Better and faster development: the regulators perspective on B/R assessment in orphan medicinal products

Better and faster development: the regulators perspective on B/R assessment in orphan medicinal products Violeta Stoyanova, MD, PhD, MPH COMP member NL Rare Disease Patient in 2030 March 30 th, 2017, Amsterdam

http://www.cbg-meb.nl/ V. Stoyanova http://www.ema.europa.eu/ 2

How do Regulators work? Utrecht London V. Stoyanova 3

28 National Competent Authorities Responsible for expertise EU institutions: Commission Parliament Management Board Committee on Herbal Medicinal Products HMPC Committee for Advanced Therapies CAT Pharmacovigilance Risk Assessment Comittee PRAC V. Stoyanova EMA Secretariat Committee for Human Medicinal Products CHMP and WPs 4 Paediatric Committee PDCO Committee for Veterinary Medicinal Products CVMP Committee for Orphan Medicinal Products COMP

Stages and interactions with regulatory authorities CBG COMP CAT SAWP COMP PDCO CHMP CAT SAG PRAC V. Stoyanova 5

Application for orphan designation COMP Prevalence Seriousness Significant benefit SAWP EC Decision on designation (assumed) Protocol assistance Application for marketing authorisation Prevalence Seriousness COMP QSE Similarity Derogations CHMP Significant benefit (confirmed) COMP Opinion on maintenance orphan status CHMP opinion 6V. Stoyanova MARKETING AUTHORISATION

Why an orphan regulation? "Society cannot accept that certain individuals be denied the benefits of medical progress simply because the affliction from which they suffer affects only a small number of people. It is therefore up to the public authorities to provide the necessary incentives and to adapt their administrative procedures so as to make it as easy as possible to provide these patients with medicinal products which are just as safe and effective as any other medicinal products and meet the same quality standards. EU Charter of Fundamental Rights V. Stoyanova 7

23 February 1995, Expert group formed with the objective of discussing recommendations on priorities for EU level research and regulatory action in the field of rare diseases and orphan drugs 16 December 1999 V. Stoyanova 8 Adapted from PAMPLIN, College of Business Magazine, Virginia Tech, 2013

Principles on European orphan drug designation Main objectives of Regulation (EC) No 141/2000 Provide incentives that stimulate research and development Modify market conditions Set up system of recognition for orphan medicines to be eligible for incentives V. Stoyanova 9

The Committee for Orphan Medicinal Products Main items on the COMP agenda Orphan designation Protocol assistance Orphan status at time of marketing authorization Advising the EC on the establishment and development of a policy on OMP in the EU Assists the EC in drawing up detailed guidelines and liaising internationally on matters relating to OMP - Involvement with patient and consumers, academia, industry - Workshop on DMD - Workshop on SMA - EURORDIS summer school - World Orphan Drug Congress V. Stoyanova 10

COMP: The ODD procedure Publication of public summary of opinion (lay language) on EMA website V. Stoyanova 11

Criteria for orphan drug designation V. Stoyanova 12

Scientific advice - EU standards EUROPE Requesting scientific advice from regulatory authorities is not mandatory but up to the company s free choice SAWP of CHMP - NCA s are represented on basis of expertise (not all 28 NCA s participate) NL is represented with 2 members and 2 alternates in SAWP MEMBER STATES At the National level, not all NCA s provide scientific advice, but the larger national authorities have it in place: e.g. NL, UK, DK, SE, DE, FR, ES, IT, PT, BE, AT V. Stoyanova 14

The impact of Scientific Advice / Protocol Assistance MAA success for MAAs with SA/PA submitted in 2008 2012 Hofer et al., Nat Rev Drug Discov. 2015 V. Stoyanova 15

CHMP: the MAA procedure (Co)Rapporteurs Assessment Report Day 80 Primary Evaluation Phase Day 1 Comments Peer review dloq (other countries) CHMP List of Questions Day 120 Stop Clock Max. 6 months Day 121 Response to LoQ Start Clock Day 150 Joint Rapp./ Co-rapp. AR Hearing? Day 180 Stop Clock Hearin g Day 181 Start Clock Secondary Evaluation Phase SAG? Day 210 Adoption of Opinion 17 V. Stoyanova

The regulatory framework For each step in the procedure: guidelines! >450 guidelines To ensure quality of the product To get high quality data (GCP, GLP) To get sufficient nonclinical and clinical data To enable an adequate Benefit/risk assessment V. Stoyanova 18

Different Phases in Drug Development * Phase I * Phase II * Scientific Advice? Phase III Registration: Full Conditional SmPC Phase IV Follow-up measures? Initial safety, pharmacology in humans. therapeutic exploratory studies in selected patients (high risk pop.), well-monitored; dose & dose regimen determination. Confirmation of clinical efficacy and safety in target patient Population (surrogate & clinical endpoints) Studies after approval e.g. on therapeutic use, drug-drug interaction, large safety studies, epidemiological studies. V. Stoyanova 19

The B/R Balance The Assessment Team Quality assessors Efficacy Safety Pre-clinical assessors PK assessors Clinical assessors External experts (patient representative, medical specialists / hospital pharmacists) V. Stoyanova 20

Can the drug be approved based on the proposed SPC? Why was the drug developed? How was the drug tested? What were the results? What is the benefit/risk balance? V. Stoyanova 21

The critical evaluation of the individual study Aim: Confirmation of effect Effect size and relevance of effect Patient population Dose recommendations (long-term) Safety information V. Stoyanova 22

Internal validity A comparative trial has internal validity if, based on the methodology, it can be expected that the observed therapeutic effect is not biased by other differences in the group caused by: Differences in the natural history Randomisation Observational errors Blinding Non-specific external facors Introduce control groups Parallel (preferred) Cross-over (disadvantage carry over & unstable disease) V. Stoyanova 23

Patients Population should reflect the target population, including gender and age Broad or narrow population? Region (standard of care may differ) Internal validity homogenous External validity - generalisable Sometimes contradictory V. Stoyanova 24

Comparator No other medicine registered for the condition A need for placebo controlled trial? Other possible solutions? If one or more medicinal products are licensed for the condition: Still a need for placebo controlled trial? A need for an active control and placebo? When are historical controls a solution? What about ethics? How to assess benefit/risk? V. Stoyanova 25

Endpoints Primary endpoint To demonstrate an effect in the required indication Secondary endpoints To support the primary endpoint To support additional claims Type of endpoint Biomarker Surrogate endpoint Clinical endpoint Cave data fishing: handling of endpoints has to be defined in the study protocol a priori! V. Stoyanova 26

Assessment of benefits and risks Dependent on disease Minimum acceptable efficacy Maximum acceptable harm for patients Maximum acceptable harm for regulators Disapprove RM Zone Approve Maximum acceptable risk Minimum acceptable efficacy for patients Minimum acceptable efficacy for regulators V. Stoyanova 27 Julie Andrews, ICPE 2006

A marketing authorisation results in: Marketing Authorisation Advice to EC Approved in all EU/EEA countries SmPC (info for healthcare professionals) PIL (info for patient) EPAR: European Public Assessment Report Nota bene! The orphan status is reassessed at the time of MAA may be maintained or not. Not all products with an orphan designation will come to the EU market as OMPs. V. Stoyanova 28

Orphan Medicinal Products Facts and Figures V. Stoyanova 29

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Orphan Applications Figures 2000-2016 350 300 250 200 150 100 50 0 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 submitted negative opinions positive opinions withdrawals during assessment EC Designations V. Stoyanova 31

The orphan status is not easy to obtain... 2000 2006 2011 2016 Total 2005 2010 2015 Applications 548 686 1151 329 2714 submitted Positive COMP 348 500 759 220 1827 Opinions Negative COMP 8 6 7 3 24 Opinions EC Designations 343 485 768 209 1805 Withdrawals during 150 144 313 77 684 assessment V. Stoyanova 32

Orphan Designated Conditions 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 18% 18% 18% 25% 28% 14% 26% 16% 23% 21% 33% 39% 42% 44% 51% 78% 49 55 64 73 80 88 73 98 107 106 128 136 148 190 187 209 0 50 100 150 200 250 NEW CONDITIONS (487) 27% TOTAL DESIGNATIONS (1805) V. Stoyanova 33

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How are medicines approved? Centralised procedure, via EMA; National licence, Mutual recognition procedure, Decentralised procedure, via NCAs. V. Stoyanova 36

The way forward towards 2030? V. Stoyanova 37

Adaptive licensing opens a window for adanced observational studies, registries and pragmatic trials Eichler HG et al. Clin Pharmacol Ther 2012; 91: 426-37. V. Stoyanova 38

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Innovative medicines faster available for the (Dutch) patient at a socially acceptable price V. Stoyanova 40

Different study methods/designs vs. types of conditions Adequate safety data Multi-arm designs and platform trial designs Decision analytic approaches and rational approaches to adjusting levels of evidence Extrapolation problems and opportunities Patients engagement in study design http://www.irdirc.org/wp-content/uploads/2016/11/spct_report.pdf V. Stoyanova 41

Thank you! Working for more, better, faster and accessible treatments for rare diseases V. Stoyanova 42