THE CLINICAL, REGULATORY & COMMERCIAL IMPLICATIONS OF RAPID APPROVAL 12 JULY 2016 ST. PANCRAS RENAISSANCE HOTEL LONDON 1
Placeholder for speaker photo PAREXEL to insert THOMAS SHOOK, M.D. Executive Vice President, Clinical Research Services and Senior Medical Officer PAREXEL International Welcome & Introduction 2
Placeholder for speaker photo PAREXEL to insert EDITH FRÉNOY Director of Market Access European Federation of Pharmaceutical Industries and Associations (EFPIA) The Opportunity Presented in Rapid Approvals: Getting Medicines to Patients Faster 3
ABOUT EFPIA The European Federation of Pharmaceutical Industries and Associations (EFPIA) represents the pharmaceutical industry operating in Europe. Through its direct membership of 33 national associations and 40 leading pharmaceutical companies, EFPIA is the voice on the EU scene of 1,900 companies committed to researching, developing and bringing to patients new medicines that will improve health and the quality of life around the world. 4
POINTS TO ADDRESS The opportunity The challenge Temporary fixes? The case for change A longer-term view Supportive action 5
BOSTON, MASSACHUSETTS THE OPPORTUNITY 6
MEDICINES ARE SOME OF THE MOST POWERFUL TOOLS IN TREATING AND CURING DISEASES 2006: First vaccine for the prevention of cervical cancer First Rx for chronic chest pain in 20 years First once-a-day HIV medicine 2012: First drug to target root cause of cystic fibrosis First drug to treat Cushing s disease 2004: First anti-angiogenic medicine for cancer New Rx for most common form of lung cancer 2008: A new type of treatment for Crohn s disease The first Rx for symptoms of Huntington s disease 2010: 2 new multiple sclerosis drugs First therapeutic cancer vaccine 2014: Oral treatments for HepC provide cure rates upwards of 90% 17 new drugs to treat patients with rare diseases 7,000 medicines in development around the world 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2005: First new kidney cancer Rx in over a decade 3 new therapies for diabetes 2007: New class of medicines to treat high blood pressure First treatment for fibromyalgia 2009: First treatment for peripheral T- cell lymphoma First new Rx for gout in 40 years 2011: First lupus drug in 50 years 2 new personalized medicines First Immuno-Oncology for metastatic melanoma 2013: 2 new personalized medicines to treat the most dangerous forms of skin cancer A new oral treatment for multiple sclerosis Note: Dates of innovation provided by the US Food and Drug Administration (FDA) Source: Health Advances analysis; PhRMA 2015 Biopharmaceuticals in Perspective 7
FOR CANCER PATIENTS, LIFE EXPECTANCY CONTINUES TO IMPROVE The use of innovative medicines has made major contribution to recent advances. 77.0 76.5 76.0 Increase of 1.74 From 2000 2009, an improvement in population weighted mean life expectancy at birth of 1.74 years was seen across 30 OECD countries. 75.5 73% 75.0 74.5 74.0 73.5 73.0 72.5 27% Innovative medicines are estimated to have contributed to 73% of this improvement once other factors are taken into account (e.g., income, education, immunization, reduction in risk factors, health system access). 72.0 2000 Other Contribution of Innovative Medicines 2009 Source: Lichtenberg, F: Pharmaceutical innovation and longevity growth in 30 developing OECD and high-income countries, 2000-2009 (2012) 8
MEDICINES ARE TRANSFORMING OUTCOMES FOR PATIENTS LIVING WITH CHRONIC DISEASE Cardiovascular Disease In Europe, biopharmaceutical companies are currently developing 172 medicines* to treat heart disease, stroke and other cardiovascular diseases. 1 New PCSK9 inhibitors have revolutionized therapy for high cholesterol. Between 2000 and 2012, the death rate from cardiovascular disease fell 37% in the EU5, 27% in Japan, and 5% in Mexico. 2 Diabetes Between 2000 and 2012, new therapies contributed to a 48% and 31% decline in the diabetes death rate in Korea and Canada, respectively. 2 Rheumatoid Arthritis The recent introduction of disease-modifying therapies has dramatically improved the lives of patients and caregivers by slowing and sometimes even reversing negative physical symptoms of the disease. 3 Death rates for noncommunicable diseases declined nearly 20% in the EU5, Australia, Canada, and Japan from 2000 to 2012 2 *Medicines in Phase I through III of development Note: The 4 main types of non-communicable diseases, also known as chronic diseases, defined by WHO are cardiovascular diseases (e.g., heart attacks and stroke), cancers, chronic respiratory diseases (e.g., chronic obstructed pulmonary disease and asthma) and diabetes Source: Health Advances analysis; 1 PharmaProjects (accessed February 2016); 2 WHO Mortality Database (accessed February 2016); 3 PhRMA 2015 Pharma Profile 9
BIOPHARMACEUTICAL COMPANIES HAVE MADE CONTINUED ADVANCES AGAINST RARE DISEASES There are approximately 7,000 different rare diseases worldwide 1 in 10 individuals in the USA and Europe are living with a rare disease 1 There are 119 OMPs authorised in the EU A-alimentary tract & metabolism B - blood & blood forming organs C - cardiovascular system D - dermatology G - genito urinary tract H - systemic hormonal preparations J & P - antiinfectives & antiparasitic L - antineoplastic agents L - immunomodulating agents M & N - musculoskeletal & nervous system R - respiratory system S - sensory organs V - various Distribution of Opinions by Therapeutic Area from Year 2000 2014 Total Opinions 1,430 7% 12% 6% 5% 2% 36% 11% 7% 3% 5% 2% 1% 3% Rare Disease Big Impact Source: Health Advances analysis; 1 PhRMA 2013 Rare Diseases Report Source: Alexis Schimmings, New active substances launch plummet, Scrip Intelligence Unit. Available at: http://www.scripintelligence.com/home/new-active-substance-launches-plummet-363577 10
TAIPEI, TAIWAN THE CHALLENGE 11
THE BIOPHARMACEUTICAL RESEARCH AND DEVELOPMENT PROCESS From drug discovery to EMA approval, developing a new medicine on average takes at least 10 years Basic Research Drug Discovery Pre- Clinical Clinical Trials EMA Review Post-Approval Research and Monitoring Post-Approval Research and Monitoring Phase 1 Phase II Phase III Phase IV 1 EMA- APPROVED MEDICINE POTENTIAL NEW MEDICINES Note: *The average R&D cost required to bring a new, FDA approved medicine to patients is estimated to be $2.6 billion over the past decade (in 2013 dollars), including the cost of the many potential medicines that do not make it through to FDA approval Key: IND: Investigational New Drug Application, NOA: New Drug Application. BLA: Biologics License Application Source: PhRMA 2016 Prescription Medicines: Costs in Context 12
COMPLEXITY OF THE REVIEW PROCESS Source: EuroStat (http://epp.eurostat.ec.europa.eu) Population of 501,103,425 as of 1 January 2010 13
DIFFERENCES IN NATIONAL REIMBURSEMENT REVIEW PROCESSES LEAD TO VARIATIONS IN TIME TO ACCESS Average Time to National Patient Access to Necessary Therapeutics Months Post Approval Approval 3 6 9 12 15 18 Limited Patient Access to Innovative Medicines Note: Timelines for EU5 countries are based on products with first sales in 2014. Timelines for Spain, Italy, UK, and France represent time to pricing and reimbursement approval. In Italy and Spain, additional time may be required for regional or local negotiations. Timeline for Japan may range from 2-3 months, and represents a conservative estimate based on publicly-available descriptions of the pricing and reimbursement approval process. Switzerland s separate regulatory approval may take at least 4-5 additional months after submission by manufacturer over timeline above. Norway is also not in EU and will need to formalize the EU approval, which may take at least 1 additional month. Source: Health Advances analysis; 1 ANSM 2014 Annual Report; 2 MHRA March 2015 EAMS Scientific Opinion for pembrolizumab 14
BOSTON, MASSACHUSETTS TEMPORARY FIXES? 15
REGULATORY Conditional marketing authorisations Marketing authorisations under exceptional circumstances Not used to their full potential 16
Source: Presentation by European Commission, Olga Salomon, STAMP meeting of May 2015 17
NATIONAL EARLY ACCESS PROGRAMMES Source: ISPOR 15th Annual European Congress, Berlin, Germany, November 3-7, 2012. Poster ref: PHP147 18
NATIONAL EARLY ACCESS PROGRAMMES, CONT. Source: ISPOR 15th Annual European Congress, Berlin, Germany, November 3-7, 2012. Poster ref: PHP147 19
ETA/ETR: WHAT IS IT? Belgium ETA: Early Temporary (market) Authorization Early: Can be asked before obtaining regular MA No limits concerning moment of application Temporary: Limited in time Expires when replaced by regular MA How? CU/MNP evaluated by FAGG/AFMPS Draft royal decree changes rules on CU/MNP in general Source: pharma.be internal presentation 20
ETA/ETR: WHAT IS IT? Belgium ETR: Early Temporary Reimbursement Early: Must be asked before one can ask for regular reimbursement Can be asked even before regular MA At the earliest: 6 m. before application for regular MA Temporary: Limited in time (4 y. max.) Does not replace regular reimbursement procedure Not possible when one can apply for regular reimb. (CHMP adv.) Obligation to ask regular reimb. 6 m. after moment that one can introduce regular reimbursement application Expires when replaced by regular reimbursement Source: pharma.be internal presentation 21
BERLIN, GERMANY THE CASE FOR CHANGE 22
TODAY MORE THAN 7,000 MEDICINES ARE IN DEVELOPMENT AROUND THE WORLD TARGETING AREAS OF HIGH UNMET NEED Medicines in Development Worldwide 2,000 1,813 1,500 1,329 1,256 1,120 1,000 500 599 511 475 159 0 Cancers Neurological Disorders Infectious Diseases Immunological Disorders Cardiovascular Disorders Mental Health Disorders Diabetes HIV/AIDS Biopharmaceutical companies are focusing on areas of high unmet need Biopharmaceutical companies have made significant gains in key disease areas Note: Defined as single products which are counted exactly once regardless of the number of indications pursued. Source: Health Advances analysis; Adis R&D Insight Database HIV/AIDS is now a manageable, chronic disease, thanks to prior advances in biopharmaceutical research 23
DISEASE DIAGNOSIS ENABLES A TARGETED APPROACH TO PERSONALISED MEDICINES The evolution of molecular characterization and targeted therapeutics has led to a decrease in the average lung cancer death rate in the United Kingdom by 37% since 1980 Age-standardized death rates per 100,000 world standard population over time 1 45.1 deaths per 100,000 32.6 deaths per 100,000 30.5 deaths per 100,000 28.4 deaths per 100,000 1980 2000 2007 2012 Adenocarcinoma KRAS Undefined KRAS EGFR Undefined ALK HER2 PI3K KRAS EGFR Undefined 0 identified 1 identified 5 identified 12 identified ALK HER2 ROS1 BRAF RET MEK PI3K MET NRAS AKT1 Identified Mutations/Rearrangements over Time 2,3 Note: WHO Mortality Database age-standardized death rates per 100,000 for malignant neoplasm of trachea, bronchus and lung. Source: Health Advances analysis; 1 WHO Mortality Database (accessed February 2016); 2 My Cancer Genome website Molecular Profiling of Lung Cancer; 3Pao 2012 Chipping away at the lung cancer genome Nat Med. 24
MEDICINES OFTEN DEMONSTRATE FAR GREATER BENEFITS THAN UNDERSTOOD AT TIME OF APPROVAL Oncology therapeutics demonstrate increasing clinical value over time long after initial approval Use in earlier lines of treatment and earlier in stages of the disease Use in additional disease indications Use in combination with other agents Use in combination with specific biomarkers Year 4: Additional Indication Mantle Cell Lymphoma (MCL) Second Line Year 6: Approved for Use Earlier in Line of Treatment MM First Line Year 11: Approved for Use Earlier in Line of Treatment MCL First Line Year 1: Initial Approval Multiple Myeloma (MM) Third Line Year 3: Approved for Use Earlier in Line of Treatment MM Second Line Additional Patients Benefiting Added Clinical Value Over Time Note: Representation of the change in clinical value over time in the US as additional data and evidence became available for Bortezomib Source: Health Advances analysis; Boston Healthcare Assoc. 2015 The Value of Innovation in Oncology 25
MEDICINES OFTEN DEMONSTRATE FAR GREATER BENEFITS THAN UNDERSTOOD AT TIME OF APPROVAL Many cancer medicines provide years of extra life but media attention is often focused on soon after launch and/or in late stage patients before it has had the chance to prove long-term value. Metastatic use Adjuvant use Oncology medicines typically launched only in metastatic setting. (i.e., very sick patients that have failed on other therapies with poor prognosis) Measured outcomes for such patients by definition will be relatively poorer Once an oncology medicine is more established it can be used in an adjuvant setting (i.e., patients with a better prognosis before tumours have spread) Measured outcomes, by definition for such patients often better than patients whose cancer is more advanced Early assessment can show relatively poor value for money but such static assessments do not reflect value over the lifecycle Often prices that were seen as high when initially assessed are seen as highly cost effective by the time a medicine is in adjuvant use Important to consider value over the lifecycle 26
A LONGER-TERM VIEW 27
ADAPTIVE PATHWAYS: WHY? To address an unmet need To overcome difficulties in following a conventional development plan To increase the B/R To decrease the time of uncertainty To plan the evidence generation Source: Guido Rasi, HTAi Annual Meeting, May 2016 28
THE ADAPTIVE PATHWAYS CONCEPT: ITERATION 1) Conditional approval scenario Knowledge required for full approval 1st approval 2nd approval AP route 2) Expansion of indication scenario AP route Source: EMA slide at Commission expert group on rare diseases, November 2015 29
EXISTING SUPPORT TOOLS FOR ADAPTIVE PATHWAYS During development Joint or parallel early dialogue or advice offered by Regulatory Agencies and/or HTA Marketing authorisation* Approval in sequential stages (e.g., using conditional approval, post-approval safety and efficacy studies, risk management plans, periodic safety update reports, license renewal procedures) Post-approval Gathering evidence through real-life use to supplement clinical trials data *MAPPs does not change the standards for the evaluation of the benefit/risk balance required to grant a marketing authorisation from a quality, safety and efficacy point of view. Source: Presentation by A Joos / M Boudes / JL Roux, Adapt Smart multi-stakeholder workshop on selection criteria, 29 February, Amsterdam 30
IMPLICATIONS BEYOND REGULATORY Joint scientific advice (SA) Joint process or parallel early for dialogue design or of advice randomised offered by controlled trials (RCTs) and Regulatory other Agencies studies and/or HTA During development Iterative HTA recommendations, Approval in starting sequential stages, with e.g. European using conditional Relative approval, post-approval safety and efficacy studies, risk Efficacy Assessment (EU management REA) at time plans, periodic of launch safety update and followed reports, license by Managed Entry Agreements renewal (MEA) procedures Marketing authorisation* Joint scientific advice (SA) process for design of randomised Post-approval controlled trials (RCTs) and other studies Gathering evidence through real-life use to supplement Clinical Trials data *MAPPs does not change the standards for the evaluation of the benefit/risk balance required to grant a marketing authorisation from a quality, safety and efficacy point of view. 31
HTA V Regulators % agreement MAKING THE CASE 56 products 100 80 60 40 20 0 Population Endpoints Comparator Recommendation http://www.efpia.eu/documents/189/61/hta-accelerator-in-depth-analysis-final-report Source: Guido Rasi, HTAi Annual Meeting, May 2016 32
HTA V Regulators % agreement CAN PARALLEL ADVICE HELP? Commonality? 100 80 60 40 20 0 Population Endpoints Comparator Overall Package Source: Guido Rasi, HTAi Annual Meeting, May 2016 Parallel Advice DIA EuroMeeting 33
ITERATIVE HTA REC. INDUSTRY VIEWS At launch Based on European joint relative efficacy assessment (EU REA) fully integrated into a comprehensive national HTA EU REA based on randomised controlled trial (RCT) data discussed in joint scientific advice (SA) process Supporting initial pricing and reimbursement decision 34
EU REA report Local considerations Decision-maker Description of the health problem Local issues related to the health problem The technology & its place in treatment pathway Local treatment pathway Relative Efficacy Appraisal recommendation Local coverage decision Relative Safety Key Economic considerations Joint Local Social values / ethical & legal issues 35
ITERATIVE HTA REC. INDUSTRY VIEWS Over time Subsequent national HTA based on additional evidence generation Feeding into managed entry agreements (MEA) These questions can be answered based early evidence from Phase I and Phase II studies Source: HTAi 2016 Annual Meeting, Tokyo, Japan 36
EXPERIENCE OF MEAS IN THE CONTEXT OF CMA Out of the 17 products with conditional approval or approval under exceptional circumstances which were discussed on our interviews, only 9 products were reported to have been subject to some form of MEA (both financial and outcomes based or a mix) 5 reported cases of financial agreements Subject to outcome-based agreements 4 reported cases of outcome-based agreements for oncology products (across 3 different countries) Oncology (no OMP) 6 5 We did not find outcomes-based agreements for orphan medicinal product (OMP) with CMA Oncology OMP Orphan Medicinal Product 6 There was a consensus amongst OMP manufacturers that given small patient pop. and the administration cost involved, outcomes-based scheme for orphan drugs were not warranted Subject to financial agreements Source: CRA report on MEA for CMA products Given high level of uncertainty and greater patient population, oncology products (without OMP status) with CMA appear to be more likely to be subject to outcomes-based MEA 37
DATA REQUESTED BY REGULATORS VS. PAYERS FOR PRODUCTS WITH CMA SUBJECT TO OUTCOMES-BASED MEAS Product Therapy area CMA Data request by EMA Type of MEA Payer data requested Product 1 Oncology mrcc Conditional Approval Review of Phase III data Conditional reimbursement (Czech republic) Not specified Product 2 Oncology NSCLC Conditional Approval Information on patient population for proof of epidemiology-eligible patient population. Phase IV trial was conducted Conditional reimbursement (Poland) Local clinical & epidemiological data (to support the reimbursement application (e.g., drawing data from electronic medical records) Product 3 Oncology CML Conditional Approval A larger study on specific patients sub population previously treated with one or more tyrosine-kinase inhibitors Conditional reimbursement (Sweden) Uncertainty in the clinical efficacy for the indicated patient population due to lack of clinical trial information Product 4 Oncology BCC Conditional Approval Additional safety study in specific patients sub population Combination of discounts & payment-by-result (Italy) Concerns on the safety and efficacy - requested additional safety data for specific sub populations Metastatic renal cell carcinoma (mrcc); non-small cell lung cancer (NSCLC); Chronic myeloid leukaemia (CML); Advanced Basal Cell Carcinoma (adv BCC) Source: CRA report on MEA for CMA products 38
WHAT IS NEEDED TO ENSURE MEAS CAN SUPPORT ADAPTIVE PATHWAYS? AN INDUSTRY PERSPECTIVE Alignment of data requirements between payers and regulator could mean that improved evidence development for MAPPs could mean greater use of outcomes-based agreements If there was the possibility to do so, many companies indicated they would be keen to explore such opportunities (as this allows price to reflect data on the value of the product) This is especially relevant in oncology products where effectively measuring health outcomes and determining clinical end points is becoming more and more relevant In today s context it is perhaps less so for orphan medicines considering the current transaction costs involved in developing additional data collection mechanism on low numbers of patients In this case there would be value in EMA coordinating with payers/htas about the additional real-world data evidence requirements This would then provide a signal for local/regional registries and regional coordinators to collect the required data with the simplest method possible 39
TAIPEI, TAIWAN SUPPORTIVE ACTION 40
PUBLIC PRIVATE PARTNERSHIP IMI Address Bottlenecks of Innovation Industry consortium IMI office = Neutral broker Process owner EU Commission In-kind contribution Value of companies' contribution = EU funding available for public partners FTEs + cash In kind translated into EU Commission matches the industry contribution Total project budget 41
MAPPS AND ADAPT-SMART MAPPS (Medicines Adaptive Pathways to Patients) is a concept that, based on scientific advances, seeks to provide timely access to medicines with potential to address unmet need(s) in specific, well-defined patient populations, in a sustainable way MAPPs cover development and regulatory approval, HTA value assessment, pricing/reimbursement decisions, and access MA and reimbursement/access decisions are made using a framework which supports the launch of a therapy based on early initial evidence Data generated post-marketing Authorisation should support progressive decrease of benefit/risk uncertainty and may lead to adjustment(s) in use, in response to the emerging RWE and eventual supplemental clinical trial data ADAPT-SMART is an IMI2 Coordination and Support Action (CSA - running to end 2017) investigating and exploring conditions and feasibility of the MAPPS concept within the current EU regulatory/legal context 42
HOW WOULD SUCCESS FOR ADAPT-SMART LOOK? (FROM AN INDUSTRY VIEW-POINT) Aligned understanding by all stakeholders How a better planned development would enable the earliest possible and sustainable access for specific novel and promising medicines in welldefined patient groups, including post-marketing Authorisation data gathering/reporting and review What is the balance of prospectively planned Randomised Controlled Trials and trials based on routinely collected evidence (Real-World Evidence) in well-defined patient populations in adaptive pathways Effective, open platform for dialogue with all stakeholders on all questions Operational predictability for companies (big and small): Road map on MAPPs criteria/tools, on methodologies/timelines, on the stakeholders to be involved at every step, and on data requirements/standards Understanding on how adaptive pathways fit in a global development framework Setting up mechanisms for continued engagement post-adapt-smart, based on its outcome(s) 43
GET REAL: OUR GOAL To show how real-world evidence can be adopted in medicine development and healthcare decision making and provide the tools required to achieve this. Software Patient and methodology data Case studies Clinical trials Network analysis Identifying the efficacy effectiveness gap and signalling solutions Innovative approaches to study design and analytics Analytical software Toolboxes and framework Guide study design Inform decision making Real-World Evidence Navigator to guide strategy, design, and interpretation by all stakeholders PragMagic to guide pragmatic trial implementation Support HTA interpretation Educate Education and Policy training Education of stakeholders HTA and end users in the use and implications of Real- R&D World Evidence is key to ensure the legacy of GetReal Academia Industry 44
GET REAL: OUR GOAL To show how real-world evidence can be adopted in medicine development and healthcare decision making and provide the tools required to achieve this. Patient data Guide study design Inform decision making Policy Case studies Network analysis HTA R&D Academia Clinical trials Support HTA interpretation Educate Industry 45
IMI BIG DATA FOR BETTER OUTCOMES (BD4BO) Goal: Support the evolution towards outcomes-focused and sustainable healthcare systems, exploiting the opportunities offered by big and deep data sources in COORDINATION AND SUPPORT ACTION (CSA) EUROPEAN DISTRIBUTED DATA NETWORK 1 2 3 4 Design sets of standard outcomes and demonstrate value Increase access to high quality outcomes data Use data to improve value of HC delivery Increase patient engagement through digital solutions ROADS: ALZHEIMER'S DISEASE HEMATOLOGIC MALIGNANCIES CARDIOVASCULAR DISEASES RARE CANCERS... ADDITIONAL TOPICS... 46