fast-tracking medicines innovation: a question of ...fast-tracking medicines innovation the...

EuropeanVoice

Sponsored by

Fast-tracking medicines innovation:a question of uncertainties

CONTENTS

The uncertainties...................... 3The old and the new.................. 4The drivers for change.............. 5Not a revolution – but hopes for a rapid evolution.................. 6Responsibilities and decision-making powers........... 7The evolution so far................... 8-9US quicker than EU?................. 10Moving from concept to action 11-12Some leading HTA-related initiatives.................................... 13 Conclusion.................................. 14

Publication of this report has been made possible byRoche. The sponsor has no control over the content, for which European Voice retains full editorial responsibility.

SOURCES

“Accelerated Access to Innovative Medicines for Patients inNeed”, Clinical pharmacology & Therapeutics, volume 96 number5, November 2014“Minds Open – Sustainability of the European regulatory systemfor medicinal products”, National Institute for Public Health andthe Environment, Netherlands “Improving the EU system for the marketing authorisation of medicines”, Escher – The TI Pharma Platform for Regulatory Innovation“Relation between pharmaceuticals regulatory framework andtimely access of patients to medicines”, European CommissionPharmaceutical Committee“New drug approvals in ICH countries 2004–2013”, Centre for Innovation in Regulatory Science “From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients”, Clinical Pharmacology & Therapeutics, volume 97, issue 3, March2015“The risks of risk aversion in drug regulation”, Nature Reviews,Drug Discovery, November 2013“Adaptive pathways to patients: report on the initial experience ofthe pilot project”, European Medicines Agency, December 2014“Expert Group on Safe and Timely Access to Medicines for Patients”, record of first meeting, European Commission, January2015“Strategy for EU co-operation on Health Technology Assessment”,EU Health Technology Assessment Network, October 2014“On effective, accessible and resilient health systems”, EuropeanCommission, 2014“Conclusions on innovation for the benefit of patients”, the EU’sCouncil of Ministers, 2014

Written by Peter O’DonnellImages: iStock

3

FAST-TRACKING MEDICINES INNOVATION

The uncertainties

The problem is obvious: a 20th-century procedure for getting newmedicines to patients is struggling to cope with 21st-century medicines. Its critics say that it is often too slow, doesn’t always askthe right questions, and doesn’t know how to pay for innovations.

For the advocates of change, the consequences are clear. Thebest treatments are frequently reaching patients only slowly ornot at all, and healthcare budgets are not always getting the bestvalue for their money. In addition, incentives for innovation sufferfrom the mismatch.

The solution, however, is neither obvious nor clear. The subjectbristles with complexities – technical, scientific, regulatory, ethical, and economic. Intensive reflections among multiplehealthcare partners are now underway, in Europe and elsewhere,but comprehensive answers are still elusive.

In the United States, further impetus was given to the debate bythe early 2015 announcement by Barack Obama, the president ofthe United States, of action to promote a more innovative approach to medicines development, and by a forward-lookingCongress initiative for legislative reform – tellingly entitled "21st-century cures". Across Europe’s more complex landscape formedicines regulation, the responses so far have been more fragmented, and at European Union level they remain administrative or technical rather than political. The advocates ofchange argue that greater engagement at political level will benecessary in Europe to ensure the framework is conducive to innovation – and not just to today’s innovation, but to the innovations that will emerge in the coming decade. This short report sets out the background and sketches the main issues.

A question of uncertaintiesAmid the many deep uncertainties that healthcare systems face,there is one obvious certainty: rapid recent advances in medicalscience are opening up huge new opportunities. But how far, and how fast, can healthcare systems adapt their procedures totake full advantage? That is the great uncertainty hanging over

patients hoping their needs for the right treatment can be met,over researchers pondering the design of their development protocols, and over drug-company managers and investors asthey try to second-guess the future.

Novel medicines are increasingly offering a targeted approach –which in the immediate future offers particular promise in thetreatment of serious and life-threatening conditions. New precision in defining sub-forms of a disease and in identifyingsmall groups of responding individuals is often allowing a closematch of treatments to individual patients. Treatments can beginearly, and can be monitored by sophisticated technology-driveninformation systems to fine-tune their use and adjust their pricein line with their observed performance.

Patients, researchers and industry executives argue that the current regulatory systems are not up to the job. The concerns areshared by a growing body of regulators – and to some extent by pay-ers – in Europe, uncomfortable gatekeepers faced with controversialchoices over who should – and should not – receive expensive buteffective new medicines for hepatitis C or cancer, and how soon.They welcome the new options that science is generating, and theywish to confront and resolve the inevitable uncertainties – includingthe uncertainties that earlier launch and variable pricing imply forthe current procedures governing patients’ access to medicines.

But healthcare gatekeepers, focused on ensuring safety and protecting the public purse, are understandably hesitant about tearing up their rule-books. After 50 years of creating an ever-tightergrid of pre-marketing evaluation systems in pursuit of safety andthrift, these authorities are not enthusiastic about embarking on ajourney into new, less secure and less charted territory. They are already struggling to balance conflicting objectives of protecting citizens and making medicines available. They see the adaptationsnow being discussed as replacing their accumulated experience intop-down, one-off decision-making by bottom-up calls for flexibilityand dialogue throughout a product’s life. Their responses tend, therefore, to avert new uncertainties by resisting change.

4

Sequence of eventsThe novelty is that a single “yes-no” choice gives way to a view ofregulation as a continuum, in which decisions about the use of a newmedicine would be taken in sequence, as knowledge of itaccumulates in routine care – what is known as ‘real-world evidence’.Joint consideration of a medicine, from its earliest stages ofdevelopment, would forge a new partnership of the formerly distinctconstituencies of industry, patients, health authorities,reimbursement bodies and prescribing physicians. A form ofpermanent dialogue would stretch from early development, throughauthorisation and reimbursement, and continue through themonitoring of subsequent product use – all the time permittingadjustments to the instructions relating to the medicine, and to itsreimbursement.

The mismatch between traditional arrangements and currentdemands is a European as well as a national issue, because EU

New active substances

Source: CIRS - Centre for Innovation in Regulatory Science

EMA

Number of new active substances approved every year

2004 2005 2006 2007 2008 2009 2010 2011 2012 20130

10

20

30

40FDA

The classic approach to making a treatment available topatients involves a lengthy sequence of clinical trials. Phase Itrials explore whether a treatment is safe for people to take,typically in around 30 volunteers. Phase II investigates thesafety and effectiveness of a potential therapy, usually in 100-300 subjects. If the treatment appears safe and promiseseffectiveness, Phase III follows, with hundreds or eventhousands of carefully selected subjects, often lasting severalyears and spread across countries. Accumulated evidence ofsafety and effectiveness in specified indications, across anaverage of these trial populations, permits the sponsor to applyfor a marketing authorisation. At this point the regulatory body(in the EU, either a member state or the European MedicinesAgency (EMA) working with member state experts) begins areview of the assembled data, and after several months (andoften more than a year) an authorisation decision – eitherpositive or negative – is taken. If the decision is positive, thecompany can then start to seek agreement on price and/orreimbursement, through each country’s autonomous system ofpayers and advisory bodies – widely varying in terms ofinstitutions, procedures, and time-lines.

Targeted medicines do not fit this decades-old “one-size-fits-all” frame. They exploit new understanding of diseaseprocesses and of individuals’ genetic make-up. Their use islinked with modern testing techniques that can predictprobable responses to treatment. So they can be administeredearlier, with more accurate impact and fewer adverse reactions.It is no longer so necessary to wait for the results of extensivepre-launch trials, since much of that prior investigation ofaverage effects can be replaced by post-launch monitoring ofthe outcome in individuals. Drug developers and health andreimbursement authorities could start much earlier to discuss

the phased launch of a product, extending it gradually to widerpopulations, in line with agreements on programmed tests thatwould validate – or invalidate – the hypotheses aboutperformance. Wider success with this form of rolling reviewwould lead to wider use – and lower performance thananticipated could equally lead to restrictions on use or even towithdrawal. Medicines already developed using approaches ofthis type are transforming the lives of patients with cysticfibrosis, and giving new hope to victims of breast, lung, andcolorectal cancers.

The old and the new

rules confer on drug developers and on regulators a mutual dutyto make treatments available to patients within a reasonabletime frame. It is a recognised health issue, too: the World HealthOrganisation (WHO) is finalising new guidelines that emphasisethe need for high-quality decision-making by regulatoryauthorities. It has global resonance too, since the challengesposed by many innovative products – which are invariablyinternational – increasingly demand greater collaboration acrossthe current – largely national – patchwork of mechanisms andcriteria for assessment and valuation.

New uncertaintiesAmong the most challenging questions raised by earlier launchare how to ensure that faster does not mean riskier, how farexisting legislation can allow for it, how soon adequate structurescan be put in place to capture and analyse data gathered afterproduct launch, how current conflicts between data privacy and

5


The drivers for change are all too familiar to anyone with aninterest in health. Healthcare budgets are under strain fromageing populations and rising costs of care, often exacerbated bypublic spending cuts. Meanwhile, innovations in diagnosis,therapy and prevention hold out the promise of major benefit topatients and, in the long term, to healthcare systems.

Among patients and treating physicians there is hunger for thebenefits of innovation, and impatience at current slow and unevenaccess to new medicines. The rare diseases organisation Eurordiswarns of bottlenecks in “regulatory procedures if they are notadapted to the evolution of science”, and the European PatientsForum calls for a greater say in the regulatory process.

Advocates of change say that innovation is handicapped whereregulation does not keep pace with science. Innovative companiessay their product pipelines would be activated through greaterclarity and synchronisation of criteria for regulatory andreimbursement processes, and through sharper focus onmeasuring real product effectiveness.

Regulators themselves, repeatedly faced with the challenges ofassessing ever-more sophisticated molecular medicines withtechniques conceived for a simpler age of chemical technology,have also been jolted by recent epidemics into accepting the

The drivers for changeneed for early patient access for vaccines and anti-virals.

Similarly, the organisations charged with assessing the value ofnew medicines perceive that their methods are beingincreasingly challenged when faced with major innovations andneed to evolve in pace with scientific advance.

Right at the end of the decision-making chain, even the bodiesthat pay for medicines – so far the least enthusiastic aboutmodifying their approach – are conscious that they are oftenspending their limited budgets on treatments that vary inresponse for patients and are therefore effective in only afraction of the population, or that may be abandoned because ofadverse reactions.

Fresh disruption has arrived with a series of expensivebreakthrough medicines. Recently-launched treatments forhepatitis C have price tags of tens of thousands of euros percourse, and new medicines are in the pipeline for cancer, heartfailure and immunotherapy at similar or greater cost. These high-profile and high-price innovations present new challenges forpayers, threatening their budgets, pitting them againstunprecedented demands from patients for access, and givingpayers new prominence as the ultimate arbiters of the treatmentthat patients may receive.

data access may be resolved, how to handle the risk that earlydisclosure of an innovation could erode its data exclusivityperiod, and how to link medicines authorisation withauthorisation of the accompanying diagnostics that targetedtherapies depend on. And introducing flexible pricing presentschallenges of agreeing criteria for linking price increases – orreductions – to use under routine care conditions, and ofattaining adequate understanding between pricing andreimbursement 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 treatmentsfor small groups of patients resent still being subject to classicrequirements to pursue average scores for efficacy and safetythrough years of data-collection on thousands of subjects. Andthe reimbursement systems necessary for patient access do notalways feel fully equipped to assess the value that innovativeproducts can have for health systems. So research progress canbe inhibited by uncertainty over how to present findings – oreven design tests – in a way that may satisfy the authorities.

It is a dilemma that advocates of change like to epitomise withwhat has become their refrain: “The safest drug that no one canafford or that arrives too late is of no benefit to a patient”. The

debate will intensify during 2015, in Europe and beyond, and itsoutcome is likely to be an influence for years to come on the carethat patients receive, on the reputation of regulatory authorities,on the pace of innovation, and on the competitiveness ofresearch-intensive companies.

6

Not a revolution – but hopes for a rapid evolutionThe essence of the adaptations now under discussion is a shiftaway from the single “yes-no” choice that for half a century has characterised most decision-making about new medicines. Thenew approach has been termed ‘Medicines Adaptive Pathways to Patients’ (MAPPs) (as well as ’staggered approval’, ’progressive licensing’, or ’adaptive licensing’).

It does not constitute a revolution. Decisions in MAPPs, as in theclassic method, would be based on a careful assessment of benefitand risk. But the evidence would be obtained at different stages ofa product’s life-cycle, and not just from clinical trials. It could promise earlier access for patients, clearer guidance for researchers, greater confidence for industry and, ultimately,broader reassurance to health systems on what they are commit-ting themselves to in approving and reimbursing costly medicines.

But even Hans-Georg Eichler, chief scientific officer at the European Medicines Agency, who is one of the leading exponentsof new thinking on how systems might adapt, acknowledges: “It is unrealistic to think that the complex ecosystem of current

regulation can change in a day.”

Drug approval and pricing is such a complex and multi-layeredbusiness that consensus is yet to emerge on what exactly shouldchange, or how – and even on whether any change at all is necessary. The diversity of healthcare systems, and of the playerswithin it, inevitably generates distinct views.

The industry that develops innovative products is largely global,but the only marketing authorisation decisions at internationallevel are those taken by the EU. And questions of reimbursementare everywhere at best national, and in many cases even regional,ie. sub-national

So the panorama in early 2015 is of multiple initiatives, mostly focused on questions of earlier marketing authorisation, some involv-ing organisations with an advisory role in reimbursement decisions –known as health technology assessment (HTA) bodies, and a few –but only a few – extending as far as the thorniest issues, of how reimbursement might function in a changed regulatory landscape.

Assessment criteria differ across Europe

Source: TOPRA

Criteria

Therapeutic benefit

Patient benefit

Cost-effectiveness

Budget impact

Pharmaceutical/innovativecharacteristics

Availability of therapeuticalternatives

Equity considerations

Public health impact

Research and development

Austria Belgium Switzerland Germany Finland France Norway Sweden UKNetherlands

7


Decision-makers

Source: European Voice

EU memberstates

EU US

Responsibilities and decision-making powers at national, local and regional levels

Decision-making on marketing authorisation:

Health technology assessment resposibility:

National

Local

National

Local

Decision-making on reimbursement:

Regional

Regional

This table oversimplifies the complexity of distinct responsibilities– particularly in Europe, where different EU-level procedures andauthorities govern pharmaceuticals, medical devices, in vitro diagnostics, or data protection, while member states retain fullresponsibility for pricing and reimbursement of healthcare products and services. Even in the US, which at least benefitsfrom a single authority for approval of healthcare products, reimbursement is governed by competing private healthcareplans.

Responsibilities and decision-making powers

The changes envisaged offer achance for innovative technologiesto be better investigated, in narrow, targeted populations of

patients.

Francesco de Lorenzo, president of the European Cancer Patient Coalition

8

Established non-standard authorisation mechanisms allowing earlier access


US

• Accelerated approval (for unmet medical need for serious conditions)

• Fast track (for drugs intended to treat a serious condition and where non-clinical or clinical data demonstrate potential to address unmet needs)

• Breakthrough therapy designation (intensive guidance for improvements over available therapies for serious conditions)

• Priority review (for drugs that are intended to treat a serious condition and suggest the potential to offer improved safety or effectiveness)

EU

• Accelerated assessment (for major public health interest, or a therapeutic innovation)

• Conditional marketing approval (for serious or life-threatening diseases, emergencies, and orphan products: early submission, post-approval clinical data required)

• Exceptional circumstances (for rare condition, limited scientific knowledge, or ethical considerations: post-approval clinical data required)

Canada

• Regulatory roadmap for health products

Japan

• Regulatory roadmap for health products

Singapore

• Abridged evaluation route

of earlier access and more rapid product development. In Belgium, a 2014 scheme allows early temporary authorisationand reimbursement of innovative treatments. In 2014 France updated its similar and slightly older scheme. In the UK, an earlyaccess to medicines scheme (EAMS) introduced in 2014 permitsprescription of medicines prior to authorisation. Since 2011 Sweden has been running a comprehensive scheme to explorethe managed introduction of selected drugs. These models tendto focus on patients with life-threatening or seriously debilitatingconditions for which there is a clear unmet medical need, andmany of them provide for early discussions between companiesand authorities on the benefit/risk balance of the medicine.

The evolution so farMaking a medicine available early and with gradual approval is notan entirely new concept. EU pharmaceutical legislation has formore than a decade permitted conditional marketing authorisations for unmet medical needs, on the basis of less complete data, subject to specific conditions and obligations. Otherexceptional routes are also available. For more than 20 years theUS has allowed accelerated approval and priority review designa-tion, subsequently introducing fast-track designation, and, most re-cently, breakthrough therapy designation. Some of theseprocedures have certainly allowed new medicines on to the market earlier – around 80 in the EU and the US between 2010 and2013 – but they are not widely used or widely loved in the EU (theyalso 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 manyillnesses that weigh heavily on society or for which no effectivetreatment yet exists.

Experiments and initiatives that overlap, at least in part, with the MAPPs concept, are being conducted by healthcare authorities around the world, and notably in the EU, the US,Canada and Singapore, examining the potential – and the limits –

Within Europe, but also on a smaller scale in all member states,we are struggling with the

availability in order to provide for unmetmedical need.

Birte van Elk, Dutch Medicines Evaluation Board

9


Currently, the most prominent official initiative is a pilotscheme launched in early 2014 by the European MedicinesAgency, known as adaptive pathways. It invites companies toengage in experimental dialogues with health regulators,patients and health technology assessment bodies onpromising products in a 'safe harbour' environment of fullconfidentiality and no binding commitments. It is designed forproducts for which companies are planning alternativeapproaches to randomised controlled trials, and for which theyhave a clear idea of how and when they aim to present health-technology-assessment (HTA)-relevant data drawn from real-world use. On a dozen selected candidate products, in-depthdiscussions have started between companies, HTA bodies andpatients’ representatives, to explore how a marketingauthorisation application and a programme of post-authorisation data-collection might be framed. At the sametime, EMA is enhancing co-ordination with national HTAbodies. The EMA pilot is not a marketing authorisationprocedure, and does not provide any new regulatory tools. It ismerely exploring how a company application might benefitfrom early discussion with other players. The outcome of thepilot is due for review late in 2015. Meanwhile, the EuropeanCommission has set up a new committee of senior memberstate officials to identify a more effective use of the EU’sregulatory framework so as to “improve safe and timely accessand availability of medicines for patients” – hence its name ofSTAMP. It held its first meeting in January 2015, and willexamine member states' views and national initiatives over thecourse of four meetings in 2015.

Elsewhere around Europe and beyond, there are numerousless official collaborations underway, bringing together diverseconstellations of healthcare players in pursuit of improvementsto the systems that govern the introduction of healthcaretechnology. One of the largest is NEWDIGS, the New DrugParadigms project hosted by the Center for Biomedical

MAPPs-related initiatives


National:

International:

Transatlantic:

Early temporaryauthorisation

Early temporaryauthorisation

Early Accessto Medicines

Managed drugsprogramme

Belgium France UK Sweden

Breakthrough

US

RegulatoryRoadmap for

Health Products

Canada

European MedicinesAgency Adaptive Pathways

EU

NEWDIGS

InnovativeMedicines Initiative IIstakeholder platform

EU

AbridgedEvaluation

Route

Singapore

New Drug Paradigms - MIT's Center for Biomedical Innovation multi-stakeholder initiative with EMA, US, Canada, France

Innovation at the Massachusetts Institute of Technology, andinvolving EMA, Health Canada, France, along with industry, HTAbodies and academics.

For its part, the Innovative Medicines Initiative, the EuropeanCommission’s public-private research partnership with thepharmaceutical industry, is developing and testing tools tosupport the implementation of MAPPs. A co-ordination groupwill be set up in 2015 to analyse needs, to steer research and toensure comprehensive information gathering on MAPPS-relateddevelopments, although this is unlikely to deliver any change inthe foreseeable future.

10

Is the US quicker than EU?In Europe, the urge to explore the potential of MAPPs is also fedby an awareness of international competition – particularly withthe US. Industry executives in Europe take the view that EU-UScompetition is frequently underestimated by member states.

New impetus has been imparted to the comparison by USPresident Barack Obama with his announcement of a “precisionmedicine initiative” in his 2015 state of the union address at theend of January. His message that he hopes “21st-centurybusinesses will rely on American science and technology,research and development” is an open challenge to Europe, andwas reinforced by the publication the same week of draft USbiomedical legislation reform, entitled “21st-century cures”, withambitious proposals for patient engagement, data collection,refinement of criteria for assessing medicines, and innovation-focused adjustments to authorisation processes.

On average, the US approves medicines faster than the EU.From 2009-13, two-thirds of all products approved by EMA andits US counterpart, the Food and Drug Administration (FDA),were submitted first to FDA, and FDA was the first to approvethree-quarters of them. Average FDA approval time was sixmonths shorter than for EMA (with one product taking 55months longer at EMA, and another, approved by FDA 17 daysafter submission of the application, taking 11 months at EMA).

A similar picture emerges for experience of early approvalmechanisms. In 2010-13, 21 distinct new medicines wereapproved in the EU through either conditional marketingauthorisation or accelerated assessment, of which 19 wereapproved also in the US. But 77 distinct new medicines wereapproved in the US through accelerated approval, priority review, fast track and/or breakthrough, of which just 57 wereapproved also in the EU. EU median approval times were alsoconsistently longer than in the US. The US also enjoys the benefitof a single authorisation system for a single – and very large –market.

Anecdotal evidence suggests widespread reluctance among EUmember states to shorten review timelines. The disparity onspeed of authorisation is further compounded by the need inEurope to seek reimbursement, after authorisation, innegotiations with multiple authorities at national, and, in somemember states, at local level.

Industry sources suggest that while Europe has an enormouspotential in leading on science, its competitive edge is vulnerableto erosion because of the current complex system ofadministrative co-operation and decision-making. But althoughEurope’s medicines approval system is often slower than the FDA,its decisions are widely accepted as of high quality.

Approval times

Note: The EMA approval time includes the European Commission time.Source: CIRS – Centre for Innovation in Regulatory Science

EMA

FDA

Median approval times in days for new active substances at the European Medicines Agency (EMA) and the US Food and Drugs Agency (FDA).

200

2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

300

400

500

600

The Ebola outbreak points to theneed for urgent change…to address the way new medicalproducts are brought to market…

Researchers, the pharmaceutical industry,and regulatory authorities joined forces tofast-track the development of Ebola vaccines, therapies, and point-of-care diagnostic tests.

Margaret Chan, Director-general of the World HealthOrganisation

11


Moving from concept to actionRemoving uncertainties over procedures will be crucial towinning acceptance of MAPPs from sceptics, and makingprogress with the concept. At technical and administrative levelthis will require candid safe-harbour discussions with all partiesaround the table, where ideas can be discussed, hypothesesexplored, and tools developed to increase confidence. Beyondthe immediate, wherever administrative and technicaldiscussions encounter issues that cannot be resolved at that level– notably where current legislative or other frameworkconditions are identified as barriers – solutions may be foundonly at a more political level.

The instinctive resistance among health and budgetaryauthorities – wary of making a serious mistake – will not beovercome unless they are reassured that the evidence base fortheir decisions will remain robust, even if the current proceduresare adapted. Otherwise, in a MAPPs environment, risk-aversedecision-makers may simply deny authorisation orreimbursement, thus preventing access to new medicines.

MAPPs advocates will have to make a convincing case that theyare not adding to uncertainty, and may in fact be reducing it.They argue that, even under current procedures, there is neverenough data to be completely sure that a product will have theexpected positive benefit/risk balance. That is one of theinescapable uncertainties in medicines regulation. Becauseclinical trials are not conducted to obtain real-world evidence,there is always a risk of unforeseen adverse events occurringafter authorisation, as soon as a new medicine reaches a widerpopulation. MAPPs, it is argued, could help to address this issue,since use of a new medicine would be expanded only gradually,with data reviewed and analysed as they become available, newstudies initiated to address open questions, and the evidencegathered under routine care conditions.

Concerns that faster access necessarily equates to lowerstandards and higher risks amount to a simplification thatignores many of the dimensions in balancing benefit and risk. Asa growing body of literature explores, the balances are muchfiner. The estimation of risk from any treatment varies accordingto the disease and its progression: at its most obvious, a patientin advanced stages of a life-threatening condition will often beprepared to entertain more of a risk than a patient with onlyearly symptoms of the same disease. The estimation of risk in adecision on authorising a medicine needs to take account of therisks from rejecting an application (in that this will preclude anybenefit that might have been enjoyed by some patients) as wellas the risks from approval. The risks that may be imputed toreducing reliance on randomised clinical trials must be offsetagainst the risks that many of the patients in a trial face of notreceiving any benefit – and even more dramatically, to the risksand frank damage that such reliance has occasionally clearly

exposed patients to from some drugs authorised on that basisover the years.

Value for moneyNot only is MAPPs presented as providing better assurances ofsafety. It is also claimed that it offers better value for money topayers, as it relieves payers of one-off commitments toreimbursement in the face of evidence gaps that even the classicmethods suffer from. MAPPs provides mechanisms to graduallyfill such gaps, allowing payers to adjust prices of expensiveproducts downwards or upwards as a medicine reveals more ofits value in routine use. And better targeting of care could reducethe waste in prescriptions to non-responders, and lower theadditional healthcare cost of treating adverse reactions. The casecan even be made – as some member states did in theircomments to the STAMP group – that MAPPs could generatebudget savings by decreasing the cost of clinical trials, andconsequently reduce the final cost of medicines.

Varying pricesBut the cost issue remains of major concern to payers – whohave no natural interest in rapid access: their priority is thesustainability of the system’s finances. Many of the likely pricingscenarios appear to them to hold traps or unwelcomeimplications. If an innovative medicine for an unmet need winsearly access through MAPPs, a company might seek a high pricefor the initial limited launch, so as to compensate for lowvolumes – against the interests of payers, who might feel thatthis was unjustified for an untried medicine. But equally, if themedicine were to be granted only a low price in its early usage ina limited population, because it was by definition still only at atentative stage of development, a problem would arise if real-world evidence showed the medicine was fulfilling its promise

Continues on page 12

12

and its use was extended to wider indications or populations –because the company might then demand a higher price. Thiswould present payers with the paradoxical demand for a higherprice for higher volumes. In addition, if the results proved to begood, payers might resent the thought of rewarding the companyfor confirmatory evidence generated during usage funded by thepayers themselves.

In addition, while conditions will be imposed on innovationsauthorised in a MAPPs environment, ensuring that thoseconditions are met may prove difficult. One likely conditionwould be a strict limitation of the disease and population forwhich the medicine could be prescribed, but deviations fromthese prescription limitations could lead to huge unplanned-forcosts for payers. Controls on prescribing are difficult in allcountries, since physicians have enjoyed wide scope forautonomous decisions. Where off-label prescribing – that is,prescribing a medicine for a use it has not been authorised for –is widespread, the risk exists that an expensive innovative targetmedicine might be prescribed to populations, and for indications,for which it was not intended. The risks are all the greater inthose European countries where authorities have recentlystarted to openly and actively support and promote off-labelprescribing.

Overall, many European payers regard MAPPs with guardedscepticism, and even the most optimistic advocates of changerecognise that full buy-in by payers could take many years.Nonetheless, comprehensive development of MAPPs is seen asinconceivable without the engagement of payers. There will beno benefit to patients if innovative medicines receiveauthorisation more quickly but do not obtain reimbursement.

A real noveltyAnother challenge facing change advocates is demonstratingthat MAPPs really brings something new, in the face of scepticalsuggestions that it is little more than a makeover for theexisting conditional marketing authorisation processes. InEurope, these procedures have not been used extensively –many companies regard them as an inferior authorisation, or amechanism of last resort, and obtaining subsequentreimbursement is particularly complex. They are also slow – inmany cases slower than the current standard procedures. SomeEU officials have argued pragmatically for fuller exploitation ofexisting procedures (and notably conditional marketingauthorisation) in parallel to entering the complex territory ofMAPPs. To convince doubters, change advocates will need tomake the case that MAPPs, with its more systematiccollaborative dialogue from the earliest stages of productdevelopment, its exploitation of new tools for targeting clearly-identified groups of patients, and its more sophisticated post-launch monitoring, constitutes a genuine advance in regulatoryprocedures.

Patient response

Source: EFPIA

Anti-depressants

(SSRIs)

38%

40%

43%

50%

70%

75%

Asthma drugs

Diabetes drugs

Arthritis drugs

Alzheimer’s drugs

Cancer drugs

Percentage (on average) of the population for which a particular drugin a class is ineffective

Seeking consistencyUncertainties also arise from divergences in the attitudes thatdistinct authorities take to medicines development. AcrossEurope, decisions on marketing authorisation are all subject toEU rules that impose basic standards – but there is no EU-wideframework for reimbursement. But discussions are developing oncloser co-operation in the advisory processes to decisions onreimbursement, including health technology assessment data onscientific relative effectiveness assessment, taking into accountthe usual circumstances of healthcare practice.

As the disciplines of HTA continue to evolve – predominantly atnational level – the nature and quantity of evidence that each HTAbody requires from companies tends also to increase, but in theabsence of any of the framework that applies in the marketingauthorisation sphere, there is little effective alignment at Europeanlevel of criteria or procedures. And a trend to demand greatervolumes of HTA data as a prerequisite to decision-making (and witha heavy reliance on evidence drawn from large-scale clinical trials),runs counter to the ambitions of change advocates and theirarguments for supporting innovative medicines with a morejudicious selection of evidence drawn from smaller populations.

Some co-ordination of HTA is underway in Europe at a technicallevel, notably through the EUnetHTA network. But this is farshort of any standardisation. It is unclear which options theEuropean Commission will explore to implement its vision ofjointly produced HTA information for use by payers in takingreimbursement decisions at national level, and for a permanentlyfunded HTA network over the coming years.

Continued from page 11

13


Some leading HTA-related initiativesDrug developers are also confronted with the need to providetwo distinct sets of evidence – one for the regulators who willmake the decisions on authorisation, and one (at least) for theHTA bodies, because they each have different criteria. (Sincethere is little standardisation of HTA requirements from countryto country, and each HTA body poses its own questions, developers may need to provide many more than two sets of evidence.)

Dialogue between HTA bodies and regulators is still at an earlystage, but could lead to some limited alignment of strategies,with improved understanding and agreement on the clinical evidence package required for regulatory approval and subsequent reimbursement decision-making. Closer collaborationis being promoted by EMA, which is engaged in a three-year action plan with EUnetHTA, which runs a programme in whichcompanies can obtain parallel scientific advice from EMA and HTAbodies, and is also integrating HTA bodies into its adaptive path-ways pilot.

Data exclusivityAnother issue for industry is data exclusivity – a form of intellectual property protection that is in many cases more valuable for medicines than patents. Under current EU rules, acompany enjoys data exclusivity for a fixed period after the firstlaunch of an innovative product. If products are now to belaunched earlier (albeit in smaller populations) as part of MAPPs,the clock will start ticking earlier on data exclusivity, potentiallyleaving the medicine unprotected by the time it has proved itsworth and can be used in wider populations.

Improving toolsSince so much of the MAPPs concept depends on effective post-launch monitoring and real-world evidence to support safe andeffective use, its advocates recognise that the tools generatingand making available good quality data will need improvement. Inthe EU, recent legislation has put in place some useful elements,including extended pharmacovigilance, risk management plans,post-authorisation safety and efficacy studies, and networks ofregistries. To exploit the rapidly developing opportunities in medicine based on constantly increasing volumes of data and

new techniques to test the underlying genomic condition of a patient and the suitability of a given treatment such as next generation sequencing, European or even global databases willbe needed to support decision-making.

Data privacyPutting in place adequate outcomes measurement will requiretime, and additional mechanisms for reliable data collection –and that in turn raises sensitive issues of privacy. The way theEU’s data protection rules evolve will have a crucial influence onthe possibility to provide protection to personal data while allowing their use for research purposes – including the development of new medicines.

Many other issues will also require elucidation before MAPPscan become a reality – notably achieving closer alignment between the authorisation processes for medicines and for thediagnostics that are an essential accompaniment of many of themedicines that might be candidates for early access. Many further questions remain: on ensuring closer engagement of patients from the earliest stages of product development; on assessing the combinations of medicines that are increasinglyused in cancer treatment; on the role and limitations of observational data; on the special challenges that advanced therapies will present, or on the continuing challenge of validating the biomarkers vital to precision medicine. Any advance towards solutions will depend on reflection among awide range of partners.


HTA-related initiatives

HTA Network

EUnetHTA

SEED Shaping European Early Dialogues

GET REAL

EMA-EUnetHTA

ENCEPP European Network of Centres of Pharmacoepidemiology

and Pharmacovigilance

EMA HTA parallel scientific advice

Patient-Centered Outcomes Research Institute (PCORI) (US)

The EU has to make existing dataprotection rights more effective inpractice, and to allow citizens to

more easily exercise their rights at a timewhen we all run our entire lives with oursmartphones.

Giovanni Buttarelli, European Data Protection Supervisor

14


ConclusionThe coincidence of new science with new demands on healthcare systems can be seen as an irresistible prompt to bring new efficienciesto the process of getting innovative medicines to patients. As Europestruggles to provide its citizens with a high level of care and to realiseits ambitious innovation targets to create growth and jobs, MAPPs isbeing depicted as an agenda of huge potential value.

Without the sort of change that MAPPs implies, researchersargue that they will find it harder to satisfactorily resolve the new uncertainties from new science. Innovative companies, facing uncertainties over regulatory strategy, will lack encouragement totackle scientific uncertainties. The funders of healthcare systems will be increasingly perplexed as to how to make best use of theirbudgets. And patients will keep wondering whether and whenthey will be able to benefit from the best levels of care.

At present, MAPPs may seem to offer more questions than answers, and no-one can predict what it may be able to deliver.But in a world of rapid change, there are merits in at least exploring its potential. Closer collaboration among all partnerscould help to make the most of what the current medicines approval framework offers, and to identify new solutions whereexisting tools are shown to be insufficient.

In Europe, the complexity of healthcare governance arrangementspresents particular impediments to innovation. Not only are currentsystems slow and largely unpredictable. The recognition of the growing challenge that innovation presents is also slow, fragmented,and in some cases openly grudging. In consequence, the responsesso far in Europe have been largely at an administrative or technicallevel, with hopes pinned on pilot projects or voluntary technicalagreements or reviewing possible new uses for existing tools. The recent creation of the STAMP group is seen by change advocates as emblematic of Europe’s piecemeal approach: a group of health

officials with a diffuse and leisurely agenda is not considered an adequate response in terms of urgency or status.

The fear is that taking too long over achieving real collaborationand taking real action could mean Europe misses the opportunityto maximise its capacities in one of the hi-tech areas where its products and its regulatory expertise still make it a world leader.Where the overlaps and gaps in national and EU competences impede effective collaboration, it is only through political commitment – in member states as much as in Brussels – that theobstacles can be cleared. But that in turn will depend on how farmember states are willing to buy in to the concept of driving pharmaceuticals as an important policy topic.

Change advocates speak of the need for a change in mentalityin Europe: “all stakeholders on a speed boat”, as one put it. Theycall for immediate action to strengthen regulatory co-operation,to take advantage of early scientific advice and rolling review to speed assessment and to make medicines available faster. They insist that a confident regulatory system should be able tounderstand that early access implies no automatic lowering of evidentiary standards. They are urging improved collaboration in health technology assessment while respecting national responsibilities for reimbursement, to match the co-operationachieved on authorisations, to synchronise it more closely withthat process, and to be more open to adapting decision-makingcriteria to new science.

Because there are so many partners to the process in Europe,with so many differing interests, the advocates of change fearthat progress may fall victim to institutional paralysis. They saythat waiting for goodwill and good luck to generate the desiredreceptiveness and adaptation may not be enough. They are looking for incisive and early political input to stimulate change.

EuropeanVoiceEuropean Voice.Dénomination sociale: EUROPEAN VOICE SPRL. Forme sociale: société anonyme. Siège social: Rue de la Loi 155, 1040 Bruxelles. Numéro d’entreprise: 0526.900.436 RPM Bruxelles.

© 2015 European Voice All rights reserved.

Neither this publication nor any part of it may be reproduced, stored in a retrieval system, ortransmitted in any form by any means, electronic, mechanical, photocopying, recording orotherwise, without prior permission. Whilst every effort has been taken to verify the accuracy of this information, neitherEuropean Voice nor its affiliates can accept any responsibility or liability for reliance by anyperson on this information.

fast-tracking medicines innovation: a question of ...fast-tracking medicines innovation the...

Documents