The Market Access EMA-HTA Parallel Scientific Advice .

EMA-HTA Parallel Scientific AdviceEarly Dialogue to Support Marketing Authorizationand Market AccessKirsten Messmer, PhD, RACPrincipal Regulatory Affairs Specialist, PPDJames McCormick, PhDSenior Director Regulatory Affairs, PPDLina Sladkeviciute, MScManaging Consultant, Market Access Consulting, EvideraDrug development is a multi-year and cost-intensiveprocess in which marketing authorization is not thefinal step on the route to optimal market access.Maximum market availability of medical productsto patients depends on pricing and reimbursementassessments and agreements made during the healthtechnology assessment (HTA) process, which cantake anywhere from six months to more than a year.Recognizing that there are two sets of standards beingconsidered for drug market access, in 2010 the EuropeanMedicines Agency (EMA) launched a parallel scientificadvice program in which sponsors can obtain input onvalue decisions from the EMA as well as various HTAbodies. The scheme was permanently implemented afterthe pilot ended in May 2015 due to the success of theprogram.The EMA or the national regulatory agencies, dependingon the marketing authorization procedure, determinewhether the evidence provided supports a positiverisk-benefit balance and warrants the granting of amarketing authorization. Any product approved by theEMA in the centralized procedure will automatically holda marketing authorization in all the European EconomicArea (EEA) member states. Regulators evaluate theevidence generated during the rigorously controlledproduct development for conformity with applicableEVIDERA.COMKirsten MessmerJames McCormickLina Sladkeviciutescientific, therapeutic, and product specific guidelines.Products need to meet the regulators’ expectations forinternal validity, quality, safety, and efficacy, while havinga positive benefit-to-risk ratio for patient outcomes.Additional evaluation criteria include the impact on thequality of life, the degree of innovation, and whetherthe medicinal product addresses an unmet medicalneed. Ideally, new medicinal products should elevate thebenefits over existing therapies.National Health Technology Assessment Bodies (HTAs,including, for example, third-party payers, patient andpublic representation, pricing and reimbursementagencies) evaluate the value and patient benefit of theapproved drug to grant access to health systems at acertain price. Almost all products approved centrally bythe EMA will be evaluated by national or regional HTAsfollowing the country’s requirements and policies. Someof the criteria used during the marketing authorizationstage are considered during the evaluation of the valueproposition against evidence requirements and criteriafor what constitutes value. HTAs will consider the patientbenefit, and selected markets consider cost-effectivenessand/or budget impact of a new medicine. ParticularlyTHE EVIDENCE FORUM May 2017

with the high price tag of some of the newest, mostinnovative medicines (e.g., newer antibodies, advancedtherapies), affordability influences the decision of makinga drug available and setting the specifications for use inthe healthcare system. The HTAs may also be responsiblefor the price, subsequent price renegotiations, and priceerosion in the case of real-world effectiveness data.Sponsors of new medicinal products have to meet thecriteria from regulators and HTAs in order to be able tomake the product available to patients in a particularmarket. Swift market availability is supported by thegeneration of both sets of evidence - in parallel whenpossible and sometimes consecutively - required forpositive decisions as early as possible during the drugdevelopment process. The regulatory evaluation issupported by guidelines issued by the regulators. TheHTA evaluation is based on guidance and criteria fordemonstrating clinical benefit, and where applicablesocial benefit, and economic benefit.with HTAs, started the pilot program offering paralleladvice on evidence requirements for either organizationto support market authorization and reimbursement/pricing decisions. Four EMA-HTA parallel adviceprocedures were conducted under the Shaping EuropeanEarly Dialogue for health technologies (SEED) umbrella.The EC-funded SEED project involved a number of HTAsto explore various ways for collaborative early dialogue.During the EMA-HTA parallel advice meetings,stakeholders can learn about the common and divergentrequirements of the agencies involved, to drive a moreefficient evidence collection during the developmentstage.The EMA-HTA parallel scientific advice procedure followsa four-step process.4,5 (Figure 1)Several initiatives between the EMA and HTAs led up tothe implementation of the EMA-HTA parallel scientificadvice.1 The initial focus sought to improve the alignmentof information handling and included the assessmentof how European Public Assessment Reports (EPARs)provide benefit and risk of medicines by the EuropeanHigh Level Pharmaceutical Forum. Recommendations toimprove the HTA effectiveness evaluation were publishedin a 2008 report.2 Directive 2011/24 (article 15) alsoallowed the European Commission (EC) to establishthe HTA network (comprised of all member states plusNorway and Iceland) calling for stronger interactionbetween the EMA and HTAs, timely exchange ofinformation to form stronger synergies, and interactionsfor all stakeholders.3 In 2010, the EMA, in collaboration Pre-Notification: The pre-notification phase startsabout six months prior to the intended meeting.During this phase the sponsor engages with theEMA and the chosen HTAs for confirmation of themeeting date, preliminary planning of the type ofquestions to be asked, and whether a pre-submissionteleconference is needed. However, the individualHTAs will decide whether to participate in the parallelscientific advice procedure. The pre-notification phaselasts about six weeks. Pre-Submission: Submission of the letter of intent anddraft briefing document to the EMA and applicableHTAs signals the start of the pre-submission phase.The pre-submission phase lasts about three weeksif the sponsor does not request a teleconference orabout seven weeks if a teleconference is requested.A pre-submission teleconference generally isrecommended for more complex and/or controversialFigure 1. Timeline for EMA-HTA Parallel Scientific AdviceTimeline for EMA-HTA Parallel Scientific Advice6 weeks2-4weeks4 months3 weeksPre-NotificationPre-SubmissionEvaluation PhaseOutcomeImplementationEMAcommentsList of IssuesSubmission ofSubmission ofEMAHTAvalidated Briefing to ApplicantLetter of Intent andminutes minutesPackage AnnexesDraft BriefingPackageEMA - HTAmeetingTelephone ConferenceEVIDERA.COMThe four phasesof the procedurewith the mainmilestone eventsare shown alongthe approximatetimeline. After theprocedure, thesponsor wouldimplement theadvice received fromthe EMA and HTAs.THE EVIDENCE FORUM May 2017

Figure 2. Degree of Agreement between the EMA and HTAs% Agreement by Domain100806040200EMA-HTAHTAPopulationFull AgreementEMA-HTAHTAEMA-HTAComparatorPartial AgreementHTAEndpointsEMA-HTAHTAOther ementThe agreement in responses to questions was analyzed by domains and evaluated by agreement between the EMA andHTAs (EMA-HTA bars) or among HTAs (HTA bar).programs. It allows for a discussion of the scope ofadvice and the appropriateness of the preliminaryquestions. Any comments on the briefing packagefollowing the pre-submission conference will be sentto the sponsor in writing by the EMA. The applicantwill then send the final, revised briefing documentwith all annexes for EMA and HTA validation. Evaluation Phase: Once the briefing package hasbeen validated, the applicant sends it to the EMA andall applicable HTAs via EudraLink. The submission ofthe briefing package marks day one of the scientificadvice procedure. The EMA and HTAs evaluate thebriefing package independently and may send listsof issues to facilitate the discussion. The evaluationphase culminates in a face-to-face meeting to discussthe questions and provide the appropriate feedbackon available and further required evidence forpositive outcomes in a future marketing or pricing/reimbursement application evaluation. Outcome: The EMA and HTAs will provide theiradvice independently. The EMA will provide writtenmeeting minutes within five working days, whereasthe HTAs provide their responses within 15 workingdays in their individually preferred format.The advice provided by the EMA and HTAs isnon-binding.During the procedure, the sponsor can direct questionsto the EMA and HTAs or only to the EMA or the HTAs.Regional and national regulations, as well as otherEVIDERA.COMfactors, will influence the responses of the HTAs and/orthe involvement of further relevant advisory bodies.Tafuri, et al.6 conducted an analysis of the agreementlevel for 31 EMA-HTA parallel scientific advice proceduresconducted between the launch in 2010 and 1 May2015 (cutoff date for the evaluation of the pilot).6 Theprocedures were analyzed based on the meetingminutes and only included those where the evaluation ofagreement between EMA and HTA advice was directlypossible. A total of 375 questions with 588 answersfrom HTAs were evaluated for their agreement with theEMA. Some 70 answers were not ‘assessable’, leavinga total of 518 answers for evaluation. The majority, 61%(317 of 518), were regarded as full agreements, whiledisagreements only accounted for 16% of the answers(83/518 – Figure 2).The analysis further groups the questions into domains:population, comparator, endpoints, other study designs,etc. The population domain includes questions regardingthe inclusion/exclusion criteria, therapeutic indication,biomarkers/subgroups, and extrapolations, while theendpoint domain includes considerations regardingprimary efficacy endpoints, patient-related outcomes,health-related quality of life secondary endpoints, andclinical relevance to effect size. Other study designconsiderations include randomization, treatment duration,dosing, and analysis methods. Tafuri, et al.6 and theEMA’s Report1 find the highest level of agreement forthe population domain with 77% in full agreement and14% in partial agreement. The lowest level of agreement- 44% in full agreement and 25% in partial agreementTHE EVIDENCE FORUM May 2017