Stimulating pharmaceutical innovation in the EU

Keywords::

• clinical trials
• intellectual property rights
• medical needs
• orphan medicines
• pharmaceutical innovation

Over the past 50 years, medicines have made a contribution to improving the health status of populations. A recent literature review concluded that medicines are among the most valuable forms of healthcare and are instrumental in treating various diseases more effectively [1]. This message is consistently corroborated by clinical trials of new medicines, studies of trends in cause-specific mortality and econometric models examining the determinants of life expectancy. In this context, stimulating pharmaceutical innovation is a means to meet the societal objectives of maximizing health within budgetary limits and to meet current unmet medical needs in the EU population. At the same time, stimulating pharmaceutical innovation also aims at promoting high-quality research in the EU and ensuring the competitiveness of the European pharmaceutical industry.

During the Belgian EU presidency in the second half of 2010, a ministerial conference was organized to make valuable innovative medicines accessible in the EU. In this respect, a medicine is called ‘truly innovative’ if, and only if, it offers additional clinical efficacy and/or effectiveness as compared with current care. If, in addition, these medicines fill an unmet medical need, such medicines are called ‘valuable’. Indeed, if a medicine is more effective than current care but its clinical benefit lies in a field where the medical need is very small, this medicine is not really valuable to society or even to the patients. Overall, in the meaning of ‘valuable’ there is an explicit connotation of need, be it a medical need, a therapeutic need or a societal need [2].

According to the High Level Pharmaceutical Forum, valuable pharmaceutical innovation should be encouraged, identified and rewarded [101]. Therefore, this article describes the current situation, challenges and initiatives, and formulates recommendations for a coordinated EU action to stimulate pharmaceutical innovation.

Current situation related to stimulating innovation

The EU has undertaken many efforts to try to stimulate innovation, through intellectual property legislation, co-financing of initiatives and the creation of clear rules of conduct in development processes, such as the legislation related to clinical trials in the EU.

A key element in promoting innovation has been the elaboration of substantive law on intellectual property applied in the EU. The international agreement on trade-related aspects of intellectual property (the TRIPS agreement), approved by the EU and its member states, contains provisions on the means of enforcing intellectual property rights.

Since the period that elapses between the filing of an application for a patent for a new medicinal product and its marketing authorization may make the period of effective protection under the patent rules insufficient to cover the investment put into the research, a supplementary protection certificate may be granted according to Regulation (EC) 469/2009 [102]. In addition, Directive 2001/83/EC lays down specific rules to protect data relating to preclinical tests and clinical trials [103]. However, public authorities of member states that want to take initiatives in promoting innovation have, however, to take into account article of the 107 Treaty on the Functioning of the European Union, stipulating that any aid granted by a member state should not distort competition or affect trade between member states [104].

The need to stimulate pharmaceutical innovation leading to the fulfillment of unmet medical needs has been expressed in the Strategic Research Agenda used to create the Innovative Medicines Initiative. The Innovative Medicines Initiative is a public–private partnership wherein the EU and the pharmaceutical industry have joined forces in order to boost investments in biopharmaceutical research and to overcome bottlenecks in the development of innovative medicines. The Strategic Research Agenda focuses on five disease areas (cancer, brain disorders, inflammatory diseases, diabetes and other metabolic diseases, and infectious diseases) that are considered important themes of unmet need affecting the lives of millions of European citizens [105].

The conduct of clinical trials is the mainstay of the development process of innovative medicines. Current EU rules aim at:

• • Harmonized procedures for the application and authorization of clinical trials by the National Competent Authority and Ethics Committee;

• • Harmonized provisions on the requirements for a clinical trial, including the rules for protection of the clinical trial participants;

• • Harmonized rules on reporting adverse events during the clinical trial.

However, the harmonization effort of the conduct of clinical trials should not be presented as a great success story to stimulate pharmaceutical innovation (attractiveness of the clinical trial environment).

Challenges & initiatives related to stimulating innovation

Given the participating nature of stimulating pharmaceutical innovation, several types of governments must play a role: health authorities, industrial policy authorities, and scientific and academic authorities, all of them on the EU and the member states levels. This requires a huge coordination that should be facilitated.

The Organisation for Economic Cooperation and Development goes one step further, stating that a key challenge for policy makers towards efficiency in pharmaceutical expenditure is to reconcile static and dynamic efficiency objectives; marrying value for money and the promotion of future innovation in medicine [3]. This statement suggests that selecting the right valuable innovations today will have an impact on available budgets and expertise for subsequent innovations with a larger incremental benefit. Dynamic efficiency indeed means that one may allow uncertainties in proof of value and inefficiencies today, in order to keep the innovation engine running, and that one can only really judge the innovation decades later. The Organisation for Economic Cooperation and Development statement, however, also suggests that any initiative to stimulate innovation must already inherently take into account and define what is meant by ‘valuable innovative’ medicines.

In the following sections, we discuss in more detail specific challenges related to the identification of medical needs (the health policy objective of stimulating innovation), the attractiveness of the clinical trial environment, orphan medicines, personalized medicine and financial issues.

Identifying medical needs

The identification of unmet medical needs, their prioritization and the resulting allocation of resources and efforts is the first example of an area where better coordination is required. If such identification is coordinated and takes place at a supranational or European level, its impact will be much stronger.

This is not an easy task. Each pharmaceutical company has its own way of identifying unmet medical needs. Most of the time, this identification is based on marketplace analyses. On the other hand, both public and private initiatives have been launched and should be further encouraged to identify pharmaceutical gaps by defining the burden of specific diseases (based on epidemiology and morbidity/mortality in specific populations), the current scientific and public health knowledge about existing interventions, and their cost–effectiveness. Examples are the Priority Medicines Project launched by WHO and the Dutch government during its EU presidency in 2004, and the Strategic Research Agenda of the Innovative Medicines Initiative mentioned previously.

In the European legislation, the concept of unmet medical need has been used in Article 11 of Commission Regulation (EC) 507/2006 on the conditional marketing authorization for medicinal products [106]. One of the requirements in granting a conditional marketing authorization is that unmet medical needs will be fulfilled. Paragraph 2 of Article 11 specifies that unmet medical needs mean a condition for which there exists no satisfactory method of diagnosis, prevention or treatment in the community or, even if such a method exists, that the medicinal product concerned will be of major therapeutic advantage to those affected. In 2006, the European Medicines Agency published a guideline to help pharmaceutical companies demonstrate that their product will fulfill unmet medical needs [107]. In addition, many companies request scientific advice from the European Medicines Agency in order to debate unmet medical needs and conditional marketing authorizations for those medicines in their pipeline that they consider most promising.

Recently, EU regulators have suggested that new medicinal products covering areas of high unmet need, such as a life-threatening disease for which there is no effective treatment, could be granted early marketing authorizations associated with a higher uncertainty about their benefit/risk balance or, alternatively, early approvals for narrowly defined subgroups within a given disease population (so-called staggered approval) [4].

We propose that, rather than attempting to delineate all possible areas of unmet medical needs, scientific advice strategies should be set up and fine-tuned to discuss with pharmaceutical companies, on a case-by-case basis, the ability of new medicines in development to fulfill specific needs, which could be medical, therapeutic or societal. Workshops could also be organized with the relevant stakeholders to make public those areas where the authorities believe there are significant unmet needs. It is noteworthy that innovation can also refer to current medicines in the market, whereby additional insights may lead to better pharmacokinetic performance or – via the identification of biomarkers – to better targeting of patients (i.e., personalized medicine).

Attractiveness of the clinical trial environment

In recent years, there here has been a widespread criticism that the Clinical Trials Directive has lead to a significant decline of the attractiveness of patient-oriented research and related studies in the EU. This could greatly reduce competitiveness in Europe in the field of clinical research, and bear a negative impact on the development of innovative treatments and medicinal products.

In fact, it has been shown that, since the directive was edited, there has in general been no decrease in clinical research activity in the EU, but that performing clinical trials, on the other hand, has become considerably more difficult and costly, with an increased and sometimes unnecessary administrative burden. Experience has shown that the requirements of the Clinical Trials Directive are applied very differently by the member states. Consequently, sponsors have to respond to the various required changes and adapt their protocol in view of diverging assessments by the member states. In some cases, sponsors have been unable to pursue the envisaged clinical trial in one or more member states. Smaller companies are affected to a greater extent by this situation. A central helpdesk is suggested to help smaller companies to implement the Clinical Trials Directive.

Any sponsor intending to start a clinical trial based on a single protocol has to wait not only for approval by several ethics committees, but also by the National Competent Authorities of each member state individually. Since the Clinical Trials Directive was implemented, the delay in starting a trial (first patient in) has increased by 90%, and is now reaching an average of 152 days. This, in turn, means that patients do not have access to new, innovative treatments and the costs for the sponsor increase.

Additional challenges related to rare diseases

A rare disease is a disease with a very low prevalence. In the EU, rare diseases are defined as life-threatening or chronically debilitating diseases that have a prevalence of 50 per 100,000 individuals or less. There are currently between 5000 and 7000 rare diseases affecting 30–40 million patients in Europe. Orphan medicines (i.e., medicines to treat rare diseases) are less likely to be developed by industry because the market is small and R&D costs are usually too high to make the products profitable. However, in the light of solidarity, patients with rare diseases should have the same rights for treatment and care as those with common diseases.

The EU has identified unmet need in the area of rare diseases by stating that, “Patients suffering from a rare condition should be entitled to the same quality of treatment as other patients’” [108] and that it is therefore necessary to stimulate the R&D and bring appropriate medicines to the market by the pharmaceutical industry. This reflects the observation that access to orphan medicines conforms to the principle of social solidarity in which vulnerable groups receive support; that orphan medicines tend to target life-threatening diseases for which there may be no alternative therapy; and that orphan medicines have a considerable impact on patients’ healthcare expenditures if they would have to incur the medicine costs themselves.

In response to this, the EU has implemented specific policies in 2000 to stimulate innovation in the field of orphan medicines, including financial incentives (assistance with R&D and tax credits), protocol assistance and expedited review by registration authorities, and guaranteed marketing exclusivity [108]. The success of these policies is reflected in the rising number of orphan designations and marketing authorizations granted by the European Medicines Agency, increasing from 270 designations and 22 authorizations by the end of 2005 to 642 designations and over 60 authorizations by March 2010. Still, it can be questioned why there are only approximately 60 marketing authorizations granted, compared with more than 600 orphan designations, and why marketing authorization seems to concentrate on very few diseases (e.g., four or five authorizations on pulmonary artery hypertension alone). It may be advisable to make access to policies to stimulate innovation of orphan medicines dependable on the identification of an unmet medical need, rather than using these policies to develop ‘me too’ medicines for the same indication.

With regard to national incentives, Article 9 of Regulation (EC) No 141/2000 requires member states to communicate to the Commission detailed information concerning any measure they have enacted to support research into the development and availability of orphan medicinal products or medicinal products that may be designated as such [108]. The European Commission regularly publishes an inventory of measures taken by member states according to Article 9. Countries such as France, Italy and The Netherlands have implemented domestic policy measures and research incentives for orphan medicines and rare diseases [5].

To stimulate R&D for rare diseases, priorities for research on rare diseases should be defined at the EU level in order to target public research funds for R&D of orphan medicines. For the high-priority rare diseases, European registries should be set up as early as possible, preferably before a medicine is being developed for the disease. Data on the natural history of the disease and baseline risks are indispensable for describing the epidemiology of the disease, and to put into context the clinical effectiveness and cost–effectiveness of a treatment. Funding and governance of the registries should be independent. Some types of tax benefits for orphan medicines may possibly also be considered. Innovative models combining European and national funds could be explored to set up such a system, the beneficiaries being the companies considering the clinical development of an orphan medicine, the medicine agencies assessing efficacy and safety, the national healthcare insurance funds and the patients.

Additional challenges related to stimulating personalized medicine

Within the recent evolution towards genetic testing for predicting risks of disease, identifying carriers, establishing prenatal and clinical diagnosis or prognosis and predicting treatment outcomes, EU countries have taken different approaches towards steering and facilitating research in this field.

The field of personalized medicine, based on a broad range of ‘genomics’ technologies (e.g., pharmacogenomics), has bloomed in the academic setting. However, whether pharmacogenomics or personalized medicine based on other biomarkers will have a significant impact on pharmaceutical innovation within the coming years is still uncertain. This uncertainty derives from several concerns of pharmaceutical companies, including ethical issues during clinical trials and post-trial biobanking, reductions in market size and difficulties in developing medicine–diagnostics combinations, in particular if the developments are from two different companies. The latter issue is particularly contentious in Europe, where no specific legislation exists regarding these combinations.

The EU should continue to stimulate R&D in personalized medicine through various initiatives designed to facilitate the recognition of validated biomarkers that can already be ‘qualified’ through specific and parallel procedures of the European Medicines Agency and the US FDA [109]. In addition, various stakeholders have stressed the need to demonstrate clinical benefit of biomarker-based personalized treatments.

Financial challenges

In 2007, the pharmaceutical industry invested approximately €26 billion in R&D in Europe. In comparison with the North American and Asian regions, Europe is still seen as a less attractive R&D investment location in terms of complexity, market size and incentives for the creation of new innovative biotechnology companies.

It should be acknowledged that a roadmap towards more coordinated action regarding the stimulation of pharmaceutical innovation, in particular in the field of personalized medicine and orphan medicines, will run against budgetary limits: the EU and member states budgets to undertake this role are limited and choices must be made to spend this money as wisely as possible.

For instance, the Innovative Medicines Initiative spends €1 billion of public money per year to achieve its objectives to modernize the development processes of medicines, provide better and higher-quality jobs for scientists, increase the European expertise and know-how in new technologies, and provide stronger competitive advantages for small- and medium-sized innovative companies. In addition, better coordination of the national budgets and stimulation of pan-European institutes will increase the performance of European R&D. As an example, a European coordinated cancer program, for example, a European Cancer Institute, would enable such performance to the benefit of patients. It could be questioned, however, why this should be the case in cancer and not in other disease areas such as cardiovascular, mental and other diseases.

Recommended ways forward

Stimulating pharmaceutical innovation is a proactive policy role. The aim is to create a sustainable R&D environment whereby the likelihood that valuable pharmaceutical innovation reaches the market place is maximized.

To achieve this aim, a novel EU policy should:

• • Identify the medical fields where innovative research is required (and hence should receive priority);

• • Assess the potential of success of innovative concepts and facilitate R&D in these directions, including the stimulation of public initiatives;

• • Steer R&D of these concepts towards a proof-of-concept;

• • Learn from past experiences, especially failures in innovation, with a goal to improving new approaches;

• • Co-finance such R&D;

• • Facilitate research by avoiding barriers for efficient clinical research programs.

Regarding the latter, the assessment of multicountry trials could be carried out by only one member state, hereinafter referred to as the reference member state, which has the expertise, staff and resources to draw up the assessment of the clinical trial [101]. The other member states concerned would be consulted and could assist in this assessment, for example by providing additional expertise with regard to certain products or product categories. The assessment of the reference member state would be applicable for the clinical trial in all member states concerned. In case of disagreement by another member state, a clear decision-making procedure would have to be established. As an alternative, a centralized approval system for pan-European trials could be introduced.

In addition, one should envisage a new ‘quality label’ indicating that a compound has the potential for early access. However, it should again be emphasized that ‘success’, already at this stage, should be interpreted as ‘leading to improvements in health outcomes’ and ‘filling in unmet medical needs’. It also needs to become clear which body, based on which criteria, can grant such a label for early access. This body needs to gain insight into the potential value for money of the candidate compounds at the earliest possible stage of the medicine development process.

We recognize that this editorial only provides a high-level overview. Some of the proposed initiatives will deserve more detailed plans in order to have an impact on the future access of medicines to all patients who are in need of them throughout the EU.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.