic medicines requires a good combination of demand-side as well


as supply-side mechanisms. This includes a flexible and adaptive pricing and reimbursement system, an appropriate level of price-sensitivity in patients (and payers where insurers/sickness funds are involved) and a sufficient level of competition among the different actors in the supply system (manufacturers, wholesalers and pharmacists, taking account of their public health role). It has also become clear that affordability has a European dimension. A similar price-level leads to a different level of affordability depending on the economic situation of each Member State. Attention could be given to measures that allow companies to offer medicines at affordable prices in each EU market. Limiting price-control only to nationally used volumes, as Recommendation 6 of the G-10 Medicines report stipulates, would allow differential pricing taking account of national socio-economic indicators like GDP-levels. Affordability could also be ensured through upfront agreements on maximal expenditure. This could allow authorities across the EU to accept similar prices for a limited number of innovative medicines while maintaining the total expenditure at a nationally affordable level, although this cannot be seen as a large-scale solution. Ensure equal availability of medicines. Several medicines are not available in some markets, in particular small or low-price markets where the potential profits may not seem to justify the investment to organise local supply. Manufacturers should commit to register and supply all EU markets at reasonable prices, including the small and low-price markets. Wholesalers should commit to supply all these EU markets at reasonable prices. Where this is not possible, purchasing and supply managed (partially or totally) by national authorities, potentially in collaboration with other Member States, are to be fully accepted as an alternative. Overall, sufficient attention should be given to patient’s concerns in the development of a pricing and reimbursement policy, in particular to the existing inequities among Member States in availability and affordability.

Optimal use of resources Limit price control to where it is needed to contain the public budget. Member State authorities usually fix prices and reimbursement levels to ensure access to medicines at affordable cost for utilisation within their territory. Member States are not interested in fixing prices of products that are only transiting through their territory to be utilised within other Member States. They should, therefore, abstain from fixing prices for products that will not be used within their territory and that will not impact on their national budgets (as outlined by Recommendation 6 of the G-10 Medicines report). Control of supply and utilisation, including a system of traceability, might be helpful. Price control is not necessary for non-reimbursed medicines. For these products, price-competition can steer the price-evolution sufficiently well. Therefore, Member States should abstain from price-control. Monitoring systems might be helpful to get an overview of market- and price-evolutions and to mitigate any potential risk of significant price increases. Set-up a consistent package of supply and demand-side measures. To manage expenditure on pharmaceuticals, authorities need to manage prices, reimbursement levels and proper use. Supply side measures, addressing prices and reimbursement levels, are, therefore, to be managed in coordination and alignment with demand side measures, determining the volume. On the demand side, the individual behaviour of doctors, pharmacists and patients will determine the total use of and expenditure on medicines. Interests of all these actors, therefore, need to be aligned with the national objectives. One or several of these actors should be motivated to push forward utilisation of medicine in a cost effective way, either


through a (financial) incentive, or through a controlled obligation. Practices (1) on prescription guidance for doctors, (2) on substitution by pharmacists and (3) on cost-sharing and price-sensitivity of patients, should therefore be aligned. In addition, upfront agreements on overall maximal expenditure, in the form of payback or price-volume agreements, allow effectively increased predictability of overall expenditure. Create the right environment for price competition. Direct or indirect control of prices, reimbursement and expenditure are clearly relevant in a market with low price-sensitivity and high market power of manufacturers, in particular for medicines under patent protection. In situations where competition between different products is possible, e.g. when generics enter the market, open price competition may lead to good containment and significant reduction in prices and costs in a less cumbersome way. On the other hand, maintaining fixed pricing or reimbursement levels, in a situation where competition is possible, could prevent price-reductions. To ensure savings, authorities need to provide for a flexible, adaptive pricing system, an appropriate level of price-sensitivity in patients (and/or payers) and a sufficient level of competition among the different actors in the supply system (manufacturers, wholesalers and pharmacists, taking account of their public health role). Particular attention is to be paid where generic prices are always defined as a fixed percentage of the originator price, regardless of the number of price-decreases of this originator. Such systems may lead generics being out-competed through consecutive price-reductions of the originator. Cost containment mechanisms can create sufficient headroom that is needed for rewarding valuable innovation. This could also benefit from a holistic and long-term perspective, aiming for sustainable financing of healthcare, beyond pharmaceuticals.

Reward for Innovation Set expectations. Limited resources force authorities to make choices on what new products to reward and pay for. Through its pricing and reimbursement decisions, each Member States tends to grant incentives (e.g. a high price and reimbursement level, or good access to the market) for those new products that it really appreciates as bringing valuable improvements compared to the standard therapy. In this way, Member States indicate what they expect from pharmaceutical R&D to deliver. It is, therefore, important to reflect what are and will be the desired additional benefits and to allocate resources accordingly. (A separate paper has been prepared for a separate discussion on what Member States consider valuable innovation. See annex) Recognise innovation. The degree of added value delivered by new medicines is often incremental and, therefore, harder to recognise. Companies should, therefore, be prepared to clearly prove this added value versus existing therapies and authorities should be prepared to recognise proven incremental benefits that are estimated valuable and reward them appropriately (i.e. with incremental price-premiums or with measures allowing a higher utilisation). Pricing and reimbursement mechanisms, as well as utilisation guidelines, should be in line with this and ensure a scaled recognition and reward. It should thus not be expected that incremental benefits would be rewarded with break-though premiums. Where added value versus existing therapies cannot be proven and recognised, timing of market entry of a new medicine should be taken into account as well as its effects on competition. Products coming to market soon after the first-in-class originator are the result of a parallel R&D process and should be rewarded in parallel to the first-in-class originator. Products entering the market significantly later should not get a similar reward.


Be consistent when giving reward. Criteria for pricing and reimbursement need to be transparent, as requested by the Transparency Directive, and consistent over time. This gives the right signals to companies on what innovations are expected and valued. Research and development of a medicine is a risky and multi-year process, in particular for small and mid-size biopharmaceutical companies. The national pricing and reimbursement decisions and related decisions on the timing and utilisation are the only indicators that show whether it will be worthwhile starting this risky process. In addition, overall cost-containment mechanisms, like price-cuts or payback, could be aligned with these initial decisions; they could, for example, foresee exemptions for those innovations that are considered very valuable and have been granted a consequent price and reimbursement level.


Ensuring availability of medicines in small national markets Promoting the sustainable availability and delivery of medicines to all European markets is one of the objectives of the Pharmaceutical Forum. This is in particular important for the smaller national markets, where some important medicines are not available.

This issue has been put forward by the participants of the Working Group Pricing of the Pharmaceutical Forum since the first session. It is in particular a worthwhile exercise for this Working Group to address the unavailability of many medicines to small national markets, as the underlying reason for this unavailability seems also to be of an economic nature. The creation and supply of medicines is usually undertaken by economic operators (manufacturers, wholesalers and pharmacists) that are driven by economic incentives. Any solution for the problem will therefore have to strike a balance between economic reward, access and cost-control.

It needs to be noted that a parallel and separate effort is ongoing from a regulatory perspective, driven by the Heads of Medicines Agencies. In their 2007 report they conclude that "Medicinal products are not made available in the markets of all Member States. Member States with small markets face significant problems of medicine availability, especially with products of low volume, low price and specialised products intended to treat severe and/or rare diseases." The European Commission has therefore been asked to see how they can improve the regulatory framework.

Both efforts should move forward in parallel, with regular mutual consultation.

Introduction While ensuring quality, safety and efficacy of the medicines in the European markets, regulatory procedures can pose some difficulties to the availability of medicines. In addition, there are several other thresholds, of more economic nature, that limit availability as economic operators need to overcome them before making a medicine available on a national market. This paper therefore aims to provide an economic overview of these main thresholds as well as some understanding on the reward for economic operators that motivates them to overcome these thresholds. In addition the paper tries to explain how these economic requirements and rewards are influenced by the (small) size of the market. This knowledge forms the basis for some options for ways forward in the last section. Of course, every country is different, and should take up those options best targeted at the situation of its own market. This paper only aims to provide a general understanding and a menu of options that could potentially improve availability. Thus, economic operators may find more options that allow them to supply medicinal products to all markets in a profitable way. At the same time, one should keep in mind that medicines can not be treated as other commodities by regulators and administrators because of their public health implications. This exact concern and responsibility should help ensure the supply of medicines on the markets of all Member States.

Although this paper includes some thoughts on the models and processes of making pricing and reimbursement decisions, it does not aim to express an opinion on the actual or appropriate levels of pricing and reimbursement. These levels are anyhow driven by a multitude of factors, and vary from country to country. Price increases or price reductions are not expected to really address the issue of availability. E.g., Iceland is a small national market


that, in spite of having amongst the highest prices in Europe100, is facing significant availability problems. On the other hand, price cuts would probably reduce necessary incentives for economic operators to supply medicines on a smaller market.

The economics of making medicines available Once the development of a medicine is completed successfully, additional steps are required to make it available on a national market. Within the current frameworks, these steps are usually undertaken by economic operators: manufacturers, marketing authorisation holders, agents, wholesalers and pharmacists. These economic operators will only do so if they can make profit out of it, meaning that costs incurred to overcome the thresholds are lower than expected revenues for doing so.

The key activities to be undertaken are: 1. Administration:

Market authorisation is a first necessary step to place a medicine on a market. This requires the preparation of a specific file, the hand-over and the administrative follow-up with the authorities. Although Marketing Authorisation files for new, innovative medicines are handled increasingly on a European level by EMEA and the European Commission, for many older medicines the files are usually handled on a national basis. In a next step, pricing decisions (where relevant) are taken. This can only take place on a national level. Also reimbursement negotiations are handled on a national basis with the local authorities. Many authorities require a fee for handling these files. This administrative preparation and follow-up of files, together with the related fees, bring an upfront investment for a manufacturer before a medicine is allowed into a specific market. At the same time, delays in decisions making can bring a significant loss of revenue for manufacturers and delay in access for the patient.

Consequently, once put on the market, there is need for additional administration like sales, marketing, pharmacovigilance and other activities to maintain the marketing authorisation for each medicine put on the market. In many countries Marketing Authorisation Holders pay a maintenance fee to the authorities, to perform ongoing tasks like pharmacovigilance. In principle, administrative work related to putting a medicine on the market is not determined by the size of the local market. For some smaller national markets these administrative tasks are performed by exclusive representatives of one or more manufacturers in the national market.

2. Manufacturing, packaging and labelling need to follow the EU legislation and the requirements of each national market, e.g. requirements related to the local language(s). Manufacturing and packaging are planned and executed in continental or global facilities, producing so-called batches (fixed quantities of medicines) specified for a local market and its requirements.

Planning and producing consignments of packs for small national markets will be less regular and requires sufficient organisational flexibility. At the same time consignments for small national markets typically have lower quantities and are therefore more expensive per unit produced. This organisation is further complicated by the fact that small national markets need to be continuously supplied, as any other market.

100 Eurostat 2007


3. Transport and wholesaling steps bring the prepared medicines from various manufacturing sites to multiple local retail points. Many Member States therefore place public service obligations on wholesalers which require them to deliver all medicines available in the market within certain time limits to all pharmacies. These full-line wholesalers therefore need to build and maintain sufficient stocks and efficient ordering systems, besides their transport capacity. This is in particular complicated for medicines with a low frequency of ordering. For some sophisticated products, manufacturers organize direct supply to the hospital (e.g. oncology). For some of the more distant small national markets like Malta, Cyprus or Iceland, transport costs can be significant. Maintaining stocks of medicines as products with an expiry date, is more complicated and expensive when demand is limited, like in small national markets. In some smaller Member States there are no full-line wholesalers. Often transport and distribution steps are there organised by an agent, who organises through a wholesaler the exclusive supply of those medicines produced by the manufacturer(s) he represents. These agents, if they are not considered wholesalers, would not be submitted to public service obligations according to the EU legislation. As compensation, wholesaling parties/agents earn a margin per unit of medicine delivered. This margin is usually a fraction (percentage) of the ex-factory price of the supplied medicines. To be profitable it is therefore important that wholesalers deliver a broad portfolio of products, so that margins of different products add up to earn sufficient margins in order to cover all costs. The creation of such portfolio also allows cross-subsidisation, so that less-expensive medicines can be supplied, which stand-alone would not offer enough margins to wholesalers to cover costs of supply. This is the basic business model of full-line wholesalers. The smaller the market, and thus the volume of each medicine needed, the broader the portfolios of individual wholesalers need to be. In this way, a wholesaler can supply sufficient high-margin products to be profitable and deliver also all low-margin products.

If medicines are to be made available on a local market, it is important that all actors can undertake their activities in a profitable way i.e. manufacturers (authorization, registration, price administration, manufacturing and packaging) wholesalers (transport, storage, wholesale/distribution) and finally also pharmacists (retailing).

As mentioned in the different paragraphs above, the specificities of small markets make it harder for each of them to be profitable.


Potential ways to facilitate availability Looking at these different steps, some ideas could be elaborated in order to improve the availability of medicines, in particular in small national markets: 1. Administration

a. The taskforce preparing this paper has discussed several regulatory ideas to reduce the administrative burden to obtain marketing authorisations. These ideas were similar to those expressed by the Heads of medicines Agencies task force on availability, discussed in the Pharmaceutical Committee.

b. Marketing authorisation holders should supply, as far as possible, each product in each national market where it is authorised. Alternatively, if a marketing authorisation holder chooses not to have a product supplied in a given Member State, there should be ways to get the product on the market where it is needed.

c. Within small national markets, companies should register trademarks, pack-sizes and forms that are similar to the ones within some larger EU markets.

d. Authorities in small national markets should ensure a pricing and reimbursement system that facilitates the placing on the market of new medicines and ensures their availability.

2. Manufacturing, packaging and labelling a. The taskforce preparing this paper has discussed several regulatory ideas to solve

the problem of availability, in particular those related to the language requirements. These ideas were similar to those expressed by the Heads of Medicines Agencies task force on availability, discussed in the Pharmaceutical Committee. Some of these ideas will also be discussed in the context of the upcoming pharmaceutical package of the Commission (expected in October 2008).

b. Companies can produce multi-lingual single packs for multiple (small) national markets. This would allow cheaper and more frequent production of consignments for the small national markets. This is allowed by Community law under Article 63 of Directive EC/2001/83 and e.g. in place in Belgium where packs are adapted to language requirements in Dutch, French and German.

3. Transport and wholesaling a. Ensure the presence of an optimal number of full-line wholesalers to ensure good

and continuous supply. Ideally, there should be sufficient full-line wholesalers so that supply problems within one wholesaling actor do not immediately lead to problems for the entire market. However, the presence of too many full-line wholesalers might lead to suboptimal supply of the market. The regulation of margins can be a tool to this end.

b. Apply public service obligations on all wholesaling actors, and encourage that as many as possible act as full-line wholesalers and continuously supply all medicines to the entire local market.

c. Public wholesaling. Public authorities can organise wholesaling themselves. This is e.g. sometimes done in the context of tendering or purchase of hospital medicines. To ensure that all products are delivered on the market, public wholesaling should be complementary and not competitive to private full-line wholesaling. Public wholesaling should therefore primarily focus on those


products that are not efficiently delivered through private wholesaling (e.g. where stock-ruptures exist). Public or short-line wholesaling of the most profitable products has an impact on the availability of the full range of products, as these most profitable products offer the main incentive for private full-line wholesalers. Public wholesaling should not pre-empt the need for public service obligations.. Of course, the use of these mechanisms needs to comply fully with the relevant competition legislation. Potentially authorities of smaller Member State could join efforts.

Of course, each country situation is different and the reasons for (un)availability vary. Some initiatives are already in place in some countries. It is therefore up to each country to take up the most adequate of the options outlined above, in order to improve availability in their local market. Further collaboration between the concerned authorities and stakeholders should be organised.

There is a need for a holistic approach, considering regulatory as well as economic aspects, considering needs and roles of authorities as well as of economic operators and considering the different activities needed to get medicines into the market. The European regulatory aspects will also be addressed by the European Commission, in joint partnership with the Member States.


Improving access to orphan medicines for all affected EU citizens The overall objective of this document is to promote the sustainable development of valuable orphan medicines and to improve sustainable access to these medicines for all affected citizens in the EU.

It is in particular a valuable exercise for the Working Group on Pricing of the Pharmaceutical Forum to address the area of orphan medicines, as these medicines amplify strongly the common tensions we have found in the field of pricing and reimbursement: assessing and rewarding innovation is difficult, budget optimisation is challenged and access for patients is limited in several countries.

Introduction Orphan diseases are life-threatening or chronically debilitating diseases that affect less than 5 out of 10.000 citizens. Although each of the orphan diseases only concerns a limited number of patients, rare diseases are socially and ethically relevant. In the EU, about 6% of the population is expected to be affected by one of 5,000-8,000 orphan diseases at one point in their life-time101. The low number of potential patients per disease may limit the economic attractiveness of undertaking research and development of medicines to treat orphan diseases. To promote such research and development, the European Union has adopted the European Regulation on Orphan Medicinal Products in 2000 (Regulation (EC) No 141/2000).This Regulation defines an orphan drug as a medicines (a) for a life-threatening or chronically debilitating condition, (b) that affects not more than 5/10,000 persons or for which a low return on investment is expected without additional incentive and (c) for which no satisfactory alternative treatment method exists or for which this new medicine brings significant benefits to patients compared to the existing treatment. This Regulation has brought some efficient incentives for R&D, in particular the provision of a 10-year market-exclusivity which has led to a significant increase of research and development in the field of rare diseases. By February 2008, 541 molecules got an orphan designation. 45 of them have gone through the entire development-process and have effectively led to a new treatment for which a marketing authorisation was granted (see annex). As such, a medicinal therapy has been developed for many diseases which previously could not be treated. For the coming 5 years a steady inflow of about 10 to 12 new orphan medicines per year is expected. By end 2012, it is anticipated that around 100 orphan medicines will be authorised in the EU. The adoption of recent European legislations like the Paediatric Regulation (Regulation (EC) No 1901/2006) or the Regulation on Advanced Therapies (Regulation (EC) No 1394/2007), has provided an additional stimulus for many orphan medicines. Many measures that were taken by individual Member States on the national level have largely contributed to this success. In spite of this, newly developed orphan medicines are not available for all citizens in the EU in a timely and equitable manner. Effective market access and utilisation vary strongly between and within Member States. Different studies, like e.g. the Alcimed study102 or the

101 These figures come from different institutions’ official documents, such as the Background Paper on Orphan Diseases for the “WHO

Report on Priority Medicines for Europe and the World” - 7 October 2004; the European Commission Consultation “Rare Diseases: Europe’s challenges” - November 2007; documents from the National Institutes for Health – Office of Rare Diseases, as well as documents from patients organisations: NORD, the National Organization for Rare Disorders in the USA, and EURORDIS, the European Organisation for Rare Diseases in the EU, in particular the document “Rare Diseases: understanding this Public Health Priority.

102 Commissioned and published by the Commission on 16/11/2004 on http://ec.europa.eu/enterprise/pharmaceuticals/pharmacos/archives_en.htm


Eurordis survey103 series, confirm this variation in access. European reference networks between centers of expertise are a way to reduce this variation in access. This paper aims to identify the main bottlenecks orphan medicines meet on their way to all affected EU citizens. These bottlenecks relate no longer just (1) to development, but also (2) to assessment, (3) to pricing and reimbursement practices by companies and by national authorities and (4) to awareness building. Consequently this paper puts some ideas forward that should be seriously explored in order to ensure timely and equitable access for all EU citizens to more orphan medicines.

Specific bottlenecks linked to rarity In spite of increased incentives and in spite of increased flexibility in marketing authorisation procedures, the development of a medicine for an orphan indication remains a risky enterprise. The low number of potential patients, the absence of patient registers and the lack of national centres of expertise complicates research and development while it makes the future return on such R&D investments uncertain. Besides the usual R&D difficulties, researching and developing orphan medicines need to deal with the identification of rare patients, the heterogeneity of the diseases, a limited basic knowledge on the diseases, the application of often novel technologies and specific logistics and infrastructure requirements to run the clinical studies (e.g. flying patients in worldwide to one expert centre). Also manufacturing processes need to be developed at the same high standard-levels of safety, quality and efficacy as for other medicines. The low number of potential patients limits the future sales volume while often high levels of pricing and reimbursement make negotiation processes difficult. Overall, this may make the expected future revenue and return on investment uncertain and unattractive, while it potentially jeopardises the important societal benefits that orphan medicines could offer. The Orphan Medicinal Products Regulation is aiming exactly to address these bottlenecks in development. Assessing the clinical added value of innovative medicines has proven to be a difficult task. Capacities and knowledge to do so are still under development. Orphan medicines add to this complexity due to the rarity of patients, the severity and the heterogeneity of the diseases addressed and the scarcity of clinical experts. Scientific data that are presented to Marketing Authorisation authorities are often limited as clinical trials can only include a low number of patients. The severity of the disease, combined with the lack of satisfactory alternatives, regularly leads to early Market Authorisations, before running phase III- trials which bring more data on a higher number of patients. Often ongoing clinical data-registration (phase IV) needs to be organised in the post-marketing phase as required by regulatory authorities. Data for value assessments (post marketing authorisation) are therefore limited, in particular for the initial assessments. In addition the know-how to make these value assessments of orphan medicines is strongly fragmented over national procedures within the individual Member States and their regions, in spite of some first efforts to collaborate. The disconnection of these national and regional processes from the knowledge and experience gathered upfront in the centralised processes (like for Orphan Designation, for Marketing Authorisation or for Paediatric Use) add to this fragmentation. Pricing and reimbursement decision-making is an area of increasing sensitivity within almost all of the European Member States. The uncertainty about the value, the lack of information, the usual high-prices, the high risk for development, the low and uncertain volumes, the occasional extensions of indications and the often life-long need for treatment add to this sensitivity when discussing pricing and reimbursement of orphan medicines. 103 Available through www.eurordis.org


Decision-making is further complicated by the frequent use of these treatments in hospitals. As explained above, only a limited set of data on clinical added value is available to justify the initial requests for high prices, while data on drug-specific costs for R&D are usually not available, as is the case for most medicines. When prices are negotiated, initial negotiations between companies and authorities should not only include agreements on price and reimbursement levels but also on monitoring utilisation (based on medical best practices), in order to control budgets in spite of high prices. Negotiations can be further complicated in case of further extension of indications. In many Member States, the national budgets for orphan medicines are still relatively limited, but seem to grow fast. These budgets may lead to different levels of affordability depending on the economic situation of a Member State. To manage budgets and make the right choices, an increasing number of Member States complement the price negotiations with practices to monitor and manage utilisation like e.g. prescription limitations, pre-utilisation approvals or exclusive use in designated expert centres. In contrast to other disease areas, health professionals have limited awareness and skills with diagnosing and treating orphan diseases. The low incidence of these diseases allows only a limited number of health professionals, usually in specialized centers, to build expertise with diagnosing and providing medical care to people affected by a rare disease. Nevertheless, an early diagnosis of these diseases, which often have a genetic origin, is one of the best guarantees for an efficient treatment from a therapeutic and cost perspective. In addition, treatments are often not curative but usually offer from limited to extensive symptomatic support. The novelty of the treatment options offered by innovative orphan medicines further limits awareness and skill levels of health professionals. Some Member States therefore organise the monitored utilisation of orphan medicines through dedicated centres of expertise, to which all patients with a specific orphan disease are referred. Alternatively Member States ask these centres of expertise to issue good practice guidelines to advise all potential concerned physicians and experts.

Potential ways forward In addition to ongoing activities promoting the development and access to medicines in the European Union, the Working Group Pricing believes that some specific activities can be explored to promote further development and access to orphan medicines. These include: o Establish early dialogue between companies and pricing and reimbursement authorities,

including clinical value assessment authorities regarding orphan medicines in the pipeline and the future needs for these medicines. This dialogue will allow in an early stage to clarify the need for a new orphan medicine under development and give an idea of the number and profile of patients in need. It would offer an early occasion to discuss what clinical data would be required for later clinical value assessments and pricing and reimbursement decisions. This will give the sponsoring company more certainty on its potential future return and will give authorities more knowledge and trust in the value of medicines it will be requested to assess and fund. Also, this will significantly facilitate long-term planning both for companies, for funding authorities and for society. Such dialogue could even help identify areas where further research and development for orphan medicines are needed, taking account of public health priorities. Early dialogue would also bring an opportunity to get more transparency on costs, including the role of publicly funded studies, and on pricing. Such dialogue might require an upfront coordination between Member States and European authorities, in full respect of different competences, in order to jointly pass common messages to the individual companies. This coordination and dialogue can be continued after regulatory approval and after initial


pricing and reimbursement decisions, where additional studies are requested regarding the utilisation of medicines. Where appropriate this can include the set-up and use of disease registries104.

o Exchange of knowledge amongst Member States and European authorities on the scientific assessment of the clinical added value of orphan medicines. Such exchange could improve the flow of knowledge from EU-level authorities (e.g., EMEA committees) to the Member State's pricing and reimbursement authorities, in particular with knowledge gathered during marketing authorisation procedures (quality, safety, efficacy), revision of the orphan designation at the time of marketing authorisation (significant benefit) and potentially the evaluation of paediatric use (paediatric investigation plans). Bundling the fragmented know-how to assess the clinical value of orphan medicines would allow the timely production of well-informed opinions, based on more data, shared information, experiences and in-depth discussion. Such opinions will form a good input and may reduce the information deficit for the national pricing and reimbursement decisions. Clinical/therapeutic aspects, rather than economic and quality-of-life aspects, should be the first focus in common approaches, as variation between Member State practices is lowest in this area. Based on exchange of knowledge, these collaborations could lead to non-binding common clinical added value assessment reports with improved information that facilitate the national pricing and reimbursement decisions, without pre-empting respective roles of the authorities. Of course the applicable rules regarding confidentiality should be considered when exchanging such information.

o Promotion of the initial uptake of orphan medicines through conditional pricing and reimbursement decisions. Such conditional decisions could allow fast access for patients to medicines, while the related conditions can, case by case, control the utilisation, specify the expected annual budgets, fix the timings for review and clarify the expected results of further studies and future pricing and reimbursement adjustments. To fully profit from conditional agreements, costs, risks and benefits must be clearly aligned and clarified upfront, in order to avoid later legal and ethical conflicts. At extension of indications a review of the conditions should be organised taking account of the additional development costs and the additional number of patients benefitting from the medicine. The related conditions usually ask for monitored utilisation allowing collection of additional data e.g., in the context of a post-marketing trial or a registry. A high quality of monitoring and data-analysis is needed in these trials. The earlier Member States adopt the utilisation of orphan medicines in such controlled settings, the earlier a substantial set of data on the impact of orphan medicines can be developed. This in return will provide a basis for the future review of pricing and reimbursement decisions. To ensure that patients in all EU and EFTA Member States can benefit early on from orphan medicines other ideas should be explored, like simultaneous applications for pricing and reimbursement to all Member States authorities, early start of national pricing and reimbursement procedures, parallel decision making with common information bases and coordinated follow-up of use and outcomes in clinical practice. Some of these ideas are already in place in some Member States, and these experiences should be shared amongst Member States. 105

o Building EU-level awareness and expertise on orphan diseases. Controlled utilisation can very well be linked to the creation of standardised patient registers106 at international level and networks of centres of expertise. Registers would also allow upfront estimates of

104 Disease registry is a specially designed database with voluntary, observational clinical data collected from physicians and intended to

explore and define the natural course and clinical characteristics of disease, as well as to track and characterize response to treatment. 105 For more specificities regarding conditional pricing and reimbursement we refer to the paper "Risk-Sharing practices and Conditional

Pricing of pharmaceuticals - How to deal with uncertainty", as well as to the "Guiding Principles Paper", adopted by the Working Group Pricing.

106 Patient register is a database (list) containing baseline information on the existence of patients with (a) certain disease(s), but without any longitudinal follow-up.


numbers and profiles of patients for study and budget purposes. Another key benefit of such registers is the upfront knowledge of where rare disease patients live so that they can be quickly enrolled in trials for new potential medicines, to the benefit of both the patient and the sponsoring company. At the same time, the set-up of disease registries will facilitate the generation of additional data on the benefits of the medicine in real life settings. These data, in their turn, will form the basis for later reviews of pricing and reimbursement decisions. All registers and registries are to be managed in compliance with data protection rules and other relevant national requirements. To fully leverage collected knowledge, the efforts need to be well coordinated within and between Member States. Within Member States, coordination should be a key element in national plans for rare diseases and orphan medicines. Between Member States, national and regional centres of expertise need to be connected in a cross-border European Reference Network for Rare Diseases. The Orphanet initiative could be a helpful reference for cross-border work in this area107. This will improve access to orphan medicines, increase quality of care, and allow to compile and compare data of all Member States.

107 www.orpha.net


List of Orphan Drugs with European Market Authorisation - 16 June 2008 Product Name MA Holder Date of MA Indication Replagal Shire 4-may-01 Fabry Disease Fabrazyme Genzyme 4-may-01 Fabry Disease

Glivec Novartis 27-aug-01 Chronic Myeloid Leukaemia Trisenox Cephalon 5-march-02 Acute Promyelocytic leukaemia Tracleer Actelion 15-may-02 PAH Somavert Pfizer 13-nov-02 Acromegaly Zavesca Actelion 20-nov-02 Gaucher Disease Carbaglu Orphan Europe 24-jan-03 NAGS Deficiency Aldurazyme Genzyme 10-june-03 MPS I

Busilvex Orfagen / Pierre Fabré 9-july-03 Conditioning prior to transplant

Ventavis Schering 16-sept-03 PAH Onsenal Pfizer 17-oct-03 Familial Adenomatous Polyposis PhotoBarr Axcan 25-march-04 Dyplasia in Barrett's Esophagus Litak Lipomed 14-apr-04 Indolent Non Hodgkins Lymphoma Lysodren HRA Pharma 28-apr-04 Adrenal Cortical Carcinoma Pedea Orphan Europe 28-july-04 Patent ductus Arteriosus Wilzin Orphan Europe 13-oct-04 Wilson's disease Xagrid Shire 16-nov-04 Essential Thromobythaemia Orfadin Swedish Orphan 21-feb-05 Tyrosinaemia Prialt Eisai Ltd. 21-feb-05 Chronic pain Xyrem UCB 13-oct-05 Narcolepsy Revatio Pfizer 28-oct-05 PAH Naglazyme BioMarin Europe 24-jan-06 MPS VI Myozyme Genzyme 29-march-06 Pompe Disease

Evoltra BioEnvision (Genzyme) 29-may-06 Acute Lymphoblastic Leukaemia


Nexavar Bayer 19-july-06 Advanced Renal Cell Cancer Sutent Pfizer 19-july-06 GIST Savene TopoTarget 28-july-06 Anthracycline Extravasation

Thelin Encysive (UK) Ltd. 18-aug-06 PAH

Exjade Novartis 28-aug-06 Iron overload req chelation

Sprycel BMS Pharma EEIG 20-nov-06 Chronic Myeloid Leukaemia

Diacomit Laboratoires Biocodex 4-jan-07 Myoclonic Epilepsy

Elaprase Shire 8-jan-07 MPS II Inovelon Eisai Ltd. 16-jan-07 Lennox Gastaut syndrome Cystadane Orphan Europe 15-feb-07 Homocystinuria Revlimid Celgene 14-jun-07 Multiple Myeloma Soliris Alexion Europe 20-jun-07 Haemolysis in Paroxysmal Nocturnal Haemoglobinuria (PNH) Siklos Addmedica SAS 29-jun-07 Vaso-occlusive crisis Increlex Tercica Europe 3-aug-07 Growth failure

Atriance Glaxo 22-aug-07 T-cell acute lymphoblastic leukaemia (T-ALL) and T-cell lymphoblastic leukaemia (T-LBL)

Gliolan Medac 7-sept-07 Visualisation of malignant tissue during surgery for malignant glioma Yondelis Pharma Mar 17-sept-07 Advanced soft tissue sarcoma Torisel Wyeth 19-nov-07 1st Line Renal Cell Carcinoma Tasigna Novartis 20-nov-07 Philadelphia chromosome positive chronic myelogenous leukaemia Thalidomide Pharmion Pharmion Ltd 16-apr-08 Untreated multiple myeloma Volibris GlaxoSmithKline 21-apr-08 PAH Firazyr Jerini AG 11-july-08 Acute attacks of hereditary angioedema * estimated cumulative number of patients treated since launch in EU-27 (non-repetitive treatment). ** reimbursed in 15 countries


Characterisation of the Value of Innovative Medicines

Introduction At the High-Level Meeting on 29 September 2006, the Pharmaceutical Forum asked the Working Group on Pricing to “further progress by …clarifying views on the value of innovation, taking account of national health systems in order to establish a sound basis for further discussion between different stakeholders…”. This mandate has been assigned to an ad hoc taskforce with the Members of the Working Group on Pricing and involving the chairman of the Working Group on Relative Effectiveness. This report does not aim to identify and implement an EU-wide definition of what is valuable innovation. It is rather a bottom-up exercise, based on the collection and discussion of views of the relevant Member State authorities on how to recognise, assess and reward valuable innovative medicines. Thus, the main objective is rather to identify the common ground between the individual Member States, as well as the different, more optional views on what can be valuable innovation. Still, the decisions on healthcare and pharmaceuticals remain a national responsibility.

Focus of this exercise It quickly became clear that the taskforce did not need to focus on innovation in se, but rather on the additional benefit(s) that an innovative medicine brings for the user-side, i.e. mainly for the patient and for society. These users do compare these additional benefits to validated existing treatment options. In this paper, the term “innovation” is therefore different from its strict legal and/or technical definition (‘novelty’ as often identified by a patent). Such potential benefits can be structured in 3 main areas: 1. “Therapeutic/Clinical” benefits refer to those new medicinal products, which are able to

treat or to prevent, in all patients or in specific patient groups, diseases lacking (adequate) treatments or diseases already treated with pre-existing medicinal products but with clinical or safety advantages.

2. “Quality of Life” benefits refer to those new medicinal products, which, compared to the existing ones, are able, in all patients or in specific patient groups, to provide quality of life gains.

3. ”Socio-economic” benefits refer to those new medicinal products, which, compared to the existing ones, are (also) able to offer benefit on a higher-level for society (e.g. related to public health or public budgets).

It is clear that the benefit brought by one medicine can cover more than one area. Furthermore, there is often interdependence between these three areas of benefit, one benefit influencing another. This is to be taken into account during assessments in order to avoid double-counting.

Process undertaken During a first brainstorming session in summer 2006, the taskforce has tried to specify further each of these areas by listing a large number of potential benefits that could be expected from new innovative medicines. This list was meant in the first place to be exhaustive and to cover all the different benefits that could be considered by each of the Member States’ competent authorities. Recognition of the benefits on this list can, therefore not be seen as mandatory,


but rather as a menu of options, from which individual Member States can choose the benefits they consider relevant. The questionnaire was also sent to a number of patients’ organisations. Table 1: potential benefits from innovative medicines Therapeutic/Clinical Quality of Life Socio-economic Higher probability of full recovery Higher physical self-

sustainibility/self-management at home

Avoiding Pandemics (vaccination, …)

Faster partial or total recovery Higher psychological self-sustainibilty

Dealing with resistance (HIV, antibiotics, …)

Slower progression of diseases Higher social self-sustainability Reduced total cost of medication Increased ability to cope with disease symptoms (e.g. analgesic)

Higher convenience/comfort for the patient and his environment

Reduced total cost of treatment

Higher probability of preventing the (re-) emergence of a disease

Reduced Non-healthcare spending

Survival rate, life expectancy Reduced cost of sick-leave Less or less severe side effects Higher productivity of the citizen Less or less severe interactions with other medicines

Higher tolerability Broader/easier dosing, improving compliance Easier administration schedule, improving compliance To collect the views of the individual Member States, the list was transformed into a questionnaire (see annex 1), adding some questions on each of the potential benefits. Firstly, whether this new benefit, when delivered through a new innovative medicine, is usually considered of value as a desired improvement. And if so, in what disease/therapeutic situation this new benefit is in particular valuable. In addition, the questionnaire tried to understand how competent authorities identify/measure these benefits as well as how they reward/incentivise a company for delivering such a benefit. The questionnaire was completed and sent out at the end of 2006 and by the beginning of 2007 fourteen answers were collected from respectively Belgium, Denmark, Finland, France, Germany, Greece, Hungary, Latvia, Malta, Netherlands, Norway, Slovenia, Sweden and the U.K.

Findings The collected results have allowed compilation of the findings in each of the 3 areas of benefits. This report provides only the summary. More detailed views can be consulted in the Member States’ individual replies. However, it is worthwhile first to mention some overall findings.


General findings: - Most competent authorities consider benefits in each of the 3 areas mentioned. Although

therapeutic/clinical benefits are mentioned as being the most important, there is a general openness to consider benefits in quality of life and/or socio-economic benefits.

- Although these benefits in se can be valuable, the value of a new medicine each time needs to be considered case-by-case, i.e. what new additional benefits the medicine brings compared to existing treatments. The type of disease and general status of the patient also play a key role in defining the value of the benefit delivered by a new medicine.

- The responses indicate that Member States know what benefits they are looking for, but that companies have difficulties in proving these benefits, and authorities have difficulties in identifying and measuring these benefits, to give them a value and reward.

- The list of benefits sent out is rather complete. Most respondents have replied on each of them, and only one reply suggested an additional benefit.

- Most respondents indicated that they work with these benefits, though they usually have no fully structured overview in place to identify and assess new medicines, as proposed in this exercise.

- Many Member States have an evaluation procedure that starts with determining the intrinsic value of innovation, based on therapeutic/clinical benefits and benefits of quality of life. Pharmaco-economic evaluations then follow in a second step.

- Replies from the patients’ organisations added the importance of the empowered patient and the importance of a societal perspective including analyses of therapeutic benefits, quality-of-life benefits and savings.

Findings on therapeutic/clinical benefits: - Therapeutic and clinical benefits are the main benefits authorities are looking for, in

particular benefits related to recovery, survival, disease progress and management of symptoms. Benefits related to side-effect and interactions of a medicine are considered as a second important category. Benefits related to improved compliance are only considered when this translates into an overall clinical benefit.

- Ideally, these benefits can be identified and captured within one over-arching parameter. QALY (quality adjusted life years) was mentioned as well as a combination of morbidity, mortality and quality of life (QoL). In most situations, however, this is not possible due to difficulties with the design, running and interpretation of clinical studies, which serve as the main source of proof of the benefit. However, these clinical studies are primarily designed to obtain marketing authorisations, not for assessments of benefits.

- Largest rewards are given to medicines that bring benefits in the fields of recovery, survival rate, disease progress and management of symptoms.

Findings on benefits for quality of life (QoL): - Benefits on QoL are considered in most countries, in particular benefits related to

(physical) self-sustainability. Of course, such benefits are often related to clinical/therapeutic benefits.

- Benefits related to convenience and comfort of the patient are considered less important, although these dimensions are indicated to be of high importance by the patient and his community/family.

- Many tools exist to measure benefits in terms of QoL, though only few of them allow an objective and validated assessment. This leads to difficulties in recognising and proving these benefits.


- As a consequence, reward and incentives related to benefits in QoL are rather limited. Although, some competent authorities mention that the individual patients might be willing to add more reward to these kinds of benefits through a higher personal co-payment.

Findings on socio-economic benefits: - Socio-economic benefits are considered in all countries. There is a high overall interest in

‘socio-’ benefits related to public health, like the management of pandemics and/or the resistance to certain antibiotics. Most countries also consider economic benefits, often savings, in particular when these relate directly to the cost of the medication or of the treatment. However, these last benefits are often only assessed in order to define an appropriate price and reimbursement level, once therapeutic/clinical benefits and/or benefits in quality of life are recognised.

- Measuring ‘socio-‘ benefits is often based on epidemiological data, which are not always easily available. Measuring economic benefits is more straightforward and often directly translated into Euros, though several issues exist with the methodologies.

- Authorities give larger incentives to benefits that address ‘socio-‘ public health concerns. The rewards given to medicines with an economic benefit are often directly related to the economic benefits.


From assessing innovative value of pharmaceuticals to pricing and reimbursement decisions

Objective This paper aims to clarify how some different European Member States use assessments of innovative medicines into their pricing and reimbursement decisions.

An increasing number of Member States develop their capacities to assess innovative medicines in order to understand the costs and benefits they bring. As a previous exercise of the Working Group Pricing has demonstrated, the benefits that are considered as added value vary between Member States, although there is a common expectation of therapeutic and clinical progress. As a consequence, assessment methods are still very different among Member States. In several EU Member States, the outcome of these assessments will be used as one element for economic pricing and reimbursement decisions and negotiations undertaken by the competent national authorities. These decisions will therefore drive at the same time expenditure for the authorities and revenue for companies. It is this revenue that makes for a company the return on investment in research and development. Hence this paper aims to understand the mechanics that drive the incentive for companies to take the risk of investing in R&D.

This information is valuable (1) for countries that in their pricing/reimbursement decisions refer to prices in Member States that assesses innovative medicines, to ensure an understanding of the rationale behind the reference price. Moreover, (2) it will benefit Member States that search for experiences and good practices to develop their own value-based pricing systems and (3) for pharmaceutical companies that need to know what revenue can be expected for the value of their medicines.

Methodology It is the Member States' authority to manage the national pharmaceutical budgets and hence to take the economic decisions that drive the expenditure for each medicine. To do so, Member States increasingly perform assessments of the value of new medicines. In this paper we therefore start to describe the systems of 6 EU Member States: France, the Netherlands, Belgium, U.K., Sweden and Germany. This paper is a dynamic document and aims to add descriptions of several other Member States. A previous literature review has provided information for each of this 6 Member States. This information was complemented with the knowledge of the representatives of these Member States in the Working Group.

In a first step, this paper aims to briefly explain what kind of value assessment these Member States are performing. It is not at all the objective of this paper to go in depth on the data and methods of these assessments. Sufficient alternative fora exist to do so. It is rather the objective to understand what is the outcome-format of these assessments that will form partial basis of the economic decisions that will follow. In a second step, this paper examines 4 pharmaco-economic decisions: (1) price level, (2) reimbursement level, (3) utilisation rules and (4) timing of uptake. While the price level drives the cost per medicinal unit, the utilisation rules impact the volume of medicinal units. Reimbursement levels will define who will bear the cost, the government or the patient.


Reimbursement decisions, also indirectly drive the volume, as they define levels of patient co-payment. With an end of exclusivity that is usually fixed by patent expiry, the speed of uptake will define the overall duration of expenditure/revenue.

a. France 1. Assessments There is a focused assessment of clinical and therapeutic benefits of new medicines. The assessment is performed by the transparency committee (“Commission de transparence” - CT) part of the Haute Authorité de Santé (HAS) and includes 2 elements.

First, the Actual Benefits (Service Médical Rendu, SMR) is assessed based on the severity of the disorder, the clinical effectiveness of the medicine and the impact on public health. This can lead to an SMR that is Major, Important, Moderate, Low or Insufficient. Second, the comparison to existing treatment options and identification of added value will drive the Improvement of Actual Benefit (Amélioration de Service Médical Rendu, ASMR). This can lead to an ASMR that is Major (I), Important (II), Moderate (III), Minor (IV) or None (V). 2. Pharmaco-economic decision making

Prices are set by the Economic Committee for Health Products in function of the ASMR. An ASMR-level I-IV can get higher prices than comparators; an ASMR-level I-III can get a price consistent with prices used in other European countries. Products with ASMR-level V will have to offer lower prices than comparators, in order to obtain reimbursement and provide a decrease in expenses for social security funds. Products with an SMR Insufficient do not receive reimbursement. The level of reimbursement and of co-payment is decided by the National Health Insurance and takes account of the SMR.

Utilisation is influenced by HAS, which together with the assessments provide recommendations on therapeutic strategies. HAS can also define restrictions of use for a new medicine. Timing: products with ASMR level I-III are eligible for faster access procedures with notification and less negotiation. Fast track procedures, early assessments and conditional decisions are foreseen for products with an expected good ASMR.

b. Netherlands 1. Assessments

Therapeutic value, together with efficiency and importance to public health are the main focuses of the assessments. The assessments are performed by the Health Insurance Board (CVZ) and include some steps. In a first step the Healthcare Insurance Board will assess whether a new product can be included in the therapeutic reference price system (Annex 1A). The following criteria are used in this assessment: same indication, same route of administration, same targeted age groups and ‘absence of clinically relevant differences’. In case these criteria are met for the new product (in practice this means that the new product is therapeutically comparable to products included in the reference price system) the product will be included in that reference system and included in a group of therapeutically comparable products. All products in that group are subject to same reimbursement limit.


In case the new product cannot be included in the reference price system (e.g. because of clinically relevant differences) the product may be included in Annex 1B. Overall, a new product is only included in Annex 1B

- if the new product cannot be included in Annex 1A - if the product shows added therapeutic value over the golden standard

- the product is cost-effective. The criteria to assess the therapeutic value are efficacy/effectiveness, side effects, applicability, convenience, experience and quality of life. Efficacy/effectiveness and side effects are the most important criteria.

Both class 1A and class 1B products can also be classified as class 2 in case of high product costs and/or a significant chance of inappropriate use.

2. Pharmcao-economic decision making Class 1B products get a price-premium above the prices of comparators Maximum wholesale prices are usually set in function of the prices in Belgium, France, UK and Germany. For class 1A products, the level of reimbursement is set within a reference price system, in function of average prices of similar products in the reference cluster. For class 1B products, no reference reimbursement level is applicable and there is no direct reimbursement limit. The price that is proposed by the manufacturer will be accepted, as long as the product is cost-effective.

Utilisation of Class 2 products can be restricted by conditional reimbursement, e.g. by limiting the indication or by reference to the treatment protocol. Insurers are also allowed to put conditions on the type of prescriber and/or to ask for prior authorisations. Timing: Fast track decision making procedures are possible for medicines that have been licensed under the EMEA 'accelerated assessment procedures'.

c. Belgium 1. Assessments

Therapeutic value is the primary focus of the assessment, with pharmaco-economics for some products. Assessments are undertaken by the Commission de Remboursement des Médicaments / Commissie Tegemoetkoming Geneesmiddelen (CRM/CTG). In first instance CRM/CTG assesses therapeutic value at hand of efficacy, safety, comfort/convenience of use, applicability and where possible effectiveness in practice. Where significant added therapeutic value is identified, the product is classified as class 1, other products are classified as class 2. For class 1 products, additional pharmaco-economic studies are requested from the companies.

2. Pharmaco-economic decision making Maximum prices for class 2 products are set in function of prices abroad and prices of comparator products. Class 1 products can get a price-premium above comparator products. The pharmaco-economic studies are required to justify the size of this premium. An Incremental Cost Effectiveness ratio (ICER) is calculated to do so. The level of reimbursement is not driven by the assessed value of innovative medicines, but by the type of disease and role of the medicine.


Utilisation of the medicine is restricted to the indications set in the SPC and to the subgroups of patients that were in the scope of the assessments. As from end 2007, separate assessments are set up to provide guidelines for health professionals.

Timing: As from end 2007 early assessments are possible for medicines expected to be class 1, e.g. orphan medicines. These assessments can take place as soon as CHMP (Committee for Medical Products for Human Use) in EMEA has brought its positive advice.

d. Sweden 1. Assessments Assessments focus on the cost/effectiveness analysis in societal perspective. As such the proposed price of the new medicine is an element in the assessment. The Pharmaceuticals Benefit Board (LFN) is in charge of the assessments.

The cost/effectiveness assessment108 considers direct costs (pharmaceutical, medical, and non-medical) as well as indirect costs (mainly the impact on the patient's productivity). The effect on health is the key benefit considered and includes clinical/therapeutic progress as well as quality of life elements and compliance.

The assessment is executed in comparison to the most appropriate alternative treatment. The outcome is preferably expressed in Quality-Adjusted Life Years (QALYs) which include cost, effectiveness and quality of life. 2. Pharmaco-economic decision making

Prices are freely proposed by the applicant. As such, the price is an input factor in the assessment of the cost-effectiveness ratio. A too high price will make the cost-effectiveness of the medicine unacceptable. Granting reimbursement takes account of the cost-effectiveness assessment, as well as of 2 other principles: human value and need and solidarity. Levels of reimbursement are progressive (from 0 to 100%) depending on previous consumptions.

The outcome of the cost/effectiveness assessment may lead to restrictions in use of medicines and may lead to conditional utilisation.

Timing: cost/effectiveness assessments do not relate to the timing of uptake.

e. United Kingdom 1. Assessments Assessments focus on the cost-utility of health related benefit (£/QALYs). As such the proposed price of the new medicine is an element in the assessment. Assessments are not automatic for all products and are carried out by the National Institute for Health and Clinical Excellence (NICE). Appraisals are performed following early identification of potential topics through horizon scanning and referred by Ministers following advice from expert panels ran by NICE and including input from clinicians and other specialists.

108 NOTE: In general, it can be said that in a cost-effectiveness analysis the costs are compared with outcomes measured in natural units (for

example, life-years gained, episode-free day, etc). In cost-utility analysis the costs are compared with “utility based" units (units that relate to a person's level of wellbeing) and quality adjusted life year (QALY) is the most common unit. Cost-benefit analysis used monetary values in cost and outcomes. Sometimes the use of the term “cost-benefit” is not used in this strict academic meaning, but more general referring to an economic evaluation (to compare cost –input- with benefits –outcomes-)


Cost-utility assessments are based on clinical/therapeutic benefit and on quality of life. The assessment includes a comparison of the new therapy against standard existing practice.. NICE takes QALYs into account as a key factor, but not as the only factor, when making its appraisal guidance. 2. Pharmaco-economic decision making

Prices are freely set by the applicant, once a marketing authorisation has been granted. As such, the price is a major input factor in the assessment of the cost-utility ratio. A too high price will make the cost-effectiveness of the medicine unacceptable. Assessments do not influence reimbursement. In principle there is an automatic reimbursement after the marketing authorisation. Unless a medicines is put on the black list (not reimbursed) or on the grey list (reimbursed only for specific indications).

Doctors do not need to await NICE guidance before prescribing a drug. Guidance has been issued to the NHS saying that other sources of information must be looked at prior to the publication of NICE guidance. A positive NICE appraisal is supported by a statutory funding direction, which ensures funding by the National Health Service (NHS). Clinicians have freedom to prescribe as they see appropriate but should be able to demonstrate that they have taken NICE guidance into account.

Timing: highly innovative products are assessed in faster procedures, so-called Single Technology Assessments.

f. Germany The system described below is currently being set-up, following a legislation adopted in 2007. To date the assessments are based on benefit analyses, while the new system is planned to be based on cost-benefit analysis. 1. Assessments

Assessments focus on cost-benefit analysis. As such the proposed price of the new medicine is an element in the assessment. Assessments are not automatic for all products, but are performed on request of the Federal Joint Committee for Medical Affairs (G-BA). The Institute for Quality and Efficiency in Health Care (IQWiG) is doing the assessments.

The cost/benefit assessment considers direct costs to the social security system or broader (including the pharmaceutical price). Benefit assessments include clinical/therapeutic benefit and quality of life. The assessment are comparative to appropriate alternative treatments. IQWiG provides as output not only a Cost/Benefit assessment but also guidances for clinical use. 2. Pharmaco-economic decision making

Prices are freely set by the applicant, after marketing authorisation. As such, the price is a major input factor in the assessment of the cost/benefit ratio and in the drafting of the guidances for clinical use. A too high price will make the cost/benefit ratio of the medicine unacceptable.

Most medicines are added to a cluster of alternative treatments. The reimbursement is then set at a similar reference price for the entire cluster. Only if significant added value is identified, medicines are not added to a cluster and are fully reimbursed. For these medicines the Cost/Benefit assessment can be used by the Federal Association of Sickness Funds to limit the amount of reimbursement.


The IQWiG guidance reports for clinical use can be used by G-BA to set mandatory utilisation restrictions for prescribers. Timing: The cost/benefits assessments do not relate to the timing of uptake (though, it needs to be noted that individual sickness funds can and do negotiate rebates and/or risk-sharing deals to facilitate the use of new medicines.)

Preliminary findings Although based on the inputs of only a limited number of Member States, we can come to some first preliminary findings:

o There seem to be 2 general approaches to assessments and related economic decisions. a. In some countries (SE, UK, GE) prices are freely set upfront by the applying

companies. The set price is then one of the input factors for the assessments that follow. These assessments compare the benefits (clinical/therapeutic, but also quality of life) with the costs of using the medicine (broader then just the cost of the medicine).

b. In other countries the process starts with an upfront assessment (FR, BE, NL), which in first place focuses on therapeutic/clinical benefits. This assessment is then basis for fixing prices, or like in NL for fixing maximum-levels of prices.

o In both approaches, authorities can use references to comparator products when defining prices and reimbursement levels of medicines without proven added therapeutic/clinical benefits. Where significant added therapeutic/value is proven, a price premium versus comparator products can be allowed and reimbursed. The assessments are usually used to define the size of this price premium.

o To optimize use of resource, assessments are regularly used to avoid over-utilisation and give (mandatory) guidance for the prescribers and/or restrict the use.

o Many countries facilitate uptake of those medicines that bring significant added value, by speeding up the procedures (in so-called fast-tracks). The assessments often are the basis for deciding whether a medicine is (expected to) bring(ing) significant added value, and can therefore apply for fast-track procedures. Though, sometimes the central opinion of CHMP (EMEA) can trigger fast-track procedures as well.


Building a toolbox of good practices to control budget, ensure access and rewards innovation The Pharmaceutical Forum meeting on 29 September 2006 called on the Working Group on Pricing to “leverage our collective knowledge to build a toolbox of concrete options and measures based on Member States' experiences”. Although each Member State setting is different, all Member States aim to offer sustainable healthcare, which is of good quality, affordable and available to all its citizens. To do this, Member States apply a set of cost containment instruments, influencing access to medicines and influencing reward for innovation. Member States, therefore, face a similar challenge to find a balance between three objectives, i.e. (1) containment of costs, (2) reward for innovation and (3) access to medicines. Member States increasingly look to the same range of practices to address these challenges. Nevertheless, in the course of the previous work of the Working Group on Pricing, it has become clear that there is need for more evidence of the benefits and risks of different practices. This increases the interest of the Member State participants in sharing their experiences and evidence on different practices. This toolbox exercise should therefore offer a view on what each practice brings for each of the three dimensions in the balance. As such, Member State authorities will have a good view on which practices to chose and implement in order to achieve their national pharmaceutical policies. It is clear that final decisions on pricing and reimbursement of medicines are a national competence, following the subsidiarity principle. This toolbox is therefore to be seen as an exercise to facilitate Member States’ choices and it is in no way binding for national authorities. The aim of the toolbox exercise presented here, is to collect and provide the answers for those questions a Member State reflects on when considering a new practice: real benefit(s) that can be expected, potential risks and interferences with other practices, driving factors of such risks or successes, etc ; the set-up of a practice. In addition, actual materials that have proven useful in a Member State while setting up a practice, can be exchanged through the toolbox (e.g., algorithms used, examples of materials used in campaigns, etc) The toolbox exercise will work in this direction through three different levels:

1. It is important to keep some principles in mind by which to implement the practices to ensure positive impact on each of the 3 desired objectives. In other words, these principles will allow good implementation of a practice. A list of principles is to be developed based on past and ongoing discussions in the Working Group.

2. A summary of each individual practice in terms of benefits and risks for each of the 3 objectives, i.e. access for patients, cost-containment and reward for innovation. This will be presented in the form of a concrete template per practice, based on evidence where possible.

3. If level 1 and 2 prove useful, an on-going process would then be developed to collect and exchange Member States’ experiences of different practices and policies. A concrete approach is to be developed and implemented.

In terms of timing, the summaries of practices and the good principles are the first steps to take, leading to concrete outputs for the High-Level Forum meeting in June 2007. Element 3 is to be elaborated by the next Forum session.


Summaries of practices Different practices in the field of pricing and reimbursement usually aim to impact on one of the three objectives, i.e. (1) containment of costs (i.e. managing limited financial resources), (2) access to medicines for patients (in hospital and ambulatory settings) and/or (3) reward for innovation (i.e. promoting those medicines bringing new added benefits). However, many practices will have an impact, intended or not, on more than one of these elements. These summaries will bring, per practice, a short and broad overview of the benefits and risks for each of these objectives, both in terms of qualitative and quantitative effects.

Most pricing and reimbursement practices use a limited set of levers to influence expenditure on pharmaceuticals, being (1) fixing a price level, (2) fixing a reimbursement level, (3) managing the volume/utilisation through guidelines and obligations, (4) managing time aspects of introducing innovators and generics and (5) using a-posteriori measures to correct overall spending. The summaries will help clarify how each practice uses these levers. The summaries come in the form of factual and dynamic templates that are subject to debate and continuous updating. However, they express the best understanding, both common or conflicting, of the participants of the Working Group on Pricing. The arguments taken up in these templates are to be as much evidence based as possible. The templates will therefore include as sections:

• A descriptive part in order to ensure a common understanding of the practice covered. The description includes all modalities, i.e. those elements and levers that need to be organised to set-up a practice. The description also mentions the most common variants of the practice, by indicating which modalities can be set up in different ways. Variants of one practice, should as far as possible be covered within one template. Where needed, i.e. when a variant leads to completely different benefits and risks, separate templates can be prepared for the most common variants.

• An impact part, including a benefit and risk matrix, per practice, which covers arguments of possible advantages (“benefits”) and possible disadvantages (“risks”). Each benefit and risk will be related to one of the 3 objectives of concern: cost containment, reward for innovation and access to medicines, covering availability as well as affordability. It is usually understood that these 3 objectives are linked to the perspectives of respectively the budget-holders (government, insurer), industry and patients. Whenever an argument of benefit or risk is added to one of the 3 objectives, coming from other than the usual perspective, this other perspective should be indicated. Arguments should be based as much as possible on analyses and facts and refer/link to these.

• Sources of evidence are to be mentioned on the bottom of the template, whenever there is a reference footnote coming with an argument. It might be possible for this to be replaced by click-through links in electronic versions of the template.

The toolbox aims to elaborate such summary-templates on all practices of interest to the members of the Working Group, in particular less common ones, on which it is harder to get some first evidence. A list of practices to elaborate, should therefore be developed within the Working Group. Participants should complete this list and thus prioritise those practices on which they want to gather more knowledge. In parallel, we need to gain first experience with these templates before the June 2007 Forum. Some first templates have therefore been developed, focusing on those 6 practices, for which evidence from literature and Member State experience has been collected within the study of


the Andalusian School of Public Health. These 6 examples are added in the annex and will be presented to the June Forum.


Practice: Reference Pricing

Description: A financing mechanism that establishes a maximum level of reimbursement for a group of drugs assumed to be bio and/or therapeutically equivalent. The share of the price above the reference price is borne by the consumer. (To be distinguished from referring national prices to cross-border prices of the same products) Modalities:

• Grouping of medicines (clusters): variant 1 – narrow clusters (ATC level 5); variant 2 –broad clusters (ATC level 4) of originators; variant 3 – broad clusters (ATC level 4) of originators + generics

• Fixing common reimbursement-value: variant 1’ – in function of cheapest product; variant 2’ – in function of average

Application in EU: BE, DE, DK, EE, EL, ES, HU, IT, LT, LV, NL, PL, PT, RO, SI, SK Impact on: Benefits Risks Cost containment • Medicinal cost reductions

up to 50%109 • Net healthcare-savings up

to 18%110 • Allows promotion of

generics111 • Creates cost-awareness in

patients and doctors

• Might create a shift to other expensive medicines (out of controlled clusters)112

• Fixed reimbursement-values can hamper further price-competitions and reductions

Reward for innovation

• Potential to incentivize valuable innovative products through exemptions

• Potential to create headroom for innovation

• Incremental value not always recognised (in case of variant 2 and 3), though exemptions possible

Access to medicines

• If one co-payment free medicine is foreseen per cluster, affordable access is ensured

• Transparent presentation of alternatives to patients, pharmacists and doctors

• In case not all medicines align prices to Reference Price, for some individual patients extra information might be needed to avoid confusion when shifting treatments113.

• In this case, price-sensitive (poorer) patients are most affected

109 Augurzky et al 2006 (14%) 110 Savings reported: CY: -20% in 1 year (-11mEUR); HU: -5% in 6 months; IT: basis for price cut in 2004 with 500-600M EUR saving (around 5%); LV: -0.6mEUR in 6 months; DK: 100mDKK (around 1,5 %) 111 PT, Aaserud et al 2006 112 Atun et al 2006 113 Atun et al 2006


Reference List Aaserud M, Dahlgren AT, Kosters JP, Oxman AD, Ramsay C, Sturm H. Pharmaceutical

policies: effects of reference pricing, other pricing, and purchasing policies. Cochrane Database Syst Rev 2006;(2):CD005979.

Atun R et Gurol-Urganci I. Impact of Regulation on the Uptake and Diffusion of

Pharmaceutical Innovations : Systematic Review. Discussion Paper 7. Tanaka Business School. Imperial College London

Augurzky B, G÷hlmann S, Gress S, Wasem J. The Effects of Reference Pricing on Ex-factory

Prices of Rx Drugs in Germany - A Panel Data Approach. SSRN eLibrary 2006.


Practice: Cost Sharing Description: A provision of health insurance or third-party payment that requires the individual who is covered to pay part of the cost of the service or product received. Cost-sharing may be in the form of deductibles, co-insurance or co-payments (OECD definition. These modalities are explained below). Cost-sharing might reduce a third-party’s pharmaceutical budget by reducing consumption and by shifting the cost to the consumer. Modalities: § Type of fee: Variant 1 - Co-payment: the user pays a fixed amount for a given service.

It is also known as a user fee. Variant 2 - Co-insurance: the user pays a percentage/proportion of the cost of the service, which can be fixed or decrease with the amount. Variant 3 -Deductible or excess: the user must pay a fixed amount for a service before any payment of benefits can take place. Variant 4 - Residual payment: the user has to pay a proportion or the full amount of the cost of a service beyond a certain ceiling. (Reference pricing actually can be considered a form of that type of cost-sharing)

§ Cost sharing schemes might apply personal exemptions or reductions in the amount to be paid. It might also exclude certain products and indications

§ Expenditure caps on cumulative payments might be implemented § Positive or negative list can be considered extreme forms of cost-sharing (0 and 100%

cost sharing, respectively): Application in EU: AT, BE, CY, DE, DK, EE, EL, ES, FI, FR, HU, IE, IT, LT, LV, NL, PL, PT, SE, SK, UK Impact on: Benefits Risks Cost containment • Creates cost-consciousness

in patients114 (This is not a final impact, but a change in consumer attitudes, that might lead to reduced consumption It acts as a price (barrier) for consumer, hence reducing consumption compared to free access)

• Reduces public expenditure by reducing consumption and shifting part of the cost to the consumer115

• The effect on overall expenditure is uncertain, and depends on whether and how the reduced drug consumption is substituted by other treatments and on the administrative costs of collecting the fees.

• Supplementary voluntary insurance can nullify the cost-awareness and the effect of cost sharing organised by the government


• It is usually assumed to be neutral regarding innovation.

• Cost-sharing might maintain use of older alternatives, even if better innovative solutions are available and hence negatively affect the reward of innovation (in case of

114 FI , LV , SE , Rubin et al 1995 115 Lexchin et al 2004


variant 2) Access to medicines

• Can be used to encourage rational use of medicine

• Cost-sharing can reduce access irrespective of effectiveness and needs, and can disproportionably affect the sicker and the poorer116. This can be addressed with correcting measures, e.g. by considering the patient’s income and made pharmaceutical expenses.

Reference List Gibson TB, Ozminkowski RJ, Goetzel RZ. The effects of prescription drug cost sharing: a

review of the evidence. Am J Manag Care 2005; 11(11):730-740. Lexchin J, Grootendorst P. Effects of prescription drug user fees on drug and health services

use and on health status in vulnerable populations: a systematic review of the evidence. Int J Health Serv 2004; 34(1):101-122.

Willard G. Manning, Joseph P. Newhouse, Naihua Duan, Emmett B. Keeler, Bernadette

Benjamin, Arleen Leibowitz, M. Susan Marquis, Jack Zwanziger (1988). Health Insurance and the Demand for Medical Care: Evidence from a Randomized Experiment. RAND Corporation, Santa Monica, CA.

Rubin RJ, Mendelson DN. A framework for cost sharing policy analysis. In: Mattison N,

editor. Sharing the costs of health: a multi-country perspective. Basel: 1995: 2-1-2-164.

116 FI , LV , Gibson et al 2005, Manning et al 1988


Practice: Payback Description: A financial mechanism that requires manufacturers to reimburse a part of their revenue to a payer/Member State authority if sales exceed a previously determined or agreed target-budget (To be distinguished from rebates and discounts that apply to the global sales of the manufacturer to a given payer). Modalities:

• Scope of medicines covered: variant 1 – overall pharma budget; variant 2 – per therapeutic area; variant 3 – per molecule/ single product

• Maximum budget allowed • Fraction of overspending to be recovered (same as for previous bullet) • Recovery over different manufacturers: variant 1’ – in function of sales; variant 2’

– in function of sales growth Application in EU: BE, FR, HU, IT, PT Impact on: Benefits Risks Cost containment • Ensures real spending fits

to budget117 thus reducing uncertainty and sharing the financial risk with the manufacturers

• Recoup of 100-500 mil€/y in larger EU MS’s118

• Allows low-price countries to accept high prices while controlling spending119 (for a limited nr of products only)

• Reduced transparency of real prices, limiting possibilities of cross-border comparisons

• In practice, real recuperation of funds from companies might be limited to a certain level

• Margin for implementing other cost-containment measures might be limited (like e.g. promotion of price competition)


• Expenses on new medicines are fast-growing, and risk therefore to contribute disproportionately (need for exemptions for valuable innovations)120(in particular in variant 1&2)

Access to medicines

• Agreements might influence access to market of specific products

• Agreements might influence access to market of specific products

117 PT, HU 118 FR: 400mEUR (’05) 2%, 160mEUR (’06e) 0,8 %; IT 800mEUR cut (‘06e) 7%; PT: 10mEUR (’06) 0,3% 119 HU 120 FR: exemption for innovatives, PT: recups go to R&D fund


Practice: Prescription Information Description: Any kind of information or recommendations made available to prescribers, by public or other funding authorities, in order to improve their prescribing behaviour. They are usually based on evidence and/or consensus on efficacy, safety, effectiveness and efficiency (cost-effectiveness) of using medicines. These instruments target the prescriber/doctor, the key agent in the demand and utilization of medicines, as it is the one that is in the best situation for combining the information on the needs of the patient and the benefits, risks and cost of a certain treatment. Modalities: § Target: Individual or all § Objectives: Treatment guidelines/instructions that cover a holistic view on the patient,

his disease, possible therapies and their overall cost-effectiveness § Format: Guidelines, Drugs bulletins, education sessions, conferences….. § Type of information: Descriptive / Normative § Follow up: Monitoring or feedback

Application in EU: AT, BE, DE, DK, EE, ES, FI, FR, HU, IT, LT, LV, MT, NL, PT, RO, SI, SE, SK, UK Impact on: Benefits Risks Cost containment • Prescription information

tools are often not primarily aimed at cost-containment, but at rational use121. They might however incorporate cost-effectiveness criteria and avoid/reduce overspending.122 They might therefore contain costs123 while avoiding or minimising negative effects on the quality of prescription and on health.

• Most common purpose of rational use of medicines instruments’ is to spend better from clinical point of view. Nevertheless, it can not be excluded that compliance with guidelines might lead to increase of the drug budget, in particular in case of under-use.

• If not supported by monitoring or/and appropriate (financial) incentives have no or very limited impact on actual prescription124

• The cost of changing prescription patterns might be significant

• Multitude of guidelines can create confusion amongst prescribers


• Prescription information tools allow promotion of valuable, cost-effective

• -

121 BE, DK 122 Soumerai et al 1989 123 LV,MT 124 FI


innovations and include the recognition of incremental innovation

Access to medicines

• Prescription information tools can improve access through a rational, cost-effective use of medicines and avoiding over-consumption

• Prescription information tools can steer prescriber to behaviour which is not optimal for the patient

• Need to avoid overloading and confusing guidelines because of risk of confusion with prescribers.

Reference List Soumerai SB, McLaughlin TJ, Avorn J. Improving drug prescribing in primary care: a critical

analysis of the experimental literature. Milbank Q 1989; 67(2):268-317.


Practice: Price Control Description: Price control is a form of market regulation that limits the capacity of the supplier to freely set the price of a product. Price control usually takes the form of a maximum price for an individual medicine, which means that supplier is not allowed to set the market price above the former. Price control is aimed at balancing suppliers market power derived from patents and other market exclusivity conditions and to the lack of price-sensitivity of the demand to prices. Modalities:

• Scope: Might be applied only to manufacturer’s price, or to wholesaler’s margins and/or pharmacist’s margins as well

• Timing: Might be applied to the initial marketing price and/or to posterior price increases

• Basis for setting (maximum) price: Variant 1- Therapeutic value/Clinical performance; Variant 2 - Economic evaluation (cost-effectiveness ratios); Variant 3 - Cost of existing treatments for the same condition or disease; Variant 4 - Cost-plus calculations (cost of production plus a certain profit margin); Variant 5 – International prices of the product; Variant 6 - Innovative character of the product

Application in EU: AT; BE, CY, DEE, EL, ES, IT, FI, FR, HU, IE, IT, LT, LV, NL, PL, PT, SI, SE, SK Impact on: Benefits Risks Cost containment • Allows controlling or

reducing pharmaceutical expenditure, in case of products under market exclusivity, not affected by competition125

• Without price-sensitivity of patients and with large market power of manufacturers, price controls still allow authorities to control expenditure.

• Price control might discourage some products to enter the market and induce a shift to treatments which are more expensive for the public system and/or for the consumer.

• As expenditure = price x quantity, price control might fail if the amount of units sold grows out of control126. Therefore there is a parallel need for measures controlling utilisation. (quantity)


• A well designed price control system allows a fair and effective incentive for true innovation, e.g. if clinical or economic evaluation is used to set the

• As new products are likely to have the highest prices, price control might discriminate against innovation and lead to reduced revenue (through,

125 Jacobzone et 2000 126 Maynard et 2003


price and allows a fair premium to innovations127

delays in market access128, lower prices and restrictions of utilisation)

Access to medicines

• Lower prices lead to better affordability and, hence, access to medicines129

• Access to improperly (too low) priced medicines might worsen because manufacturers might not have the necessary incentives to develop, manufacture and market them130.

• Defining prices of generics as fraction of originators, allows originators to out-compete and make disappear generics through multiple price-decreases. Can be avoided in a reference pricing system

• Delays on pricing and reimbursement decisions can hinder/delay product availability

Reference List Calfee JE. Pharmaceutical price controls and patient welfare. Ann Intern Med 2001;

134(11):1060-1064. Danzon PM, Wang YR, Wang L. The impact of price regulation on the launch delay of new

drugs--evidence from twenty-five major markets in the 1990s. Health Econ 2005; 14(3):269-292.

Hassett KA. Pharmaceutical Price Controls in OECD Countries. AEI publication 2004. Jacobzone S. Pharmaceutical policies in OECD countries: reconciling social and industrial

goals. 2000. Labour Market And Social Policy - Occasional Papers No. 40. Kessler DP. The Effects of Pharmaceutical Price Controls on the Cost and Quality of Medical

Care:A Review of the Empirical Literature. 2004. Maynard A, Bloor K. Dilemmas in regulation of the market for pharmaceuticals. Health Aff

2003; 22(3):31-41. 127 Dickson et al 2003, Office of Fair Trade 2007 128 Danzon et at 2005 129 Kessler 2004, Santerre 2004 130 Calfee 2001, Hassett 2006


Dickson M, Hurst J and Jacobzone S. OECD HEALTH WORKING PAPERS. Survey of Pharmacoeconomic Assessment Activity in Eleven Countries. 2003 Office of Fair Trading. The Pharmaceutical Price Regulation Scheme. An OFT market study. 2007 Santerre REJA. A Cost-Benefit Analysis of Drug Price Controls in the U.S. 2004. AEI-

Brooking Joint Center for Regulatory Studies.


Practice: (Generics) Substitution (by pharmacists) Description: Practice of substituting a prescribed pharmaceutical, whether marketed under a trade name or generic name (branded or unbranded generic), by a pharmaceutical, often a cheaper one, containing the same active ingredient(s). (PPRI Glossary) (The product delivered must also have the same administration route, dosage, etc. and have a proven bioequivalence/interchangeability/therapeutic equivalence with the product prescribed) . Modalities: § Mandatory or voluntary substitution by pharmacist § Substitution might require the consent of the prescriber or the consumer § Substitution might be supported by financial incentives

Application in EU: CY, DE, DK, ES, FI, FR, HU, IT, LV, MT, NL, PL, PT, SI, SE, SK Impact on: Benefits Risks Cost containment • It reduces cost to the

insurer and/or the consumer while maintaining a standard quality131.

• Improving current measures can generate additional savings of 27-48% depending of Member State132

• The shifts to a different brand might generate extra doctor visits in order to adjust the prescription

• Cost savings might be suboptimal if regulations and incentives towards pharmacists are not coherent.

• Risk of missing price decreases, if not sufficient generic alternatives enter the market to create a price-competition.


• By reducing expenditure in older, out-of patent drugs, generics policies allow countries to spend more on innovative drugs133.

Access to medicines

• Reduced cost and hence, increased affordability for patients (not in case of fixed co-pay)134. In the case of budget constraints, it also allows an increase in provision of other medicines and treatments

• Frequent changes in brand and shape of preferred medicine might generate confusion and other inconveniences to (mainly older) patients if insufficient information is provided

• Lack of perceived credibility of generics in what concerns the generics quality, efficacy and safety135 if patients,

131 FI , ES , Andersson et al 2005, Engstrom et al 2006 132 Simoens et al, 2006, pp11, 84-91 133 LV 134 FI 135 PT, SI


doctors and pharmacists are not sufficiently informed.

Reference List Andersson K, Bergstrom G, Petzold M, Lonnroth K, Carlsten A. Effects of generic

substitution on the development of pharmaceutical expenditures during the period January 1998 to May 2005. Value in Health 2005; 8(6):186.

Engstrom A, Jacob J, Lundin D. Sharp drop in prices after the introduction of generic

substitution. 2006. Simoens and Decoster, Sustaining Generic Medicines Markets in Europe, Research Center for

Pharmaceutical Care and Pharmacoeconomics, April 2006,


Risk-Sharing practices and Conditional Pricing of pharmaceuticals How to deal with uncertainty – Some EU Member State practices Introduction Over the last years, an increasing number of member States have set-up risk sharing practices and conditional pricing and reimbursement practices. These practices allow competent authorities and pharmaceutical companies to build clinical experience with medicines which might normally not be eligible for reimbursement. Such practices allow budget-control and the identification and reward of valuable innovative medicines. At the same time, they provide access for patients to highly innovative treatments. This balanced objective is completely in line with the overall objectives of the Pharmaceutical Forum, and therefore part of our scope. This paper will first describe how these practices are set-up in different Member States and eventually try to deduct some common findings. The Netherlands – Conditional reimbursement in hospitals Background

The costs of expensive new medicines in hospitals, in particular in the field of oncology, are growing rapidly and may be an increasing burden to the individual hospital's budget. As such, the availability of these medicines might be inequal depending on the hospital and the resources available in the hospital, although this has not been demonstrated in practice. In addition, it often concerns innovative medicines of which the added value may not be fully proven in real practice.

To address these concerns, the Dutch authorities have created a separate fund for the use of such medicines in hospitals within a research setting. The fund foresees additional funding during the 3 first years of use of an expensive innovative medicine. Funding goes up to 80% of expensive medicines, and even up to 100% for orphan medicines. It is essential that involved parties, such as hospitals, ensure proof of value of the medicine by the end of this period, in order to ensure further funding of the medicine.

Mechanism The NZa (the Dutch Healthcare Authority), upon advise of the HCIB (Healthcare Insurance Council), decides whether a new expensive medicine is eligible for this temporary additional funding. The medicine therefore needs to (1) bring added value, to (2) exceed a certain threshold of cost-prognosis and to (3) come with a list of open unanswered research questions.

While taking up the use of these medicines, representative bodies of hospitals or other relevant parties have to organise for outcome-research. By doing so, these parties must ensure the generation of additional data regarding therapeutic value and cost-effectiveness in clinical practice. The generated data should bring answers to the open questions regarding cost-effectiveness, in a re-appraisal procedure. The maximum time to come with this evidence is 3 years.


Outcome

In case the new data prove an acceptable cost/effectiveness ratio, the NZa provides further indefinite additional funding. In case the new data do not prove the desired cost/effectiveness, NZa will stop the additional funding. Experience

The mechanism has been set-up in 2006. To date 23 medicines are subject of this practice. It considers 6 orphan drugs and main indications relate to oncology, auto-immune diseases and macular degeneration. The first 3-year appraisals will only take place at end 2008. In the meantime, the practice has allowed to combine a high need with a high cost, an uncertain value, and to offer quick access to some medicines of which therapeutic and economic value is still uncertain.

Some discussion points have been raised regarding the roles of the involved parties, in particular who will conduct the outcome research and who will pay for it. Discussions also concerned the infrastructures and how to weigh the different decision making criteria (therapeutic value, cost-effectiveness and impact for public health).

Further info: CIRCA-Library: Working Group on Pricing/Working Group on Pricing 2007/9th Working Group Pricing 12.12.2007/Inputs Risk Sharing/Presentation NL Belgium – Conditional reimbursement Background

Since 2002, the new Belgian pricing and reimbursement system requires the Commission Remboursement de Medicaments / Commissie Tegemoetkoming Geneesmiddelen (CRM/CTG) to distinguish a separate class of medicines with claimed added value, because they offer specific benefits compared to existing therapies, and therefore eligible to obtain a price-premium (Class I). It soon became clear that this distinction often needs to be made based on unknown hypothetical factors. Belgium has therefore established a conditional reimbursement procedure, leading to a second mandatory evaluation after 18-36 months.

Mechanism Eligible medicines need to be classified as Class I by CRM/CTG. This classification is based on the profile of the medicine regarding efficacy, safety, comfort/convenience of use, applicability and, where possible, effectiveness in practice.

At the moment that CRM/CTG classifies medicines as Class I, it also specifies a list of the hypothetical 'unknown' factors it had to take into account. These factors most frequently relate to (1) effectiveness in clinical practice, (2) pharmaco-economics in clinical practice, (3) size of the target group, (4) sales volumes and (5) reimbursement status in other EU Member States. Additional elements can relate to recent CRM-guidelines, scientific studies, yearly cost evolution in the therapeutic class, prescribed daily dose, applicability or consensus reports.

A draft guideline is being developed on pharmaco-economic submissions. The CRM/CTG also pre-defines a timing, somewhere between 18 and 36 months, after which the sponsoring company is expected to deliver the additional data that will allow to clarify the 'unknown' hypothetical factors taken into account at the moment of the initial price decisions.


Outcome

In case the new data confirm the hypotheses taken into account, the existing pricing and reimbursement decisions continue to apply. If this is not the case, the CRM/CTG can decide on several types of changes like limiting the target patient groups for which the medicine can be used or restricting the group of potential prescribers for this medicine. In the worst case the re-appraisal can lead to a withdrawal of the medicine from the reimbursement list. Experience

In reality missing evidence almost always relates to effectiveness in clinical practice and cost-effectiveness.

By first half 2007, 18 products were re-appraised of which only 1 was withdrawn from reimbursement. For some the reimbursement conditions were adapted.

These first experiences have also made clear the importance of good upfront communication on the expected deliverables, preferably through a formal meeting between CRM/CTG and applicant. Other helpful factors are quality control procedures and the support of the headquarters for this additional work undertaken by a Belgian affiliate of a pharmaceutical company. Further info:

CIRCA-Library: Working Group on Pricing/Working Group on Pricing 2007/9th Working Group Pricing 12.12.2007/Inputs Risk Sharing/Input BE

U.K. – Performance Cost-Sharing Background

Following NICE’s conclusion that Velcade (bortezomib) is not considered cost-effective as treatment for relapsed multiple myeloma without possibility of bone transplantation, Johnson & Johnson (J&J) put forward its ‘risk-sharing’ scheme to make the product available. The scheme was agreed with the Department of Health and NICE recommended that Velcade could be prescribed on the NHS under the conditions outlined in the scheme. This scheme was developed in collaboration with haematologists and pharmacists and was launched in 2007 and runs until reviewed by NICE. During this period the clinical experience will generate further data on the cost-effectiveness of the treatment. Mechanism

Patients are eligible if they suffer from progressive multiple myeloma, with a first relapse, after trying out 1 prior therapy and when bone transplant is not an option. For these patients the scheme is immediately available and NHS foresees initial funding. NICE has drafted guidance for medical doctors that clearly defines when patients are eligible for treatment with Velcade. Doctors are allowed to start the treatment with Velcade. After 4 cycles the impact of the treatment is measured by a serum protein test. If serum proteins are reduced by 50% or more, the treatment is considered to be effective. For patients without sufficient serum proteins, an alternative urine test is performed.

Outcome If the serum protein test is showing effectiveness after 4 cycles of treatment with Velcade, treatment can be continued through further cycles. The entire treatment is funded by NHS.


When the serum protein test does not show sufficient effectiveness, the treatment with Velcade is stopped and the sponsoring company (J&J) will refund the cost of the first 4 cycles.

Further info: www.velcade.co.uk

CIRCA-Library: Working Group on Pricing/Working Group on Pricing 2007/9th Working Group Pricing 12.12.2007/Inputs Risk Sharing/Input UK Velcade U.K. – Research on cost-effectiveness Background

This practice was taken up as NICE did not consider Beta-Interferons, nor Glatiramer, to be cost-effective for treatment of multiple sclerosis. Nevertheless NICE recommended the DH explore ways of more cost-effective use. An acceptable cost-effectiveness level of 36,000£/QALY was defined and a prospective study was launched in 2002 to assess the cost-effectiveness of 4 products. The study runs until 2012, with a mid-term review early 2008. The study envisaged to include 7,500-9,000 patients.

Mechanism Patients are eligible for inclusion in the study if they suffer from relapsing, remitting MS or a secondary progressive form of MS with relapses and if they match the criteria drawn up in 2001 by the Association of British Neurologists (ABN). Patients can only be included in specialist centres with the appropriate infrastructure. NHS foresees funding for all recruited patients.

Eligible patients are enrolled in the study and each of them was attributed in cohorts to one of the 4 medicines. Target outcomes for the patients have been agreed upfront and match to the expected cost/QALY outcome. Patients' enrolment implies agreement to regular monitoring from which the impact on QALY is measured. Consequently, for each of the 4 medicines, the QALY-impact can be measured and a cost/QALY ratio is calculated. The practicalities for monitoring, assessment, outcome statistics, price adjustments and practical implementation have been written upfront. Outcome

If the calculated Cost/QALY of a medicine is found to be above the pre-established acceptable level, the price of the medicine is reduced. If the Cost/QALY is below this level, the price of the medicine can be increased. Monitoring and price adjustments are expected to continue over a 10-year period.

Experience A first evaluation is expected early 2008. Preliminary experiences have highlighted the complexities, mainly scientific and methodological. It is also clear that the definition of clear markers to determine patients' responses is a prerequisite.

Further info: http://www.dh.gov.uk/en/Publicationsandstatistics/Lettersandcirculars/Healthservicecirculars/DH_4004332


CIRCA-Library: Working Group on Pricing/Working Group on Pricing 2007/9th Working Group Pricing 12.12.2007/Inputs Risk Sharing/Input UK multiple Sclerosis First common findings It seems that the adoption of a risk-sharing or conditional pricing practice is case-specific and triggered by the combined presence of 2 factors. The concerned medicine (1) brings a potential significant clinical/therapeutic benefit, usually for a severe disease and at the same time (2) raises serious doubts about its (cost-)effectiveness. These medicines are then often used within a setting that allows for a controlled utilisation. This can be through a study-setting (like MS-UK), through a limited number of expert centers (e.g., NL) and through the use of clear parameters to monitor each patients (e.g., Velcade and MS-UK). Key objective is to build further knowledge on the cost-effectiveness or other elements that are still unclear but needed for decision making on pricing and/or reimbursement. Several elements need to be pre-agreed before starting the practice. In particular the outcomes that can be expected and how these will be measured. E.g., the interpretations of a clear labo-parameter in the case of Velcade, the calculation and comparison of a Cost/QALY ratio for MS and/or a pre-defined list of expected data in order to answer some open questions on unknown hypotheses in BE and NL.

Also the timings need to be clearly pre-agreed. The impact of Velcade is measured after 4 cycles. Timings for the company to come up with study results and deliver the required data, are set upfront in BE, NL and UK. Finally, also the consequences need to be clear upfront. This is in particular important, as funding authorities often fear to be limited in possibilities to adapt or stop funding in a later phase. Velcade is continued or stopped and funded by NHS or by the sponsoring company. A medicine is further funded or not by the NHz in NL. Pricing, reimbursement and utilisation decisions can be adapted in BE and in the UK.