Final Report On The Adaptive Pathways Pilot
28 July 2016EMA/276376/2016European Medicines AgencyFinal report on the adaptive pathways pilotSummaryIn March 2014 EMA launched a pilot project to explore the adaptive pathways approach, a scientificconcept of medicines development and data generation intended for medicines that address patients’unmet medical needs.Adaptive pathways seeks to balance timely access for patients who are likely to benefit most from themedicine with the need to provide adequate evolving information on the benefits and risks of themedicine itself.Adaptive pathways is not a new route of approval for medicines. It makes use of existing approvaltools, in particular conditional marketing authorisation, which has been in operation in the EuropeanUnion (EU) since 2006. It also builds on the experience gained with strengthened post-marketingmonitoring tools introduced by the 2012 pharmacovigilance legislation (e.g., post-authorisation studiesand patient registries).The adaptive pathways concept is not meant to be applicable to all medicines, but only to medicinesthat are likely to offer help for a patient population with an unmet medical need, and where the criteriafor adaptive pathways apply.As for any medicine, a marketing authorisation will only be granted if the balance of benefits and risksfor a defined patient population is found to be positive; the same principles and legal tools apply as forany other new medicine.Adaptive pathways can be defined as a prospectively planned, iterative approach to bringing medicinesto market. The iterative development plan will initially target the development to a well-defined groupof patients that is likely to benefit most from the treatment. This is followed by iterative phases ofevidence gathering and progressive licensing adaptations, concerning both the authorised indicationand the potential further therapeutic uses of the medicine, to expand its use to a wider patientpopulation as more data become available.A key aspect of adaptive pathways is the involvement of all relevant decision-makers in the processacross the life span of the medicine, including those who decide about patient access in the MemberStates: to help determine which medicines could be appropriate for adaptive (iterative) development;to jointly agree a data generation plan to meet the needs of regulators and health technologyassessment bodies (HTAs) and to ensure that the use of the medicine is well monitored and managed.The aim of this collaboration is to achieve better patient access to important medicines.30 Churchill Place Canary Wharf London E14 5EU United KingdomTelephone 44 (0)20 3660 6000 Facsimile 44 (0)20 3660 5555Send a question via our website www.ema.europa.eu/contactAn agency of the European Union European Medicines Agency, 2016. Reproduction is authorised provided the source is acknowledged.
All involved stakeholders agree upfront on a plan of post-licensing knowledge generation for amedicine, before it is authorised, and the marketing authorisation holder commits to carrying out thisplan. Once a marketing authorisation has been granted, the post-authorisation plan becomes a legallybinding regulatory obligation.The cooperation between stakeholders and a strong pharmacovigilance system are the basis for thesystematic monitoring of the safety and the overall performance of a medicine in clinical practice;these are the two key elements underpinning the adaptive pathways concept which makes use of thetools provided by the pharmacovigilance legislation to their fullest extent.The pilotIn March 2014 EMA launched a pilot project to explore the practical implications of the adaptivepathways concept with medicines under development. The pilot was designed as a learning exerciseproviding insight into the characteristics of development programmes where the adaptive pathwaysconcept could be applied. EMA invited companies to submit ongoing medicine developmentprogrammes that met the following criteria:1. An iterative development plan, prospectively planned. This means that evidence can beacquired step-wise to either expand the target population from an initial approval in the populationwith high(est) medical need, or to progressively reduce uncertainty with additional data collection afteran initial (conditional) marketing authorisation based on surrogate endpoints, early time points, or asmaller population sample.2. The involvement of HTAs and other downstream stakeholders, with proposals for how thedemands of these stakeholders can be met. As the adaptive pathways development will beiterative, aspects like plans for demonstration and change of the value proposition within an evolvingdata set can be discussed with HTAs; while control of prescription, relevance of early endpoints andrisk management can be discussed with patient representatives.3. Real-world data as a complement to RCTs. in an adaptive pathways proposal, a coherent,prospective plan for real world evidence is designed to collect high-quality data to further refine thebenefit/risk profile, the therapeutic value and the price of a medicine.EMA’s adaptive pathways pilot is now closed, as it has reached the target planned in the interim reportof six products going through parallel EMA-HTA advice.This report reflects the experience gained in the pilot project, discusses the practical findings andoutlines the next steps to further explore the concept. The report also reflects the differentperspectives on the adaptive pathways concept that were collected through a questionnaire circulatedvia the European Commission Expert Group on Safe and Timely Access to Medicines for Patients(STAMP) to the Member States, EUNetHTA and network of Competent Authorities for Pricing andReimbursement (nCAPR), and a company survey conducted within the ADAPT-SMART IMI project.Key figuresEMA received 62 applications. Eighteen proposals were selected for in-depth, face-to-face meetingswith the participation of other stakeholders. At the end of the pilot, seven of these applications hadprogressed to a formal scientific advice (one) or parallel regulatory-HTA scientific advice (six).The pilot received applications covering a wide range of therapeutic areas, with oncology accountingfor a third of the total initial submissions.Final report on the adaptive pathways pilotEMA/276376/2016Page 2/23
The majority of the proposals received did not fulfil the eligibility criteria for the pilot, and applicantshave been advised to pursue traditional development routes. Reasons for non-acceptance in the pilotincluded: development programmes that did not afford scope for expansion and iteration; proposals for areas without unmet need; and late stage development programmes (where no changes to the plan could be effected).Of the proposals accepted into the pilot, some did not progress beyond the initial discussions becausethe subsequent scientific advice on more detailed protocols cast doubt on the feasibility andmethodological robustness of the development plan. If the adaptive pathways approach is no longerdeemed appropriate at a certain point in the medicine’s development, it is possible to revert totraditional development routes.Key learningsThe pilot showed that: adaptive pathways can foster multi-stakeholder dialogue, bringing regulators, interested HTAs,healthcare professionals and patients around the same table to discuss a product developmentparadigm for medicines addressing unmet medical needs. Agreement between stakeholders can bereached on a prospective approach to evidence generation across the lifespan of a medicine inareas of high unmet need, with a view to optimising and aligning their requirements as much aspossible; the benefit of adaptive pathways lies in appropriate prospective planning to incorporate multiplestakeholders’ requirements upfront to avoid the need to request additional studies later indevelopment, and in exploring the full potential of utilising the real world evidence generated inclinical practice to refine regulators’ and other stakeholders’ decisions; as the proposed evidence set makes use of different data sources aiming to create a commonevidence base to address both regulators’ and HTAs’ needs, consulting all concerned decisionmakers on their respective requirements is essential; adaptive pathways can support medicine development in therapeutic areas where evidencegeneration is challenging, such as infectious diseases, Alzheimer’s disease, degenerative diseases,and rare cancers; adaptive pathways should focus on medicines that can plausibly address an unmet medical needin a defined population, where there is scope to explore feasible data collection plans (randomisedcontrolled trials (RCTs) and registries) based on reliable, clear-cut and actionable endpoints; adaptive Pathways is not a suitable approach for the development of all products. Certain preconditions have to be met for adaptive pathways, such as:- the availability of clear-cut, actionable endpoints for post-authorisation decision making ofregulators and HTAs (and - if relevant - payers);- the setting of checkpoints across the development pathway to revise and adjust thedevelopment programme to the level of evidence required by the decision makers;- controllable prescription so that the medicine can only be prescribed to the patient population forwhich the benefit/risk has been demonstrated;Final report on the adaptive pathways pilotEMA/276376/2016Page 3/23
- the ability to arrange managed entry agreements and entry and exit strategies if these areconsidered relevant by the concerned stakeholders. the regulatory framework offers robust mechanisms to ensure close monitoring of a medicine’sbenefits and risks once it is on the market, and that prompt regulatory reassessment and actioncan be taken if needed. Development plans should make use of these tools in an optimal andconvincing way in order to be accepted by regulators. When the proposed plan for the collection ofpost-authorisation data is not considered feasible or robust enough, companies have been advisedto pursue a traditional development route. pre-requisites for companies to come forward and discuss early developments in the setting ofadaptive pathways include trust in the non-binding nature of adaptive pathways, and an openmindset to consider a flexible lifecycle development, including the discussion of potential scenarios.These qualities enable productive interaction and facilitate the understanding of the advantages,requirements and constraints behind each proposed development route.Issues identified for further reflection Involvement of patients and healthcare professionalsIncreased patient participation in the future will assist in the selection of candidates for whichaccelerating access is particularly desirable, and to provide insights on feasibility and ethical aspects,and to support enrolment in trials and registries. Input from healthcare professionals on the feasibilityof implementing patient registries in clinical practice and on the control of prescription should besought.Further discussions on the application of the current definition of unmet need in the adaptivepathways setting (unmet medical need, public health need, healthcare cost savings) with thecompetent stakeholders would be helpful. Post-authorisation data gathering plansThe challenge remains to identify methodologically sound strategies of real-world evidence collection tosupport the assessment of both efficacy and effectiveness. These issues need to be discussed further inappropriate stakeholder fora and research programmes. Involvement of payersMember States’ organisations and entities responsible for decisions on pricing and reimbursement onthe basis of HTA body recommendations (referred to as ‘payers’ in this report) were not part of thepilot discussions. In some cases, which needed input on the design, acceptability and feasibility ofadaptive pricing strategies linked to the data collection, payers’ input on the principles and feasibility ofsuch schemes would be important early in the process if they are envisaged as part of thedevelopment plan. In line with the Council conclusions1, possible synergies between the work ofregulatory bodies, HTA bodies and payers, in order to ensure timely and affordable access of patientsto innovative medicines, may be explored in the future.Next stepsEMA will further explore the adaptive pathways concept as an approach to bringing promisingmedicines to patients with an unmet need in a timely manner.1Council conclusions on strengthening the balance in the pharmaceutical system in the EU and its Member armaceutical-system/Final report on the adaptive pathways pilotEMA/276376/2016Page 4/23
Future discussions on adaptive pathways will be incorporated into the existing operational platform ofEMA parallel regulatory-HTA scientific advice, with the inclusion of other stakeholders (patients,interested HTAs and, if relevant, payers will also be invited) relevant to the specific issues underdiscussion. An additional pre-submission meeting (two for SMEs) will be granted as compared to theparallel regulatory-HTA scientific advice.Adaptive pathways is still a concept in development which will be fine-tuned as more medicines indevelopment are considered for this approach.EMA values contributions from stakeholders on its initiatives, as feedback and open debate areessential for adapting and fine-tuning concepts and approaches and ensuring that they meetstakeholders’ expectations.EMA will organise a workshop in the fourth quarter of 2016 to gather the views and proposals from itsstakeholders on the adaptive pathways approach.Final report on the adaptive pathways pilotEMA/276376/2016Page 5/23
ContentsSummary . 1The pilot . 2Key figures . 2Key learnings . 3Issues identified for further reflection . 4Next steps . 41. Introduction and background . 72. Experience from the pilot . 92.1. Medicines in development submitted in the pilot. 102.2. Involvement of stakeholders . 122.3. Use of Real-world data . 132.4. Marketing authorisation route . 142.5. Prescription control . 142.6. Chemical, Manufacturing and Controls (CMC) issues . 153. Products submitting a parallel regulatory-HTA scientific advice . 154. Key learnings and issues identified for further reflection . 165. Next steps . 226. List of abbreviations . 23Final report on the adaptive pathways pilotEMA/276376/2016Page 6/23
1. Introduction and backgroundStriving to ensure that patients have timely access to promising medicines is an important goal forpublic health and should be undertaken in a way that does not compromise patients’ safety. TheAgency uses a wide range of regulatory mechanisms to achieve these aims, and continuously reviewsand improves its processes. A number of early access tools for medicines addressing unmet medicalneeds have been available in the EU for many years. These include, compassionate use programmes2,accelerated assessment, reinforced recently with the introduction of the PRIME scheme, andconditional marketing authorisation (CMA). An overview of existing tools is available on the EMA website.In March 2014 EMA launched a pilot project to explore a concept of medicines development and datageneration intended for medicines that address patients’ unmet medical needs – the adaptivepathways approach. This report provides further information on the adaptive pathways concept andexperience gained with the pilot.Figure 1What is adaptive pathways?Adaptive pathways can be defined as a prospectively planned, iterative approach to bringing medicinesto market. The iterative development plan initially targets the development to a well-defined group ofpatients that is likely to benefit most from the treatment. This is followed by iterative phases of2http://www.ema.europa.eu/docs/en GB/document library/Other/2016/03/WC500202631.pdfFinal report on the adaptive pathways pilotEMA/276376/2016Page 7/23
evidence gathering and progressive licensing adaptations, concerning both the authorised indicationand the potential further therapeutic uses of the medicine, to expand its use to a wider patientpopulation as more data become available.Adaptive pathways seeks to balance timely access for patients who are likely to benefit most from themedicine with the need to provide adequate evolving information on the benefits and risks of themedicine itself.Adaptive pathways is not a new route of approval for medicines. It makes use of existing approvaltools (Figure 1), in particular conditional marketing authorisation, which has been in operation in theEU since 2006. It also builds on the experience gained with strengthened post-marketing monitoringtools introduced by the 2012 pharmacovigilance legislation (e.g. post-authorisation studies, patientregistries) that facilitate the gathering of real-world data post-authorisation.As for any medicine, a marketing authorisation will only be granted if the balance of benefits and risksfor a defined patient population is found to be positive; in other words, the same criteria and legaltools will apply as for any other new medicine.The adaptive pathways concept is not meant to be applicable to all medicines, but only to medicinesthat are likely to address an unmet medical need, and where the criteria of adaptive pathways apply: astaggered approval from very small, restricted patient populations to increasingly wider populations; abinding plan of post-licensing evidence gathering; and involvement of key stakeholders in the process.A key aspect of adaptive pathways is the involvement of all relevant decision makers in the medicine’slifecycle. Dialogue between all these actors is important across the life span of the medicine to helpdetermine which medicines could be appropriate for adaptive (iterative) development; to jointly agreea data generation plan to meet the needs of regulators and HTA bodies and to ensure that the use ofthe medicines (i.e. restricted prescribing) is well monitored and managed.This allows for agreement to be reached upfront on a development plan that meets the datarequirements for the benefit-risk assessment carried out by regulators and also for the assessment ofa medicine’s added value carried out by HTA bodies. The aim of this collaboration is better patientaccess to important medicines.All involved stakeholders agree upfront on a plan of post-licensing knowledge generation for amedicine, before it is authorised, and the marketing authorisation hold
EMA/276376/2016 . European Medicines Agency . Final report on the adaptive pathways pilot . Summary In March 2014 EMA launched a pilot project to explore the adaptive pathways approach, a scientific concept of medicines development and data generation intended for medicines that address patients’ unmet medical needs.
May 02, 2018 · D. Program Evaluation ͟The organization has provided a description of the framework for how each program will be evaluated. The framework should include all the elements below: ͟The evaluation methods are cost-effective for the organization ͟Quantitative and qualitative data is being collected (at Basics tier, data collection must have begun)
Silat is a combative art of self-defense and survival rooted from Matay archipelago. It was traced at thé early of Langkasuka Kingdom (2nd century CE) till thé reign of Melaka (Malaysia) Sultanate era (13th century). Silat has now evolved to become part of social culture and tradition with thé appearance of a fine physical and spiritual .
On an exceptional basis, Member States may request UNESCO to provide thé candidates with access to thé platform so they can complète thé form by themselves. Thèse requests must be addressed to esd rize unesco. or by 15 A ril 2021 UNESCO will provide thé nomineewith accessto thé platform via their émail address.
̶The leading indicator of employee engagement is based on the quality of the relationship between employee and supervisor Empower your managers! ̶Help them understand the impact on the organization ̶Share important changes, plan options, tasks, and deadlines ̶Provide key messages and talking points ̶Prepare them to answer employee questions
Dr. Sunita Bharatwal** Dr. Pawan Garga*** Abstract Customer satisfaction is derived from thè functionalities and values, a product or Service can provide. The current study aims to segregate thè dimensions of ordine Service quality and gather insights on its impact on web shopping. The trends of purchases have
Chính Văn.- Còn đức Thế tôn thì tuệ giác cực kỳ trong sạch 8: hiện hành bất nhị 9, đạt đến vô tướng 10, đứng vào chỗ đứng của các đức Thế tôn 11, thể hiện tính bình đẳng của các Ngài, đến chỗ không còn chướng ngại 12, giáo pháp không thể khuynh đảo, tâm thức không bị cản trở, cái được
Le genou de Lucy. Odile Jacob. 1999. Coppens Y. Pré-textes. L’homme préhistorique en morceaux. Eds Odile Jacob. 2011. Costentin J., Delaveau P. Café, thé, chocolat, les bons effets sur le cerveau et pour le corps. Editions Odile Jacob. 2010. Crawford M., Marsh D. The driving force : food in human evolution and the future.
Le genou de Lucy. Odile Jacob. 1999. Coppens Y. Pré-textes. L’homme préhistorique en morceaux. Eds Odile Jacob. 2011. Costentin J., Delaveau P. Café, thé, chocolat, les bons effets sur le cerveau et pour le corps. Editions Odile Jacob. 2010. 3 Crawford M., Marsh D. The driving force : food in human evolution and the future.
