Improving patients recruitment

Improving patients recruitment October, 16 th 2012 Marie LANG Director of CeNGEPS

CeNGEPS The picture of French commercial clinical research

Amiens Lille Bichat St Louis Robert Debré Île-de-France R.Poincaré Cochin Necker CNO 15/20 St Antoine Brest Caen Rouen Ile-de-France Reims Nancy Strasbour g HEGP Pitié- Salpêtrière IGR & Curie Albert Chenevier Henri Mondor Rennes Angers Tours Nantes Dijon Besançon 264 000 French medical doctors = potential Poitiers investigators Limoges Clermont Ferrand Lyon CHU & CLCC A very fragmented landscape with multiple different research institutions Bordeaux CHU & CLCC Saint Etienne Grenoble Map legends Toulouse CHU & CLCC Montpellier Nîmes Marseille Nice Hospital Clinical Research and innovation department (DRCI) Interregional Clinical Research Office (DIRC) Clinical investigation center (CIC-P) Clinical Epidemiology center (CIC-EC) Clinical investigation center integrated in biotherapy (CIC - BT) Clinical investifation center specializedi n technologic innovations (CIC-IT) Fort de France Pointe à Pitre GH Sud Réunion Centers / Networks on care and research CTRS / RTRS

Registered clinical trials : French national regulatory Authority (ANSM) - 40% in 10 years

In all Western Europe, rate of participation in CTs is close and globally in decline Average speed of recruitment between 2004 and 2012/per study/ per month Europe Scandinavie 13,0 13,1 Allemagne Espagne France Royaume Uni Italie 11,0 9,0 7,0 5,0 7,2 7,4 6,8 6,6 6,5 6,3 5,6 8,3 8,1 8,1 7,8 7,6 9,7 6,7 6,6 6,3 5,2 4,8 4,8 6,1 6,1 4,7 5,1 3,8 3,0 2004 2006 2008 2010 2012 Seules les études impliquant la France ont été retenues 5

Average speed of recruitment 2012 : heterogeneity between Nombre moyen de patients therapeutic recrutés par areas centre actif : hétérogénéité entre les aires thérapeutiques Average speed of recruitment in 2012 : 4,7 patients recruited by active center per month Nombre moyen de patients recrutés par centre actif Onc olog ie /Onc o-hématolog ie C ardiovas c ulaire/métabolis me Diabète Neurolog ie/p s yc hiatrie/alz heimer Asie 4,9 Moy. Scandinavie 11,4 Am. Latine 12,0 Europe Est 6,2 Europe Est 4,7 Monde 3,8 Europe Est 10,7 Australasie 7,9 Afr. Moyen Or. 5,3 Am. Latine 4,1 Am. Latine 10,3 Asie 7,8 Allemagne 5,2 Moy. Australasie 3,8 Asie 9,7 Moy. Canada 5,1 Europe Est 7,7 Moy. Europe France 3,8 Moy. Australasie 9,5 Monde 9,1 Autres Eur. Ouest 5,1 7,6 Monde 7,0 5,1 Europe Moy. Allemagne Scandinavie 3,5 3,8 Autres Eur. Ouest 9,0 Europe Espagne 5,1 Canada 6,9 Moy. Canada 3,4 Afr. Moyen Or. 8,8 9,1 Asie 4,8 6,9 Monde 5,0 Espagne Autres Eur. Ouest 3,4 Royaume Uni 8,7 Moy. Etats-Unis 4,7 Scandinavie 5,8 Allemagne 3,4 Espagne 7,5 Europe Australasie 4,6 Royaume Uni Autres Eur. Ouest 5,6 6,5 3,3 Allemagne 7,4 Am. Latine 4,4 Afr. Moyen Or. Etats-Unis 5,5 3,2 Etats-Unis 7,0 France 4,3 Espagne Royaume Uni 5,3 3,2 Canada 7,0 Scandinavie 4,2 Italie 3,2 Afr. Moyen Or. 4,9 Italie 6,1 Italie 4,1 Etats-Unis 2,8 Italie 4,2 France 4,6 Royaume Uni 4,1 France 4,0 Anti Infec tieux/ Virolog ie/vac c ins Maladies R ares Inflammation/R humatolog ie R es piratoire Asie 45,5 Asie 6,2 Am. Latine 7,5 Scandinavie 10,7 Am. Latine 17,8 Autres Eur. Ouest 4,4 Asie 10,3 15,0 Moy. Monde Europe Est 6,5 Scandinavie Royaume Uni 4,2 10,1 Asie 5,4 Afr. Moyen Or. 10,2 Allemagne 10,4 France 4,2 Canada 5,2 Europe Est 7,9 Europe Est 8,5 Am. Latine 4,2 Moy. Australasie 7,7 Espagne 8,2 Canada 4,0 Moy. Etats- Unis 4,8 Monde 4,8 Moy. Allemagne 6,3 France 7,9 Europe Est Monde 3,7 Australasie 4,5 Monde 7,0 4,0 Moy. Espagne 6,3 Australasie 7,7 Moy. Afr. Moyen Or. Allemagne 4,3 3,4 Europe Moy. Europe 7,6 Moy. Royaume Uni 6,2 Royaume Uni 6,8 Allemagne Espagne 4,2 4,4 3,1 Europe Europe Etats-Unis 6,2 Canada 6,6 Italie 2,7 3,9 France 3,6 6,8 Autres Eur. Ouest 6,1 Etats-Unis 6,3 Australasie 2,6 Scandinavie 3,3 Am. Latine Afr. Moyen Or. 5,9 Scandinavie 2,3 Italie 3,3 5,4 Autres Eur. Ouest Italie 4,7 4,1 Etats-Unis Espagne 2,2 2,2 Autres Eur. Ouest Royaume Uni Afr. Moyen Or. 3,2 3,0 2,9 France Canada Italie 5,3 5,1 4,6 S eules les études impliquant la F rance ont été retenues

«Public interest group»: CeNGEPS A public/private partnership created in 2007 for a high performing commercial clinical research : «recruit more patients, faster and better»

CeNGEPS : gathering the main clinical research stakeholders in France PUBLIC members 51% 49% PRIVATE members DIRC Est 6% DIRC Ile de France 6% DIRC Grand Ouest 6% Following positive evaluation of AERES : renewal of «CeNGEPS» 2011-2015 DIRC Nord Ouest 6% Syndicat représentant les laboratoires pharmaceutiques en France DIRC Rhône Alpes Auvergne 6% DIRC Sud Méditerranée 6% DIRC Sud Ouest Outre Mer 6% Inserm 9% 4 partenaires associés Agence nationale de sécurité du médicament et des produits de santé (ANSM) Fédération hospitalière de France (FHF) Fédération nationale des centres de lutte contre le cancer (FNCLCC) Conférence des présidents d université (CPU)

Action plan : 10,5M /year for 7 priorities to improve performance of French commercial clinical research CeNGEPS works as a funding agency : 2 national calls Set up «points of contact / one stop-shops» in hospitals More human resources (CTAs, study nurses) to support investigators Reduce the number of centres without recruitment to <15% Encourage the assessment of feasibility / trial site evaluations Support of 23 national disease-oriented research networks Find new investigators and patients Speed up study start up and costing/contract negotiations providing standard templates «to take part in clinical research, a right/a duty for French citizens» ( Information on clinical research towards the general public)

CeNGEPS Funding of 230 CTAs/study nurses helping investigators to recruit and support commercial clinical trials carried out in French hospitals

Funding of resources to set up 7 «points of contact» in France and funding of 300 jobs to support recruitment, mainly CTAs DIRC Ile de France Francis WILLIG francis.willig@sls.aphp.fr 01 40 27 57 46 DIRC Nord Ouest Mariam PETROSYAN m-petrosyan@chru-lille.fr 03 20 44 67 37 DIRC Grand Ouest Stéphanie DUMONT stephanie.dumont@chu-rennes.fr 02 99 28 41 17 DIRC Sud Ouest Outre Mer Eric DONOIS eric.donois@chu-bordeaux.fr 05 57 82 08 48 To DIRC Est Identify high performing (or new) sites Know their reliability/availability Solve problems in the set up of trial Alban DUPOUX alban.dupoux@chu-dijon.fr 03 80 29 35 84 DIRC Rhône Alpes Auvergne Dr Marie-Claire MAZE marie-claire.maze@chu-lyon.fr 04 72 40 68 54 Samia ATOUI samia.atoui@chu-lyon.fr 04 72 40 68 70 DIRC Sud Méditerranée Véronique REY Veronique.bourgarel@ap-hm.fr 04 91 38 11 51

230 «CeNGEPS CTAs», what for? Mission : thorough evaluation of the recruitment capabilities of a potential site and support to recruitment at the site level Pre-screening and screening of medical records of all patients eligible in a trial given inclusion/exclusion criteria, recruitment capabilities of the site, number of trials under way in the site Evaluation of adequate resources to conduct the trial Participation to the trial set up meeting with sponsors Organisation and taking care of targeted patients (contact; invitation ; RDV ; medical records «CeNGEPS» CTAs differ from CTAs supporting recruitment until study delivery

Types of clinical trials supported by CeNGEPS CTAs 2011/2012 (DB EXTRANET) RÉPARTITION DES CENTRES SUIVIS PAR # THÉMATIQUE THEMATIQUE Nbre de centres 1 Cancérologie 483 27% 2 Gastroentérologie / hépatologie 203 11% 3 Neurologie 179 10% 4 Cardiologie 123 7% 5 Pneumologie 98 5% Autres 717 40% % RÉPARTITION DES CENTRES SUIVIS PAR PHASE 3% 3% 2% 1% Phase I 7% Phase II 19% Phase IIa 2% Phase IIb 4% Phase III 59% Phase I-II Phase II-III

Gold standards and incentives : National call 2013 for the 7 interregions 2013: 3 international «Gold-standards» to measure performance : - Objective 1 : 60 days for signature of contract for 80% centres - Objective 2 : < 15 % centres showing recruitment = 0 - Objective 3 : 80 % of centres recruiting over 80% patients/target number of patients planned according to protocol Comparison of each region s performance with gold standards gives +/-5% in funding

Impact of CeNGEPS CTAs support? Approximately 20% of French commercial clinical trials supported by CeNGEPS CTAs Performance in 2011 in completed clinical trials supported by CeNGEPS CTAs: + 68% improvement in rate of recruitment (median rate= recruited patients/target number) - 51% of closed centers without recruitement WITHOUT CTA WITH CTA WITHOUT CTA WITH CTA 67% 26.6% 40% 13.1%

20% [15 26%] clinical trials supported by CeNGEPS CTAs What about the rest? Ensure feasibility check/site evaluation and try to reduce the number of centres showing recruitment = 0 to a rate under 15%

Reduce the number of centres «open/closed without recruitment» Centres in 2011 DIRC % centres fermés sans inclusion À 0% d'inclusion Entre 1% et 49 % d'inclusion À 100% d'inclusion et plus Est 22,4% 45 68 54 Grand Ouest 21,8% 71 76 108 Ile de France 30,5% 195 141 181 Nord Ouest 24,2% 44 45 46 Rhône Alpes et Auvergne 20,1% 53 56 102 Sud Méditerranée 19,6% 58 0 84 Sud Ouest et Outre Mer 19,3% 40 0 71 National 23,9% 506 511 646

Reduce the number of centres «open/closed without recruitment» 8 possible explanations for lack of recruitment Design of protocol too complex trial impossible to be carried out (inclusion/exclusion criteria too complicated/too numerous) No precise knowledge by investigator of recruiting possibilities Over-estimation of recruitment by investigator in order to be selected Bad management of clinical research activity in the centre (too many trials under way; no follow-up) «Key opinion leaders»,often insufficient recruiters No/bad preparation of trial (multicentres ) Accident (investigator or member of staff/collaborator leaving ) Trial stopped (recruitment completed in other countries) Solution? Feasibility assessment Use of database, EMR allowing good evaluation of the patient population calculation of recruitment Funding 2011 = 540k to support new proactive tools : data warehouses, web browsers..

Disease-oriented investigators networks

Support in 2012 of 23 national disease-oriented investigators networks = 3,2M Priority therapeutic areas Infectiology/Vaccines Neurosciences «Brain disorders» (Alzheimer, psychiatry ) Oncology / Onco-hematology Cardiology/thrombosis Rare diseases Pediatry Nutrition/diabetes Digestive inflammatory (rhumatology, ) Respiratory diseases Intensive care + 50 employees For coordination and management : Medical Doctors, clinical trials assistants, Trial managers, study nurses Organisation : National level Access to new patients general hospitals and not only CHU Access to new investigators : GPs /Hospitals for Chronic diseases

Une Charte pour orienter et harmoniser Un texte incitatif Définition: «Un réseau d investigation clinique (RIC) est composé de médecins investigateurs et/ou un groupement de structures de recherche clinique (CIC, services cliniques, Unité de recherche clinique ) qui s engagent à travailler ensemble sur des projets communs d investigation clinique conformément aux BPC et à la réglementation française» Un coordonnateur assisté d une équipe + Un comité de pilotage Engagements des membres du réseau Base de données communes Une identité ou un support juridique Stick to the principles of the Charter Gold standards coordination? Harmonisation Objectives and projects

OBJECTIVES Create interactions between researchers, paediatricians and pharmaceutical industries to conduct clinical research projects in order to : Develop clinical research and collaborate with all medical and surgical departments, medico-technical departments, Inserm and University research units. Train physicians and nurses to clinical research and Good Clinical and Laboratory Practices Provide scientific, ethical and practical information on clinical research Give support to children and their parents during participation in medical research

THE PAEDIATRIC CIC NETWORK Contribute to translational research from bench to bed-side, by collaborating with researchers and paediatric investigators. Contribute to biological and technical innovations, to their validation and standardisation, in order to optimise investigations. Identify the best design for the trial and provide support to investigators, from design through the conduct of investigator initiated or industrially sponsored clinical research protocols. Insure high ethical standards and conduct trials in accordance with Good Clinical Practice (GCP) guidelines. Develop all the procedures, recruiting centers and allowing the collaboration between partners. Provide physicians, pharmacists, and nurses with specific training in paediatric clinical research. Develop and provide competences required to conduct clinical research in paediatrics, including paediatric experts, competences in pharmacology, methodology, epidemiology, statistics modelisation. Make facilities available for the conduct of research in children and support parents and their children during participation in medical research. Ensure the general coordination of the high standard research activities and smooth communication between partners.

Speed up study start up and costing/contract negotiations by providing standard templates

Several national Templates : www.cengeps.fr Purpose : Speed up delays in negotiations Convention hôpital - promoteur industriels Grille nationale de calcul des surcoûts hospitaliers Updated Standard contracts : January 2012/ national costs template : August 2012

Signature of hospital contracts Median time between submission to Authorities and 1st hospital contract signature (in days) : gain of 29 days -11% -10% Études 2010 : 117 jours Études 2011 : 104 jours * Signature du 1 er contrat hospitalier 26:01:2011 26

Increase trial participation and recruitment by informing the general public about clinical research : www.notre-recherche-clinique.fr

Clinical research in the mass media : mistrust and fear

http://notre-recherche-clinique.fr October 2012 : Over 200 000 visits 900 000 pages since April 2010 118 Clinical trials in directory (both academic and industry sponsors) Four items : Take part in a trial Clinical trials in France Research stakeholders Our mission

Take part in a trial priority trials for sponsors; information for patients Look for a trial interactive map: localisation of centers Web browser e-volunteer alerts Inclusion/exclusion criteria contacts Directory 30

Videos : patients share their experience of clinical research, Patients associations explain their role and vision of clinical research. Diabète Rhumatismes infantiles KOURIR Maladies cardio-vasculaires Diabète AFD Cancer Cancer Europa Donna

Join www.notre-recherche-clinique.fr notre-recherche-clinique.fr www.facebook.com/notrerechercheclinique www.dailymotion.com/cengeps_capl www.vimeo.com/cengeps

Thank you for your attention