LUIGI MORO
Transcript
LUIGI MORO
Simposio AFI 2011 Forme farmaceutiche a rilascio modificato nel trattamento delle malattie intestinali Luigi Moro Cosmo Pharmaceuticals 1 MMX - Multi Matrix System From: AFI simposio 2001 Stomach Duodenum 2 MMX: Proving extended release and persistence of radioactive traces released by MMX in gut 1h 30’ duodenum 10h trasverse colon 4h 30’ ascending colon 16h descending colon 7h 30’ trasverse colon 24h rectum 3 Product pipeline Product and Indication Lialda ®/ Mezavant ®/Mesavancol® Mild to moderate Ulcerative Colitis Zacol NMX® Intestinal Disorders (nutraceutical) Budesonide MMX® (Cortiment MMX®) Mild to moderate Ulcerative Colitis Rifamycin SV MMX® Drug type Phase I Phase II Phase III MA Launch Partner USA Shire/Giuliani 5-ASA EU Dietary supplement ITA Corticosteroid 2010 Antibiotic 2010 Travellers’ Diarrhoea H2/11 EU H1/12 USA 3 EASTERN EUROPEAN COUNTRIES EU H1/12 USA H2/12 Dr. Falk Ferring – Worldwide Santarus - USA Dr. Falk – Eu & Australia Santarus - USA LMW Heparin MMX® 2010 - Induction of remission in UC H2/12 EU Biologic - Maintenance treatment for UC of all severities CB-17-01 Chromendoscopy CB-01-16 Opioid Induced Constipation H2/12 H2/11 Diagnostic Opioids Antagonist Q4 11 4 2010 The dilemma of pharma companies: high costs of developing a NCE, low probabilities of success Biology Chemistry HTS Preclinical Screening Optimization Phase 0 Leads Drug candidates IND 5.0% 0.00021% 50.0% 40.0% 70.0% 52.0% 65.0% 91.0% # targets input 1,000 50.0 # compounds input 625,000 31,250,000 32.2 12.9 9.0 4.7 3.0 Value Chain Target ID/val1 Target Val II Clinical Phase I Phase II FDA Phase III Terminology Activity/output Circumstantial val Functional val Probability to pass # IDval1 exp. run 333 # pot. tgts/IDval1 exp. 3 64.4 # candidates input Running total $m % of total Subtotal % NDA 25,5 231,3 271,4 390,2 484,5 531,2 616,0 716,6 742,3 3.4% 27.7% 5.4% 16.0% 12.7% 6.3% 11.4% 13.6% 3.5% 21.4% 12.7% 31.3% 3.5% 31.2% Source: Boston Cons. Matrix 2004 5 Cosmo strategy: go for lower risks & higher probabilities of success Preclinical to market phase I to market phase II to market phase III to market Post phase III to market Classical NCE(1) probability of success 9% 22% 31% 59% 91% Gastro NCE probability of success 12% 31% 50% 64% 91% Gastro ACE(2) probability of success 40% 50% 55% 64% 91% Probabilities (1) (2) NCE: new chemical entity ACE: previously approved chemical entity 6 The therapeutic gap in conventional therapy: from Lialda® to corticosteroids like Budesonide MMX® Lialda® for active Ulcerative Colitis • Improvement is achieved in 70% of patients • Remission rates @ 8 weeks • Remission definition: DAI <1 • 517 patients, mild-moderate UC • Placebo vs 2.4g/d vs 4.8g once daily Sandborn et al APT 2007;26:205 100 90 80 70 60 50 40 30 20 10 0 Therapeutic gap Placebo MMx MMx 4.8g 2.4g/d od PROVEN, PROPRIETARY, PATENTED MMX® TECHNOLOGY Proof of concept achieved Base for further product development and replenishment of pipeline 7 Multi-matrix System (MMX®) • Multi-matrix system (MMX®) – a unique technology • Targeted drug delivery to entire colon, the site of UC • Potential for efficacy of conventional steroid, while minimizing systemic side effects • MMX® technology has previously been successfully applied to IBD (Lialda®) 8 Budesonide MMX® • Budesonide • Highly potent non-halogenated corticosteroid • Low systemic bioavailability • Established value as topical therapy in UC and targeted delivery for CD • Budesonide MMX® • Gastro-resistant MMX® delivery 9 Budesonide MMX ® PK Comparison vs. Entocort Comparative bioavailability study: Bioavailability profile of a new MMX™ Budesonide Extended release (6, 9 mg tablets) formulation compared vs. A controlled ileal release formulation, Entocort® 3 x 3 mg capsules, in healthy volunteers Mean Plasma Budesonide concentration after single oral dose concentration (pg/mL) E n t o c o r t ® E C 3 m g × 3 c a p s u le s B u d e s o n id e M M X ™ 9 m g B u d e s o n id e M M X ™ 6 m g 200 0 150 0 100 0 500 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 T im e ( h ) 10 % Remission Budesonide MMX® Phase 3 Study Results Primary Efficacy Endpoint Remission after 8 weeks of treatment 20 18 16 14 12 10 8 6 4 2 0 N = 410 17,4 * 12,6 + 8,3 4,5 Placebo N=89 Remission, n(%) 4 (4.5%) MMX 9 mg MMX 6 mg Entocort EC N=109 19 (17.4%) N=109 9 (8.3%) N=103 13 (12.6%) ∆ vs. Placebo -- 12.9% 3.8% 8.1% P-value -- 0.0047* 0.2876 0.0481+ * Statistically significant (p < 0.025) + Statistically significant (p < 0.05) Study not powered to show a statistical difference between budesonide MMX® and Entocort® EC treatment arms 11 Remission at Week 8 Primary Efficacy Endpoint % Remission N = 489 N=121 N=123 N=121 N=124 9 (7.4) 22 (17.9) 16 (13.2) 15 (12.1) ∆ vs. Placebo -- 10.4% 5.8% 4.7% P-value -- 0.0143* 0.1393 0.2200 Remission, n(%) 12 * Statistically significant (p < 0.025) Not powered to show statistical difference between budesonide MMX® treatment arms and Asacol® Morning Plasma Cortisol Symbols indicate mean plasma cortisol level for each visit for each treatment. 13 Sviluppo internazionale: difficoltà tipiche Livello REGOLATORIO Tipo ● Agenzie diverse con richieste di struttura del dossier personalizzate a livello locale ● Guidelines diverse nelle specifiche di reclutamento (histology EU, not US) ● Non accettazione di atti da altre Agenzie Regolatorie ● Advisor meetings gestiti con diverse procedure (moltiplicazione della documentazione) ● IND – CTX - Tempi di approvazione diversi (da qualche settimana a >6 mesi) - Possibilità di rifiuto sulla stessa domanda accettata da altri Paesi in EU (feasibility allargata e frazionamento del reclutamento come risk management tool) 14 Logistics of Phase III budesonide-MMX (Cortiment®) development: Example-Time to open new sites/countries In Europe the time to set up sites varies by county from 12 -27 weeks. Multiple steps required: •National regulatory approval •Site Site contracts •Local ethics approval •Drug import (subject to national approval first) 15 Sviluppo internazionale: difficoltà tipiche Livello Tipo •REGOLATORIO - Agenzie diverse con richieste di struttura del dossier personalizzate a livello locale - Guidelines diverse nelle specifiche di reclutamento (histology EU, not US) - Non accettazione di atti da altre Agenzie Regolatorie - Advisor meetings gestiti con diverse procedure (moltiplicazione della documentazione) - IND – CTX - Tempi di approvazione diversi (da qualche settimana a >6 mesi) - Possibilità di rifiuto sulla stessa domanda accettata da altri Paesi in EU (feasibility allargata e frazionamento del reclutamento come risk management tool) • CLINICO - Richiesta di un numero di pazienti in costante aumento rendono indispensabile coinvolgere paesi emergenti (es. Russia, India, etc.) con imprevedibili riflessi sulla qualità dei dati - Competizione tra diversi clinical trials nei siti più noti ed affidabili prolungano i tempi di reclutamento (20 mesi per 8 settimane di trattamento) 16 Logistics of Phase III budesonide-MMX (Cortiment®) development 4 Phase III trials completed Study design # active centres # screened patients # treated patients CB-01-02/01 Countries Randomised double blind.8 weeks treatment 108 803 509 USA,Canada,Mexi co, India CB-01-02/02 Randomised double blind.8 weeks treatment 69 613 511 Western & Eastern Europe,Israel, Australia CB-01-02/04 Randomised double blind.Upto 12 months treatment 60 123 123 USA, Canada, Eastern and Western Europe, India CB-01-02/06 Open Label 8 weeks treatment 15 61 61 India 17 Logistics of Phase III budesonide-MMX (Cortiment®) development: Study site distribution 18 Sviluppo internazionale: difficoltà tipiche Livello •REGOLATORIO • CLINICO Tipo - Agenzie diverse con richieste di struttura del dossier personalizzate a livello locale - Guidelines diverse nelle specifiche di reclutamento (histology EU, not US) - Non accettazione di atti da altre Agenzie Regolatorie - Advisor meetings gestiti con diverse procedure (moltiplicazione della documentazione) IND – CTX - Tempi di approvazione diversi (da qualche settimana a >6 mesi) - Possibilità di rifiuto sulla stessa domanda accettata da altri Paesi in EU (feasibility allargata e frazionamento del reclutamento come risk management tool) - Richiesta di un numero di pazienti in costante aumento rendono indispensabile coinvolgere paesi emergenti (es. Russia, India, etc.) con imprevedibili riflessi sulla qualità dei dati - Competizione tra diversi clinical trials nei siti più noti ed affidabili prolungano i tempi di reclutamento (20 mesi per 8 settimane di trattamento) - Criteri sempre più severi nella definizione degli Endpoints rendono penalizzanti i confronti con farmaci già approvati da qualche anno 19 Dates of FDA approval for Common IBD Drugs Administrative changes in Changes in FDA since 1938 Agencies evolution and drugs approval 1962: Kefauver – Harris amendments - products must be proven both safe and effective prior to marketing 1984: Hatch-Waxman Act (bioequivalence) 1997: FDA Modernization Act -includes regulation of marketing for off label use 1973: Center for Biologics Evaluation and Research (CBER) established within FDA 2003:Responsibility for biological agents transferred to Center for Drug Evaluation and Research (CDER) 1938: FDA established 2005: Infliximab approved for UC 1953: 6MP and methotrexate approved 1992: Mesalamine approval for UC 1968: 6MP and methotrexate approved 1995: Cyclosporine approved 2008: Certolizumab and Natalizumab approved for CD 1998: Infliximab approved for CD 1977: Sulfasalazine approved for UC 2002: Adalimumab approved for CD 20 Summary of different properties measured in clinical activity indices (1955) (1982) (1987) (1989) (1994) (1998) (1998) 21 Taken from Trials 2007, 8:17 Summary of activity indices used for ulcerative colitis Index Year Also known as Clinical/ biomedical Truelove & Witts’ Powell Tuck Rachmilewitz Lichtiger Walmsley Feagan 1978 1988 1990 1992 1998 2005 St. Mark’s Index Clinical Activity Index (CAI) Modified Truelove & Witts’ Activity Index (AI) Simple Clinical Colitis Index (SCCAI) Ulcerative Colitis Clinical Score (UCCS) 1987 1987 Mayo score, Disease Activity Index (DAI) UC Disease Activity Index (UCDAI) 1993 1998 2002 2005 PGA assessment score Composite (clinical and endoscopic) Schroeder Sutherland Evaluation Physician’s Global Evaluation Investigator’s Global Evaluation Individual Symptom Score Patient Defined Remission Taken from Trials 2007, 8:17 22 Indices and endpoints used in recent clinical trials with patients in active disease Drug/Study Index/Score system Endpoint Definition of Remission ASCEND II [20] Mayo Clinic Index (DAI) Overall improvement from baseline ( treatment success) Complete remission: A normal stool frequency and normal endoscopy findings No rectal bleeding PGA score of 0 and PFA score of 0 MEZAVANT [21] Modified UC Disease Activity Index (UCDAI) including Clinical and endoscopic evaluation Modified UC-DAI ≤ 1 Stool frequency – score 0 and Rectal bleeding – score 0 and Combined PGA score and sigmoidoscopy score ≤ 1 ( no friability) and ≤ 1 point reduction from baseline in sigmoidoscopy score PINCE [16] UCDAI including Clinical and endoscopic evaluation UC-DAI <2 Sum of stool frequency and rectal bleeding and mucosal appearance and PGA is 0 or 1 SALOFALK [14] CAI Only Clinical evaluation CAI≤ 4 Number of stools; percentage of bloody stools; abdominal pain and general well being in last 7 days; temperature due to colitis; presence of EIMs; laboratory findings (ESR and Hb) ACT I/II [18] Mayo Clinical Index (DAI) ) including Clinical and endoscopic evaluation Score ≤ 2; no individual subscore >1 Sum of stool frequency; rectal bleeding; Mucosal appearance; PGA 23 Impact of different definitions of remission threshold on clinical trial outcomes ASCEND I/II [5, 20, 23] Study Mayo Score/DAI Index Criteria included Remission indicated by score Remission rate Stool frequency compared to normal Rectal bleeding Sigmoidoscopy PFA PGA 0 ≤1 ≤2 22% 28% 50% 24 Sviluppo internazionale: difficoltà tipiche Livello •REGOLATORIO • CLINICO Tipo - Agenzie diverse con richieste di struttura del dossier personalizzate a livello locale - Guidelines diverse nelle specifiche di reclutamento (histology EU, not US) - Non accettazione di atti da altre Agenzie Regolatorie - Advisor meetings gestiti con diverse procedure (moltiplicazione della documentazione) IND – CTX - Tempi di approvazione diversi (da qualche settimana a >6 mesi) - Possibilità di rifiuto sulla stessa domanda accettata da altri Paesi in EU (feasibility allargata e frazionamento del reclutamento come risk management tool) - Richiesta di un numero di pazienti in costante aumento rendono indispensabile coinvolgere paesi emergenti (es. Russia, India, etc.) con imprevedibili riflessi sulla qualità dei dati - Competizione tra diversi clinical trials nei siti più noti ed affidabili prolungano i tempi di reclutamento (20 mesi per 8 settimane di trattamento) - Criteri sempre più severi nella definizione degli Endpoints rendono penalizzanti i confronti con farmaci già approvati da qualche anno - Problemi di confezionamento (etichette, IC e CRF multilingua) e distribuzione degli IMPs - Comitati Etici locali con richieste diverse nella struttura dai contratti (220 contratti da proporre, negoziare e firmare) 25 Logistics of Phase III budesonide-MMX (Cortiment®) development: Bio sample and drug distribution (*) Gary Lichtenstein. Gastroenterology 2007; 132: 516-26 26 Logistics of Phase III budesonide-MMX (Cortiment®) development: Some other cost drivers Item Count Approx. number of laboratory blood, urine, stool and histology samples analysed during PIII Cortiment® studies. 28,784 Number of data items captured in eCRF during PIII studies CB-01-02/06 CB-01-02/04 CB-01-02/01 CB-01-02/02 – 110,728 – 151,729 – 1,112,340 – 785,110 Total: 2,159,907 Logistic costs to distribute IMPs worldwide 85,500 € 27 Sviluppo internazionale: difficoltà tipiche Livello Tipo •REGOLATORIO - Agenzie diverse con richieste di struttura del dossier personalizzate a livello locale - Guidelines diverse nelle specifiche di reclutamento (histology EU, not US) - Non accettazione di atti da altre Agenzie Regolatorie - Advisor meetings gestiti con diverse procedure (moltiplicazione della documentazione) IND – CTX - Tempi di approvazione diversi (da qualche settimana a >6 mesi) - Possibilità di rifiuto sulla stessa domanda accettata da altri Paesi in EU (feasibility allargata e frazionamento del reclutamento come risk management tool) • CLINICO - Richiesta di un numero di pazienti in costante aumento rendono indispensabile coinvolgere paesi emergenti (es. Russia, India, etc.) con imprevedibili riflessi sulla qualità dei dati - Competizione tra diversi clinical trials nei siti più noti ed affidabili prolungano i tempi di reclutamento (20 mesi per 8 settimane di trattamento) - Criteri sempre più severi nella definizione degli Endpoints rendono penalizzanti i confronti con farmaci già approvati da qualche anno - Problemi di confezionamento (etichette, IC e CRF multilingua) e distribuzione degli IMPs - Coinvolgimento obbligato di CRO multistrutturate (impatto sui costi) 28 Main costs of Phase III Budesonide-MMX (Cortiment®) development due to clinical organizations CRO costs mainly driven by: • • • • Number of countries and sites initiated. Number of patients screened and randomised Duration of studies Complexity of studies • Number of data points collected • Sites required pre-study visits, interim monitoring visits and close-out visits • Investigator fees, variable depending on region (Some US investigators charge up to $9,000 per completed patient) • Protocol Local Approval (e.g. central IRB in the USA, national competent authority in EU member states) • Local site ethics committee approval required for many sites (particularly in Europe). 29 Main costs of Phase III Budesonide-MMX (Cortiment®) development due to Study complexity - Studies included up to 2 colonoscopies (with biopsies for histology confirmation) - Microbiology, haematology, chemistry, urinalysis testing: all samples required transport and analysis. - Statistical analysis, medical writing • Each patient required : blinded drug treatment kits. Laboratory testing kits. Translated patient diaries, signed informed consent, travel expenses rembursement. • Drug kits required temperature recording during transit and insulated (expensive) packaging in some cases (e.g winter months, tropical climates). • Multiple warehouses with temperature controlled storage were established and integrated with the randomisation (IVRS) and drug distribution process. • Data collection via online electronic CRF system (contracted supplier). • Comparator drugs Entocort and Asacol required purchase, over-encapsulation, release and re-packaging/labelling to maintain blinded treatment allocation. 30 Sviluppo internazionale: difficoltà tipiche Livello Tipo •TECNICO - ANALITICO - Specifiche diverse in funzione delle varie Farmacopee richiedono SOPs analitiche multiple in funzione del Paese di destinazione o gestione separata dei prodotti/IMPs. - La distribuzione del prodotto in vari Paesi impone presentazioni diverse con materiali di confezionamento personalizzati (lingua, dimensioni) - Possibilità di ispezioni dell’unità produttiva da Paesi non Europei (Korea, Brasile,etc.) - L’invio del prodotto in paesi a clima diversificato impone studi di stabilità in diverse condizioni aggiuntive • GESTIONALE - Creazione di Teams dedicati per le diverse tipologie di problemi (risorse umane specialistiche?) - Creazione di unità di controllo costi/investimenti con conoscenza dei mercati internazionali e delle loro regole - Reperimento di Problem Solving Units in diverse parti del mondo per la risoluzione dei problemi locali 31 Budesonide –MMX Project timelines & costs • • • • • • • • • • • Ph I PS + PK studies Ph II POC study Pre-IND meeting with FDA Tox. Bridging study New Ph. I comparative study FDA Special Protocol Assess. Ph III - First Patient In Ph III - Last Patient Out Final Ph. III CSRs MA submission MA Approval • Total development time • Total development costs 2002 - 2004 2005 2006 2007 2007 - 2008 2008 2008 2010 2011 2011 ? (2012) 10 years several milions € 32 Top issues impacting pharmaceutical market access in 2011 The two main challenges faced by the pharmaceutical industry with regard to market access in 2011 are likely to be the end of free-pricing and the continued importance of innovative contracting and patient access schemes. Budget driven reform may end free-pricing The end of free-pricing in 2011 has been signalled by two of the traditional free-pricing markets changing their reimbursement systems. Germany – demonstrated incremental benefit required for 12 months of free-pricing The Act on the restructuring of the German pharmaceutical market (Arzneimittelmarkt-Neuordnungsgesetz; AMNOG) came into force in January. Under the new Act, the Federal Joint Committee (G-BA) will assess value dossiers submitted by the pharmaceutical company, to establish if a new product demonstrates incremental benefit against an appropriate comparator. If a drug does not offer incremental benefit over the comparator, then its reimbursement price will be based on the comparator, if appropriate, as part of the reference pricing (Festbetrage) system. However, if incremental benefit over the comparator is demonstrated, then the company's launch price will be reimbursed for a period of 12 months. For such a product, longer-term reimbursement figures will be negotiated with the price agreed by the GKV-Spitzenverband (the statutory health insurance umbrella organisation) or an arbitration board. UK – White Paper changes lead to uncertainly over market access, and the promise (threat?) of a new pricing system …. The Government claims that these changes will help them to reduce National Health Service (NHS) administration costs, make the service more responsive to patient needs and improve services, as they maintain their commitment to preserve NHS spending levels. Currently free pricing is allowed for all new medicines at launch and all licensed medicines are automatically reimbursed by the NHS; but free-pricing is irrelevant if a pharmaceutical company can not gain effective market access. Even under the existing system, restrictions are placed on patient access and prescribing, for example with National Institute for Health and Clinical Excellence (NICE) denying access to some medicines or issuing guidelines restricting use. At a more regional level, SHAs and PCTs in England were responsible for enacting such guidelines within their budgets. 33 L’incubo dei prezzi • L’innovazione dovrebbe essere premiata da un Premium Price a supporto degli investimenti a rischio effettuati • La variabile prezzo condiziona per i farmaci innovativi: - il tempo di arrivo nel mercato del singolo Paese - la possibilità che in qualche Paese non entri affatto nel repertorio farmacetico 34 Innovazione: Premium price ? Market Lialda/Mezavant ITALY 59,43€ (60 tab) 1 tab= 0,99 € USA 204.73 USD (30 tab) 1 tab= 6.82USD (4,66 €) NETHERLANDS 150€ (120 tab) 1 tab= 1,25 € CANADA 213€ (120 tab) 1 tab= 1,77 € IRELAND 109,11€ ( 60 tab) 1 tab=1,81 € UK 54,64£ (60 tab) 1 tab= 1,018 € Currency US dollar :1.46 € Currency GBP: 1,12 € 35 MMX: innovazione tecnologica al servizio del paziente 36 Conclusioni L’innovazione è un processo che contempla anni di investimenti rischiosi, che richiede competenze complesse, risorse e organizzazioni efficienti dedicate. A fronte di questi impegni le società farmaceutiche non si augurano di trovare, oltre alle difficoltà tecniche prevedibili, altri ostacoli di non facile previsione, quali - Incertezza e variabilità nei meccanismi regolatori e autorizzativi - impossibilità di svolgere un Mktg efficace attraverso confronti con farmaci già sul mercato - negoziazioni critiche con gli enti predisposti al riconoscimento del prezzo di vendita L’innovazione porta vantaggi prima di tutto al paziente: in una società che guarda al futuro essa va incentivata e sostenuta da tutte le componenti del mondo del farmaco. To be successfull in drug research & development…. - Geschick Geduld Glück Geld 4 G are needed : (Ability) (Patience) (Luck) (Money) [Paul Ehrlich] 37