Fast-Tracking Medicines Innovation: a Question of Uncertainties

EuropeanVoice Fast-tracking medicines innovation: a question of uncertainties

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“Accelerated Access to Innovative Medicines for Patients in Need”, Clinical pharmacology & Therapeutics, volume 96 number The uncertainties...... 3 5, November 2014 The old and the new...... 4 “Minds Open – Sustainability of the European regulatory system for medicinal products”, National Institute for Public Health and The drivers for change...... 5 the Environment, Netherlands Not a revolution – but hopes “Improving the EU system for the marketing authorisation of medicines”, Escher – The TI Pharma Platform for Regulatory for a rapid evolution...... 6 Innovation Responsibilities and “Relation between pharmaceuticals regulatory framework and decision-making powers...... 7 timely access of patients to medicines”, European Commission Pharmaceutical Committee The evolution so far...... 8-9 “New drug approvals in ICH countries 2004–2013”, Centre for US quicker than EU?...... 10 Innovation in Regulatory Science “From adaptive licensing to adaptive pathways: delivering a Moving from concept to action 11-12 flexible life-span approach to bring new drugs to patients”, Some leading HTA-related Clinical Pharmacology & Therapeutics, volume 97, issue 3, March initiatives...... 13 2015 “The risks of risk aversion in drug regulation”, Nature Reviews, Conclusion...... 14 Drug Discovery, November 2013 “Adaptive pathways to patients: report on the initial experience of Written by Peter O’Donnell the pilot project”, European Medicines Agency, December 2014 Images: iStock “Expert Group on Safe and Timely Access to Medicines for Patients”, record of first meeting, European Commission, January 2015 “Strategy for EU co-operation on Health Technology Assessment”, EU Health Technology Assessment Network, October 2014 “On effective, accessible and resilient health systems”, European Commission, 2014 Publication of this report has been made possible by “Conclusions on innovation for the benefit of patients”, the EU’s Roche. The sponsor has no control over the Council of Ministers, 2014 content, for which European Voice retains full editorial responsibility. FAST-TRACKING MEDICINES INNOVATION The uncertainties

The problem is obvious: a 20th-century procedure for getting new patients hoping their needs for the right treatment can be met, medicines to patients is struggling to cope with 21st-century over researchers pondering the design of their development medicines. Its critics say that it is often too slow, doesn’t always ask protocols, and over drug-company managers and investors as the right questions, and doesn’t know how to pay for innovations. they try to second-guess the future.

For the advocates of change, the consequences are clear. The Novel medicines are increasingly offering a targeted approach – best treatments are frequently reaching patients only slowly or which in the immediate future offers particular promise in the not at all, and healthcare budgets are not always getting the best treatment of serious and life-threatening conditions. New value for their money. In addition, incentives for innovation suffer precision in defining sub-forms of a disease and in identifying from the mismatch. small groups of responding individuals is often allowing a close match of treatments to individual patients. Treatments can begin The solution, however, is neither obvious nor clear. The subject early, and can be monitored by sophisticated technology-driven bristles with complexities – technical, scientific, regulatory, information systems to fine-tune their use and adjust their price ethical, and economic. Intensive reflections among multiple in line with their observed performance. healthcare partners are now underway, in Europe and elsewhere, but comprehensive answers are still elusive. Patients, researchers and industry executives argue that the current regulatory systems are not up to the job. The concerns are In the United States, further impetus was given to the debate by shared by a growing body of regulators – and to some extent by pay- the early 2015 announcement by Barack Obama, the president of ers – in Europe, uncomfortable gatekeepers faced with controversial the United States, of action to promote a more innovative choices over who should – and should not – receive expensive but approach to medicines development, and by a forward-looking effective new medicines for hepatitis C or cancer, and how soon. Congress initiative for legislative reform – tellingly entitled "21st- They welcome the new options that science is generating, and they century cures". Across Europe’s more complex landscape for wish to confront and resolve the inevitable uncertainties – including medicines regulation, the responses so far have been more the uncertainties that earlier launch and variable pricing imply for fragmented, and at European Union level they remain the current procedures governing patients’ access to medicines. administrative or technical rather than political. The advocates of change argue that greater engagement at political level will be But healthcare gatekeepers, focused on ensuring safety and necessary in Europe to ensure the framework is conducive to protecting the public purse, are understandably hesitant about innovation – and not just to today’s innovation, but to the tearing up their rule-books. After 50 years of creating an ever-tighter innovations that will emerge in the coming decade. This short grid of pre-marketing evaluation systems in pursuit of safety and report sets out the background and sketches the main issues. thrift, these authorities are not enthusiastic about embarking on a journey into new, less secure and less charted territory. They are A question of uncertainties already struggling to balance conflicting objectives of protecting Amid the many deep uncertainties that healthcare systems face, citizens and making medicines available. They see the adaptations there is one obvious certainty: rapid recent advances in medical now being discussed as replacing their accumulated experience in science are opening up huge new opportunities. But how far, top-down, one-off decision-making by bottom-up calls for flexibility and how fast, can healthcare systems adapt their procedures to and dialogue throughout a product’s life. Their responses tend, take full advantage? That is the great uncertainty hanging over therefore, to avert new uncertainties by resisting change. 3 The old and the new The classic approach to making a treatment available to New active substances patients involves a lengthy sequence of clinical trials. Phase I Number of new active substances approved every year trials explore whether a treatment is safe for people to take, typically in around 30 volunteers. Phase II investigates the EMA FDA 40 safety and effectiveness of a potential therapy, usually in 100-300 subjects. If the treatment appears safe and promises effectiveness, Phase III follows, with hundreds or even thousands of carefully selected subjects, often lasting several 30 years and spread across countries. Accumulated evidence of safety and effectiveness in specified indications, across an average of these trial populations, permits the sponsor to apply 20 for a marketing authorisation. At this point the regulatory body (in the EU, either a member state or the European Medicines Agency (EMA) working with member state experts) begins a review of the assembled data, and after several months (and 10 often more than a year) an authorisation decision – either positive or negative – is taken. If the decision is positive, the company can then start to seek agreement on price and/or reimbursement, through each country’s autonomous system of 0 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 payers and advisory bodies –widely varying in terms of Source: CIRS - Centre for Innovation in Regulatory Science institutions, procedures, and time-lines. Targeted medicines do not fit this decades-old “one-size-fits- all” frame. They exploit new understanding of disease the phased launch of a product, extending it gradually to wider processes and of individuals’ genetic make-up. Their use is populations, in line with agreements on programmed tests that linked with modern testing techniques that can predict would validate – or invalidate – the hypotheses about probable responses to treatment. So they can be administered performance. Wider success with this form of rolling review earlier, with more accurate impact and fewer adverse reactions. would lead to wider use – and lower performance than It is no longer so necessary to wait for the results of extensive anticipated could equally lead to restrictions on use or even to pre-launch trials, since much of that prior investigation of withdrawal. Medicines already developed using approaches of average effects can be replaced by post-launch monitoring of this type are transforming the lives of patients with cystic the outcome in individuals. Drug developers and health and fibrosis, and giving new hope to victims of breast, lung, and reimbursement authorities could start much earlier to discuss colorectal cancers.

Sequence of events rules confer on drug developers and on regulators a mutual duty The novelty is that a single “yes-no” choice gives way to a view of to make treatments available to patients within a reasonable regulation as a continuum, in which decisions about the use of a new time frame. It is a recognised health issue, too: the World Health medicine would be taken in sequence, as knowledge of it Organisation (WHO) is finalising new guidelines that emphasise accumulates in routine care – what is known as ‘real-world evidence’. the need for high-quality decision-making by regulatory Joint consideration of a medicine, from its earliest stages of authorities. It has global resonance too, since the challenges development, would forge a new partnership of the formerly distinct posed by many innovative products – which are invariably constituencies of industry, patients, health authorities, international – increasingly demand greater collaboration across reimbursement bodies and prescribing physicians. A form of the current – largely national – patchwork of mechanisms and permanent dialogue would stretch from early development, through criteria for assessment and valuation. authorisation and reimbursement, and continue through the monitoring of subsequent product use – all the time permitting New uncertainties adjustments to the instructions relating to the medicine, and to its Among the most challenging questions raised by earlier launch reimbursement. are how to ensure that faster does not mean riskier, how far existing legislation can allow for it, how soon adequate structures The mismatch between traditional arrangements and current can be put in place to capture and analyse data gathered after demands is a European as well as a national issue, because EU product launch, how current conflicts between data privacy and

4 FAST-TRACKING MEDICINES INNOVATION data access may be resolved, how to handle the risk that early disclosure of an innovation could erode its data exclusivity period, and how to link medicines authorisation with authorisation of the accompanying diagnostics that targeted therapies depend on. And introducing flexible pricing presents challenges of agreeing criteria for linking price increases – or reductions – to use under routine care conditions, and of attaining adequate understanding between pricing and reimbursement authorities, particularly in the European market.

The clash is largely about a balance of evidence versus access, safety versus speed, and innovation versus affordability. Researchers working at the forefront of science on treatments for small groups of patients resent still being subject to classic requirements to pursue average scores for efficacy and safety through years of data-collection on thousands of subjects. And the reimbursement systems necessary for patient access do not always feel fully equipped to assess the value that innovative products can have for health systems. So research progress can be inhibited by uncertainty over how to present findings – or even design tests – in a way that may satisfy the authorities. debate will intensify during 2015, in Europe and beyond, and its outcome is likely to be an influence for years to come on the care It is a dilemma that advocates of change like to epitomise with that patients receive, on the reputation of regulatory authorities, what has become their refrain: “The safest drug that no one can on the pace of innovation, and on the competitiveness of afford or that arrives too late is of no benefit to a patient”. The research-intensive companies.

The drivers for change

The drivers for change are all too familiar to anyone with an need for early patient access for vaccines and anti-virals. interest in health. Healthcare budgets are under strain from ageing populations and rising costs of care, often exacerbated by Similarly, the organisations charged with assessing the value of public spending cuts. Meanwhile, innovations in diagnosis, new medicines perceive that their methods are being therapy and prevention hold out the promise of major benefit to increasingly challenged when faced with major innovations and patients and, in the long term, to healthcare systems. need to evolve in pace with scientific advance.

Among patients and treating physicians there is hunger for the Right at the end of the decision-making chain, even the bodies benefits of innovation, and impatience at current slow and uneven that pay for medicines –so far the least enthusiastic about access to new medicines. The rare diseases organisation Eurordis modifying their approach – are conscious that they are often warns of bottlenecks in “regulatory procedures if they are not spending their limited budgets on treatments that vary in adapted to the evolution of science”, and the European Patients response for patients and are therefore effective in only a Forum calls for a greater say in the regulatory process. fraction of the population, or that may be abandoned because of adverse reactions. Advocates of change say that innovation is handicapped where regulation does not keep pace with science. Innovative companies Fresh disruption has arrived with a series of expensive say their product pipelines would be activated through greater breakthrough medicines. Recently-launched treatments for clarity and synchronisation of criteria for regulatory and hepatitis C have price tags of tens of thousands of euros per reimbursement processes, and through sharper focus on course, and new medicines are in the pipeline for cancer, heart measuring real product effectiveness. failure and immunotherapy at similar or greater cost. These high- profile and high-price innovations present new challenges for Regulators themselves, repeatedly faced with the challenges of payers, threatening their budgets, pitting them against assessing ever-more sophisticated molecular medicines with unprecedented demands from patients for access, and giving techniques conceived for a simpler age of chemical technology, payers new prominence as the ultimate arbiters of the treatment have also been jolted by recent epidemics into accepting the that patients may receive.

5 Not a revolution – but hopes for a rapid evolution

The essence of the adaptations now under discussion is a shift regulation can change in a day.” away from the single “yes-no” choice that for half a century has characterised most decision-making about new medicines. The Drug approval and pricing is such a complex and multi-layered new approach has been termed ‘Medicines Adaptive Pathways to business that consensus is yet to emerge on what exactly should Patients’ (MAPPs) (as well as ’staggered approval’, ’progressive change, or how – and even on whether any change at all is licensing’, or ’adaptive licensing’). necessary. The diversity of healthcare systems, and of the players within it, inevitably generates distinct views. It does not constitute a revolution. Decisions in MAPPs, as in the classic method, would be based on a careful assessment of benefit The industry that develops innovative products is largely global, and risk. But the evidence would be obtained at different stages of but the only marketing authorisation decisions at international a product’s life-cycle, and not just from clinical trials. It could level are those taken by the EU. And questions of reimbursement promise earlier access for patients, clearer guidance for are everywhere at best national, and in many cases even regional, researchers, greater confidence for industry and, ultimately, ie. sub-national broader reassurance to health systems on what they are commit- ting themselves to in approving and reimbursing costly medicines. So the panorama in early 2015 is of multiple initiatives, mostly focused on questions of earlier marketing authorisation, some involv- But even Hans-Georg Eichler, chief scientific officer at the ing organisations with an advisory role in reimbursement decisions – European Medicines Agency, who is one of the leading exponents known as health technology assessment (HTA) bodies, and a few – of new thinking on how systems might adapt, acknowledges: but only a few – extending as far as the thorniest issues, of how “It is unrealistic to think that the complex ecosystem of current reimbursement might function in a changed regulatory landscape.

Assessment criteria differ across Europe

Criteria Austria Belgium Switzerland Germany Finland FranceNetherlands Norway Sweden UK

Therapeutic beneﬁt

Patient beneﬁt

Cost-effectiveness

Budget impact

Pharmaceutical/innovative characteristics

Availability of therapeutic alternatives

Equity considerations

Public health impact

Research and development

Source: TOPRA

6 FAST-TRACKING MEDICINES INNOVATION

Responsibilities and decision-making powers

This table oversimplifies the complexity of distinct responsibilities Decision-makers – particularly in Europe, where different EU-level procedures and Responsibilities and decision-making powers at national, local and regional levels authorities govern pharmaceuticals, medical devices, in vitro diagnostics, or data protection, while member states retain full responsibility for pricing and reimbursement of healthcare EU member EU US products and services. Even in the US, which at least benefits states from a single authority for approval of healthcare products, Decision-making on marketing authorisation: reimbursement is governed by competing private healthcare plans. Health technology assessment resposibility:

National

Regional

Local The changes envisaged offer a chance for innovative technologies Decision-making on reimbursement: to be better investigated, in National narrow, targeted populations of Regional patients. Local Francesco de Lorenzo, president of the European Cancer Patient Coalition Source: European Voice

7 Established non-standard authorisation mechanisms allowing earlier access

Canada Japan • Regulatory roadmap • Regulatory roadmap for health products for health products

US EU Singapore • Accelerated approval (for unmet medical • Accelerated assessment (for major • Abridged need for serious conditions) public health interest, or a evaluation route • Fast track (for drugs intended to treat a therapeutic innovation) serious condition and where non-clinical or • Conditional marketing approval clinical data demonstrate potential to (for serious or life-threatening address unmet needs) diseases, emergencies, and orphan • Breakthrough therapy designation products: early submission, (intensive guidance for improvements over post-approval clinical data required) available therapies for serious conditions) • Exceptional circumstances (for • Priority review (for drugs that are intended rare condition, limited scientific to treat a serious condition and suggest the knowledge, or ethical considerations: potential to offer improved safety or post-approval clinical data required) effectiveness)

Source: European Voice The evolution so far

Making a medicine available early and with gradual approval is not of earlier access and more rapid product development. In an entirely new concept. EU pharmaceutical legislation has for Belgium, a 2014 scheme allows early temporary authorisation more than a decade permitted conditional marketing and reimbursement of innovative treatments. In 2014 France authorisations for unmet medical needs, on the basis of less updated its similar and slightly older scheme. In the UK, an early complete data, subject to specific conditions and obligations. Other access to medicines scheme (EAMS) introduced in 2014 permits exceptional routes are also available. For more than 20 years the prescription of medicines prior to authorisation. Since 2011 US has allowed accelerated approval and priority review designa- Sweden has been running a comprehensive scheme to explore tion, subsequently introducing fast-track designation, and, most re- the managed introduction of selected drugs. These models tend cently, breakthrough therapy designation. Some of these to focus on patients with life-threatening or seriously debilitating procedures have certainly allowed new medicines on to the conditions for which there is a clear unmet medical need, and market earlier – around 80 in the EU and the US between 2010 and many of them provide for early discussions between companies 2013 – but they are not widely used or widely loved in the EU (they and authorities on the benefit/risk balance of the medicine. also show divergence in transatlantic comparisons (see page 10).

MAPPs is conceived as a significant advance on the existing procedures, and a response to strong pressure to tackle the many Within Europe, but also on a illnesses that weigh heavily on society or for which no effective smaller scale in all member states, treatment yet exists. we are struggling with the

Experiments and initiatives that overlap, at least in part, availability in order to provide for unmet with the MAPPs concept, are being conducted by healthcare medical need. authorities around the world, and notably in the EU, the US, Canada and Singapore, examining the potential – and the limits – Birte van Elk, Dutch Medicines Evaluation Board

8 FAST-TRACKING MEDICINES INNOVATION

Currently, the most prominent official initiative is a pilot scheme launched in early 2014 by the European Medicines MAPPs-related initiatives

Agency, known as adaptive pathways. It invites companies to National: engage in experimental dialogues with health regulators, Belgium France UK Sweden patients and health technology assessment bodies on Early temporary Early temporary Early Access Managed drugs promising products in a 'safe harbour' environment of full authorisation authorisation to Medicines programme confidentiality and no binding commitments. It is designed for products for which companies are planning alternative US Canada Singapore approaches to randomised controlled trials, and for which they Breakthrough Regulatory Abridged have a clear idea of how and when they aim to present health- Roadmap for Evaluation technology-assessment (HTA)-relevant data drawn from real- Health Products Route world use. On a dozen selected candidate products, in-depth International: discussions have started between companies, HTA bodies and patients’ representatives, to explore how a marketing EU EU authorisation application and a programme of post- European Medicines Innovative authorisation data-collection might be framed. At the same Agency Adaptive Pathways Medicines Initiative II stakeholder platform time, EMA is enhancing co-ordination with national HTA bodies. The EMA pilot is not a marketing authorisation Transatlantic: procedure, and does not provide any new regulatory tools. It is NEWDIGS merely exploring how a company application might benefit New Drug Paradigms - MIT's Center for Biomedical Innovation from early discussion with other players. The outcome of the multi-stakeholder initiative with EMA, US, Canada, France pilot is due for review late in 2015. Meanwhile, the European Commission has set up a new committee of senior member Source: European Voice state officials to identify a more effective use of the EU’s regulatory framework so as to “improve safe and timely access Innovation at the Massachusetts Institute of Technology, and and availability of medicines for patients” – hence its name of involving EMA, Health Canada, France, along with industry, HTA STAMP. It held its first meeting in January 2015, and will bodies and academics. examine member states' views and national initiatives over the course of four meetings in 2015. For its part, the Innovative Medicines Initiative, the European Commission’s public-private research partnership with the Elsewhere around Europe and beyond, there are numerous pharmaceutical industry, is developing and testing tools to less official collaborations underway, bringing together diverse support the implementation of MAPPs. A co-ordination group constellations of healthcare players in pursuit of improvements will be set up in 2015 to analyse needs, to steer research and to to the systems that govern the introduction of healthcare ensure comprehensive information gathering on MAPPS-related technology. One of the largest is NEWDIGS, the New Drug developments, although this is unlikely to deliver any change in Paradigms project hosted by the Center for Biomedical the foreseeable future.

9 Is the US quicker than EU?

In Europe, the urge to explore the potential of MAPPs is also fed by an awareness of international competition – particularly with Approval times Median approval times in days for new active substances at the the US. Industry executives in Europe take the view that EU-US European Medicines Agency (EMA) and the US Food and Drugs competition is frequently underestimated by member states. Agency (FDA).

New impetus has been imparted to the comparison by US 600 President Barack Obama with his announcement of a “precision medicine initiative” in his 2015 state of the union address at the EMA end of January. His message that he hopes “21st-century 500 businesses will rely on American science and technology, research and development” is an open challenge to Europe, and was reinforced by the publication the same week of draft US biomedical legislation reform, entitled “21st-century cures”, with 400 ambitious proposals for patient engagement, data collection, refinement of criteria for assessing medicines, and innovation- FDA focused adjustments to authorisation processes. 300

On average, the US approves medicines faster than the EU. From 2009-13, two-thirds of all products approved by EMA and its US counterpart, the Food and Drug Administration (FDA), 200 were submitted first to FDA, and FDA was the first to approve 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 three-quarters of them. Average FDA approval time was six Note: The EMA approval time includes the European Commission time. months shorter than for EMA (with one product taking 55 Source: CIRS – Centre for Innovation in Regulatory Science months longer at EMA, and another, approved by FDA 17 days Anecdotal evidence suggests widespread reluctance among EU after submission of the application, taking 11 months at EMA). member states to shorten review timelines. The disparity on speed of authorisation is further compounded by the need in A similar picture emerges for experience of early approval Europe to seek reimbursement, after authorisation, in mechanisms. In 2010-13, 21 distinct new medicines were negotiations with multiple authorities at national, and, in some approved in the EU through either conditional marketing member states, at local level. authorisation or accelerated assessment, of which 19 were approved also in the US. But 77 distinct new medicines were Industry sources suggest that while Europe has an enormous approved in the US through accelerated approval, priority potential in leading on science, its competitive edge is vulnerable review, fast track and/or breakthrough, of which just 57 were to erosion because of the current complex system of approved also in the EU. EU median approval times were also administrative co-operation and decision-making. But although consistently longer than in the US. The US also enjoys the benefit Europe’s medicines approval system is often slower than the FDA, of a single authorisation system for a single – and very large – its decisions are widely accepted as of high quality. market.

The Ebola outbreak points to the need for urgent change…to address the way new medical products are brought to market… Researchers, the pharmaceutical industry, and regulatory authorities joined forces to fast-track the development of Ebola vaccines, therapies, and point-of-care diagnostic tests.

Margaret Chan, Director-general of the World Health Organisation

10 FAST-TRACKING MEDICINES INNOVATION Moving from concept to action

Removing uncertainties over procedures will be crucial to winning acceptance of MAPPs from sceptics, and making progress with the concept. At technical and administrative level this will require candid safe-harbour discussions with all parties around the table, where ideas can be discussed, hypotheses explored, and tools developed to increase confidence. Beyond the immediate, wherever administrative and technical discussions encounter issues that cannot be resolved at that level – notably where current legislative or other framework conditions are identified as barriers – solutions may be found only at a more political level.

The instinctive resistance among health and budgetary authorities – wary of making a serious mistake – will not be overcome unless they are reassured that the evidence base for their decisions will remain robust, even if the current procedures are adapted. Otherwise, in a MAPPs environment, risk-averse decision-makers may simply deny authorisation or exposed patients to from some drugs authorised on that basis reimbursement, thus preventing access to new medicines. over the years.

MAPPs advocates will have to make a convincing case that they Value for money are not adding to uncertainty, and may in fact be reducing it. Not only is MAPPs presented as providing better assurances of They argue that, even under current procedures, there is never safety. It is also claimed that it offers better value for money to enough data to be completely sure that a product will have the payers, as it relieves payers of one-off commitments to expected positive benefit/risk balance. That is one of the reimbursement in the face of evidence gaps that even the classic inescapable uncertainties in medicines regulation. Because methods suffer from. MAPPs provides mechanisms to gradually clinical trials are not conducted to obtain real-world evidence, fill such gaps, allowing payers to adjust prices of expensive there is always a risk of unforeseen adverse events occurring products downwards or upwards as a medicine reveals more of after authorisation, as soon as a new medicine reaches a wider its value in routine use. And better targeting of care could reduce population. MAPPs, it is argued, could help to address this issue, the waste in prescriptions to non-responders, and lower the since use of a new medicine would be expanded only gradually, additional healthcare cost of treating adverse reactions. The case with data reviewed and analysed as they become available, new can even be made – as some member states did in their studies initiated to address open questions, and the evidence comments to the STAMP group – that MAPPs could generate gathered under routine care conditions. budget savings by decreasing the cost of clinical trials, and consequently reduce the final cost of medicines. Concerns that faster access necessarily equates to lower standards and higher risks amount to a simplification that Varying prices ignores many of the dimensions in balancing benefit and risk. As But the cost issue remains of major concern to payers – who a growing body of literature explores, the balances are much have no natural interest in rapid access: their priority is the finer. The estimation of risk from any treatment varies according sustainability of the system’s finances. Many of the likely pricing to the disease and its progression: at its most obvious, a patient scenarios appear to them to hold traps or unwelcome in advanced stages of a life-threatening condition will often be implications. If an innovative medicine for an unmet need wins prepared to entertain more of a risk than a patient with only early access through MAPPs, a company might seek a high price early symptoms of the same disease. The estimation of risk in a for the initial limited launch, so as to compensate for low decision on authorising a medicine needs to take account of the volumes – against the interests of payers, who might feel that risks from rejecting an application (in that this will preclude any this was unjustified for an untried medicine. But equally, if the benefit that might have been enjoyed by some patients) as well medicine were to be granted only a low price in its early usage in as the risks from approval. The risks that may be imputed to a limited population, because it was by definition still only at a reducing reliance on randomised clinical trials must be offset tentative stage of development, a problem would arise if real- against the risks that many of the patients in a trial face of not world evidence showed the medicine was fulfilling its promise receiving any benefit – and even more dramatically, to the risks and frank damage that such reliance has occasionally clearly Continues on page 12

11 Continued from page 11 and its use was extended to wider indications or populations – Patient response because the company might then demand a higher price. This Percentage (on average) of the population for which a particular drug would present payers with the paradoxical demand for a higher in a class is ineffective price for higher volumes. In addition, if the results proved to be good, payers might resent the thought of rewarding the company Anti-depressants 38% for confirmatory evidence generated during usage funded by the (SSRIs) payers themselves.

Asthma drugs 40% In addition, while conditions will be imposed on innovations authorised in a MAPPs environment, ensuring that those conditions are met may prove difficult. One likely condition Diabetes drugs 43% would be a strict limitation of the disease and population for which the medicine could be prescribed, but deviations from these prescription limitations could lead to huge unplanned-for Arthritis drugs 50% costs for payers. Controls on prescribing are difficult in all countries, since physicians have enjoyed wide scope for autonomous decisions. Where off-label prescribing – that is, Alzheimer’s drugs 70% prescribing a medicine for a use it has not been authorised for – is widespread, the risk exists that an expensive innovative target medicine might be prescribed to populations, and for indications, Cancer drugs 75% for which it was not intended. The risks are all the greater in those European countries where authorities have recently Source: EFPIA started to openly and actively support and promote off-label prescribing. Seeking consistency Uncertainties also arise from divergences in the attitudes that Overall, many European payers regard MAPPs with guarded distinct authorities take to medicines development. Across scepticism, and even the most optimistic advocates of change Europe, decisions on marketing authorisation are all subject to recognise that full buy-in by payers could take many years. EU rules that impose basic standards – but there is no EU-wide Nonetheless, comprehensive development of MAPPs is seen as framework for reimbursement. But discussions are developing on inconceivable without the engagement of payers. There will be closer co-operation in the advisory processes to decisions on no benefit to patients if innovative medicines receive reimbursement, including health technology assessment data on authorisation more quickly but do not obtain reimbursement. scientific relative effectiveness assessment, taking into account the usual circumstances of healthcare practice. A real novelty Another challenge facing change advocates is demonstrating As the disciplines of HTA continue to evolve – predominantly at that MAPPs really brings something new, in the face of sceptical national level – the nature and quantity of evidence that each HTA suggestions that it is little more than a makeover for the body requires from companies tends also to increase, but in the existing conditional marketing authorisation processes. In absence of any of the framework that applies in the marketing Europe, these procedures have not been used extensively – authorisation sphere, there is little effective alignment at European many companies regard them as an inferior authorisation, or a level of criteria or procedures. And a trend to demand greater mechanism of last resort, and obtaining subsequent volumes of HTA data as a prerequisite to decision-making (and with reimbursement is particularly complex. They are also slow – in a heavy reliance on evidence drawn from large-scale clinical trials), many cases slower than the current standard procedures. Some runs counter to the ambitions of change advocates and their EU officials have argued pragmatically for fuller exploitation of arguments for supporting innovative medicines with a more existing procedures (and notably conditional marketing judicious selection of evidence drawn from smaller populations. authorisation) in parallel to entering the complex territory of MAPPs. To convince doubters, change advocates will need to Some co-ordination of HTA is underway in Europe at a technical make the case that MAPPs, with its more systematic level, notably through the EUnetHTA network. But this is far collaborative dialogue from the earliest stages of product short of any standardisation. It is unclear which options the development, its exploitation of new tools for targeting clearly- European Commission will explore to implement its vision of identified groups of patients, and its more sophisticated post- jointly produced HTA information for use by payers in taking launch monitoring, constitutes a genuine advance in regulatory reimbursement decisions at national level, and for a permanently procedures. funded HTA network over the coming years. 12 FAST-TRACKING MEDICINES INNOVATION Some leading HTA-related initiatives

Drug developers are also confronted with the need to provide new techniques to test the underlying genomic condition of a two distinct sets of evidence – one for the regulators who will patient and the suitability of a given treatment such as next make the decisions on authorisation, and one (at least) for the generation sequencing, European or even global databases will HTA bodies, because they each have different criteria. (Since be needed to support decision-making. there is little standardisation of HTA requirements from country to country, and each HTA body poses its own questions, Data privacy developers may need to provide many more than two sets of Putting in place adequate outcomes measurement will require evidence.) time, and additional mechanisms for reliable data collection – and that in turn raises sensitive issues of privacy. The way the Dialogue between HTA bodies and regulators is still at an early EU’s data protection rules evolve will have a crucial influence on stage, but could lead to some limited alignment of strategies, the possibility to provide protection to personal data while with improved understanding and agreement on the clinical allowing their use for research purposes – including the evidence package required for regulatory approval and development of new medicines. subsequent reimbursement decision-making. Closer collaboration is being promoted by EMA, which is engaged in a three-year Many other issues will also require elucidation before MAPPs action plan with EUnetHTA, which runs a programme in which can become a reality – notably achieving closer alignment companies can obtain parallel scientific advice from EMA and HTA between the authorisation processes for medicines and for the bodies, and is also integrating HTA bodies into its adaptive path- diagnostics that are an essential accompaniment of many of the ways pilot. medicines that might be candidates for early access. Many further questions remain: on ensuring closer engagement of Data exclusivity patients from the earliest stages of product development; on Another issue for industry is data exclusivity – a form of assessing the combinations of medicines that are increasingly intellectual property protection that is in many cases more used in cancer treatment; on the role and limitations of valuable for medicines than patents. Under current EU rules, a observational data; on the special challenges that advanced company enjoys data exclusivity for a fixed period after the first therapies will present, or on the continuing challenge of launch of an innovative product. If products are now to be validating the biomarkers vital to precision medicine. Any launched earlier (albeit in smaller populations) as part of MAPPs, advance towards solutions will depend on reflection among a the clock will start ticking earlier on data exclusivity, potentially wide range of partners. leaving the medicine unprotected by the time it has proved its worth and can be used in wider populations. HTA-related initiatives Improving tools ƭɥ$.1, +ɥɥ%1.4/(-%ɥ.$ɥɥ Since so much of the MAPPs concept depends on effective post- HTA Network ."(#2ɥ(-ɥ41./#ɥ launch monitoring and real-world evidence to support safe and effective use, its advocates recognise that the tools generating ƭɥ2!(#-3(Ɗ!ɥ -"ɥ3#!'-(! +ɥ EUnetHTA and making available good quality data will need improvement. In !.ǈ./#1 3(.-ɥ$.1ɥɥ#36.1* the EU, recent legislation has put in place some useful elements, SEED Shaping European ƭɥ, ).1ɥɥ,#, #1ɥ23 3#2ɥ -"ɥ including extended pharmacovigilance, risk management plans, Early Dialogues 23 *#'.+"#12Ʀɥ+#"ɥ 8ɥ1 -!# post-authorisation safety and efficacy studies, and networks of registries. To exploit the rapidly developing opportunities in ƭɥ ɥ!.-2.13(4,ɥ.-ɥ42(-%ɥ GET REAL 1# +ǈ6.1+"ɥ" 3 medicine based on constantly increasing volumes of data and The EU has to make existing data EMA-EUnetHTA ƭɥ!.++ .1 3(.- ENCEPP European Network of ƭɥ234"(#2ɥ3.ɥ+(-*ɥɥ -"ɥ protection rights more effective in Centres of Pharmacoepidemiology 43'.1(2 3(.- practice, and to allow citizens to and Pharmacovigilance EMA HTA parallel scientiﬁc advice ƭɥ6(3'ɥɥ ."(#2ɥ.$ɥ, -8ɥ more easily exercise their rights at a time ,#, #1ɥ23 3#2 when we all run our entire lives with our Patient-Centered Outcomes ƭɥ1#2# 1!'ɥ.-ɥ!.,/ 1 3(5#ɥ smartphones. Research Institute (PCORI) (US) #Ɖ#!3(5#-#22

Giovanni Buttarelli, European Data Protection Supervisor Source: European Voice

13 FAST-TRACKING MEDICINES INNOVATION

Conclusion

The coincidence of new science with new demands on healthcare officials with a diffuse and leisurely agenda is not considered an systems can be seen as an irresistible prompt to bring new efficiencies adequate response in terms of urgency or status. to the process of getting innovative medicines to patients. As Europe struggles to provide its citizens with a high level of care and to realise The fear is that taking too long over achieving real collaboration its ambitious innovation targets to create growth and jobs, MAPPs is and taking real action could mean Europe misses the opportunity being depicted as an agenda of huge potential value. to maximise its capacities in one of the hi-tech areas where its products and its regulatory expertise still make it a world leader. Without the sort of change that MAPPs implies, researchers Where the overlaps and gaps in national and EU competences argue that they will find it harder to satisfactorily resolve the new impede effective collaboration, it is only through political uncertainties from new science. Innovative companies, facing commitment – in member states as much as in Brussels – that the uncertainties over regulatory strategy, will lack encouragement to obstacles can be cleared. But that in turn will depend on how far tackle scientific uncertainties. The funders of healthcare systems member states are willing to buy in to the concept of driving will be increasingly perplexed as to how to make best use of their pharmaceuticals as an important policy topic. budgets. And patients will keep wondering whether and when they will be able to benefit from the best levels of care. Change advocates speak of the need for a change in mentality in Europe: “all stakeholders on a speed boat”, as one put it. They At present, MAPPs may seem to offer more questions than call for immediate action to strengthen regulatory co-operation, answers, and no-one can predict what it may be able to deliver. to take advantage of early scientific advice and rolling review But in a world of rapid change, there are merits in at least to speed assessment and to make medicines available faster. exploring its potential. Closer collaboration among all partners They insist that a confident regulatory system should be able to could help to make the most of what the current medicines understand that early access implies no automatic lowering of approval framework offers, and to identify new solutions where evidentiary standards. They are urging improved collaboration existing tools are shown to be insufficient. in health technology assessment while respecting national responsibilities for reimbursement, to match the co-operation In Europe, the complexity of healthcare governance arrangements achieved on authorisations, to synchronise it more closely with presents particular impediments to innovation. Not only are current that process, and to be more open to adapting decision-making systems slow and largely unpredictable. The recognition of the criteria to new science. growing challenge that innovation presents is also slow, fragmented, and in some cases openly grudging. In consequence, the responses Because there are so many partners to the process in Europe, so far in Europe have been largely at an administrative or technical with so many differing interests, the advocates of change fear level, with hopes pinned on pilot projects or voluntary technical that progress may fall victim to institutional paralysis. They say agreements or reviewing possible new uses for existing tools. The that waiting for goodwill and good luck to generate the desired recent creation of the STAMP group is seen by change advocates receptiveness and adaptation may not be enough. They are as emblematic of Europe’s piecemeal approach: a group of health looking for incisive and early political input to stimulate change. 14

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