1. An agency of the European Union The older patient. Can the EMA assist in determining cost-effectiveness of treatments? Presented by: Francesca Cerreta – EMA Safety and Efficacy of medicines

2. What does EMA do? 1 What do HTA bodies do? HTA bodies carry out their own assessments of medicines once they have received a marketing authorisation. HTA bodies compare the relative effectiveness of medicines and take their financial cost into account. This can lead to differences in the types of studies needed to support the assessment carried out by regulators and HTA bodies. The Agency is responsible for the scientific evaluation of applications for medicines in the European centralised procedure. This benefit-risk assessment forms the basis for EU marketing authorisations.

3. 2 Precedents (compounds with same/ similar MoA, recent assess- ment procedures, etc.) Project-specific data (from pharmaceutical, non- clinical and clinical develop- ment including publications) Constraints (legal requirements, regula- tory guidelines, scientific advice received) Development strategy to achieve the Target Product Profile Generate data for Regulatory Approval and Health Technology Assessment Defining a Strategy

4. EMA / HTA Dialogue 3 Mandate from High Level Pharmaceutical Forum in 2008: EMA, Member States and HTAs should cooperate so that Assessment Report can contribute to relative effectiveness assessment (EPAR improvement project) Cross Border healthcare directive 2011/24/EU: support of the collaboration activities of the voluntary network of HTA agencies Exchange on scientific / methodological principles between Regulators and HTAs beneficial to avoid double-standards: Parallel Scientific Advice/Early dialogue Consultation on Guidelines (now routine) Relative effectiveness assessment Databases for post-marketing data generation Specific measures for orphan medicines

5. Parallel HTA-EMA Scientific Advice - examples  Diabetes, Heart Failure,  Alzheimer’s, Depression,  Lung Cancer, Breast Cancer, Melanoma, Pancreas-Ca, Mesothelioma  Asthma, Rheumatoid Arthritis  Multi-resistant Infections,  Food Allergies  Orphan conditions The majority had new mechanisms of action (new monoclonal antibodies, new chemicals, tumour vaccines) HTAs and payers from UK, Sweden, France, Italy, Netherlands, Spain, Germany, Belgium 14 big companies, 2 SMEs 4

6. First experiences with Parallel Regulatory/HTA Scientific Advice5 5 Topic Areas Note: based on first 11 procedures.

7. Some discussion examples Is impact to the caregiver an important piece of the value proposition when evaluating a treatment for prodromal Alzheimer’s disease? Advice on selection of instruments in the clinical trial to capture the burden to the caregiver (Dependence Scale)? Value of MRI imaging as indicator of progression of atherosclerosis? If final data on cardiovascular events cannot be provided for diabetes preauthorisation what alternatives are there for the company from the Regulators and HTA point of view? The cost-effectiveness of the product will be strongly influenced by the extent to which treatment prolongs the prodromal Alzheimers disease phase, delaying progression to more costly states associated with potentially lower quality of life and greater cognitive impairment. This would potentially result in a greater proportion of residual life being spent with lower disability and lower medical costs. However, delaying progression may also extend life expectancy and time in the moderate and severe disease states, which could result in higher total lifetime costs and reduce the cost-effectiveness of treatment. Modelling will be necessary to project out the implications of potential post-trial scenarios. Advice on approaches taken to establish the most plausible scenario and required analyses to support the plausibility of the scenario? 6

8. What about older patients? 7 Major consumers of medications ADRs hospital admissions significantly higher in older people Incidence on pharmaceutical and healthcare costs - sustainability

9. 8 Medicines used by geriatric patients must be of high quality, and appropriately researched and evaluated.. for use in this population. EMA Geriatric medicines strategy (2011): TWO PRINCIPLES Improve the availability of information on the use of medicines for older people Informed prescription Evidence based medicine

10. 9 Evidence based medicine (1) Potential questions Is the clinical trial population representative of real-life? Cost-effectiveness over established (generic) comparator What do we know about the risk of polymedication? Will frail patients have the same benefit/risk profile? Costs and benefits for individual and society? Challenges Balancing risk of involving frail/older patient in clinical trials Creating an “orphan” older population? (not authorising/not reimbursing) Design appropriate pharmacovigilance for unknowns Communicating to reduce inappropriate prescription The EMA has not so far received a parallel SA/HTA request on elderly (except Alzheimer) BUT Our mission is to make sure that medicines are assessed as safe and effective for the population of use, and the assessment results are communicated appropriately

11. eCTD ModuleAge 65-74 number / total number (all ages) Age 75-84 number / total number (all ages) Age 85+ number / total number (all ages) Efficacy and Safety Studies Human PK Studies Human PD Studies Biopharmaceutical Studies MedDRA Terms Age <65 number (percentage) Age 65-74 number (percentage) Age 75-84 number (percentage) Age 85+ number (percentage) Total ADRs Serious ADRs – Total - Fatal - Hospitalization/prolong existing hospitalization - Life-threatening - Disability/incapacity - Other (medically significant) AE leading to drop-out Psychiatric disorders Nervous system disorders Accidents and injuries Cardiac disorders Vascular disorders Cerebrovascular disorders Infections and infestations Quality of life decreased Sum of postural hypotension, falls, black outs, syncope, dizziness, ataxia, fractures Evidence based medicine (2) Assessment report- geriatric tables ( Under amendment after initial experience/feedback (CHMP/PRAC/SA group)) Take home messages: 1) Qualitative not statistical- focus attention of reviewer on available data in relation to epidemiology of disease 2) Adaptations might be appropriate depending on product/disease 3)statements made after consideration of these data should be meaningfully reflected in the product information.

12. Evidence based medicine (3) Guidelines Geriatric Expert Group and HTAs will routinely comment on guidelines prior to their release. Points to consider on Frailty should be developed. Geriatric formulations guideline under development Scientific Advices/Scientific Advisory Groups Geriatricians have been involved in a number of these A member of the GEG is now member of the Scientific Advice working Party

13. Evidence based medicine (4) New EU pharmacovigilance tools Tools relevant to reaching to real-life: Legally binding Risk Management Plans for all new products Legally binding post-authorisation safety studies, when justified Legally binding post-authorisation efficacy studies, when justified Confirm a risk Quantify a risk Fill a knowledge gap, eg. efficacy in sub-groups Off-label use Measure the effectiveness of risk minimisation Legal responsibility to measure the effectivess of risk minimisation 12

14. Informed prescription(1) EPAR to provide clear information, including to HTA bodies SmPC and PIL to reflect in a significant way: Reflect clearly what is known. Be relevant on: Drug-drug and drug-disease interactions (cross refer) Dose adjustment (cross refer) Administration/ no crushing (cross refer) Need for follow up foreseen in RMP

15. Informed prescription(2) Risks of antipsychotics in people with dementia Two safety bulletins sent by MHRA….

16. Antipsychotics: advice to avoid use in dementia

17. 16 Thank you