EMEA experience with endpoints for EMEA experience with endpoints for Oncology drug approval Oncology drug approval EMEA/CHMP Biomarkers Workshop 16 December 2005 Francesco Pignatti, MD Francesco Pignatti, MD The European Medicines Agency (EMEA) The European Medicines Agency (EMEA) London - - United Kingdom United Kingdom London
Contents Contents � Endpoints commonly used in oncology � Legal requirements � EMEA Experience with oncology drugs EMEA Experience with oncology drugs � – Endpoints in pivotal trials for registration – Endpoints in pivotal trials for registration – Common reasons for rejection – Common reasons for rejection � FDA Experience FDA Experience � � EU oncology guideline ( EU oncology guideline ( New New ) ) � – OS – OS v v PFS PFS � Summary Summary � 2
Clinical trial endpoints commonly used in oncology Survival Survival -Overall Overall - -Disease Disease- -free free - -Progression Progression- -free free - -Tumor (usually based on imaging results) - Tumor (usually based on imaging results) -Onset or worsening of disease related symptoms - Onset or worsening of disease related symptoms Response Response -Tumor (usually based on imaging results) Tumor (usually based on imaging results) - -Patient Benefit (palliation, improvement in symptoms) - Patient Benefit (palliation, improvement in symptoms) Protection against toxicity with no decrease in survival Protection against toxicity with no decrease in survival Reduction in the risk of disease Reduction in the risk of disease -From initial onset in a high risk population From initial onset in a high risk population - 3
Legal requirements Legal requirements � Randomized controlled clinical trials (if possible) Randomized controlled clinical trials (if possible) � � Versus placebo and versus an established Versus placebo and versus an established � treatment (as appropriate) treatment (as appropriate) � Minimize bias and uncertainty Minimize bias and uncertainty � � Authorisation Authorisation refused if medicinal product refused if medicinal product � � Efficacy insufficiently substantiated or lacking Efficacy insufficiently substantiated or lacking � � Harmful Harmful � � … … � 4
ICH E8 and E9 ICH E8 and E9 � Confirmatory Confirmatory trials should demonstrate trials should demonstrate � clinical benefit clinical benefit � The primary endpoint The primary endpoint � � Should Should provide the most clinically relevant provide the most clinically relevant � and convincing evidence and convincing evidence � Valid and reliable measure of some Valid and reliable measure of some � clinically relevant and important treatment clinically relevant and important treatment benefit benefit 5
The EMEA experience The EMEA experience
EMEA Experience: Approved New Agents EMEA Experience: Approved New Agents N = 25 N = 25 Cytotoxic agent a a 16 (64%) Cytotoxic agent 16 (64%) Monoclonal antibody, 7 (28%) Monoclonal antibody, 7 (28%) biopharmaceuticals b b biopharmaceuticals Endocrine agent c c 2 (8%) Endocrine agent 2 (8%) a – Alimta,Caelyx, DepoCyte, Foscan, Glivec, Hycamtin, Litak, Myocet, Panretin, Paxene, Targretin, Taxotere, Temodal, Trisenox, Velcade, Xeloda b – Avastin, Beromun, Erbitux, Herceptin, MabCampath, Mabthera, Zevalin c - Fareston, Faslodex Pignatti et al. Crit Rev Oncol Hematol. 2002 May;42(2):123-35. Chaplin et al. ESMO 2004. Pignatti, DIA Annual Meeting 2005. 7
Approved Indications Indications Approved Site of primary and endpoints Site of primary and endpoints N = 47 Endpoints N = 47 Endpoints 13 (28%) PFS, RR 13 (28%) PFS, RR Hematological malignancy malignancy Hematological 13 (28%) OS, PFS, RR 13 (28%) OS, PFS, RR Breast Breast 5 (11%) RR 5 (11%) RR Sarcoma Sarcoma 5 (11%) OS 5 (11%) OS Lung cancer Lung cancer 3 (6%) OS, RR 3 (6%) OS, RR Colorectal Colorectal 3 (6%) OS, PFS, RR 3 (6%) OS, PFS, RR Brain cancer Brain cancer 3 (6%) PFS, RR 3 (6%) PFS, RR Ovarian Ovarian 1 (2%) RR 1 (2%) RR Head and neck Head and neck 1 (2%) OS 1 (2%) OS Prostate Prostate Indications: includes new drug application and extensions of indication 8
Design of pivotal trials (N=47 approved Design of pivotal trials (N=47 approved indications) ) indications RR: 22 (47%) PFS: 16 (34%) OS: 9 (19%) RR: 22 (47%) PFS: 16 (34%) OS: 9 (19%) Design Endpoint n Reason for accepting design Design Endpoint n Reason for accepting design RR RR 18 18 outstanding activity outstanding activity Phase II Phase II AND AND PFS 2 PFS 2 no established treatments no established treatments RR 4 * RR 4 * Phase III Phase III RCT RCT PFS PFS 14 14 OS 9 OS 9 * variation of established drugs 9
Pivotal trials: primary endpoints and design Pivotal trials: primary endpoints and design (N=48 approved indications) 12 1995-1999 2000-2004 RR OS/PFS (N=20) (N=28) 10 RCT No. of indications Endpoint OS 2 (11%) 6 (21%) 8 PFS 3 (16%) 11 (39%) 6 RR 15 (79%) 11 (39%) 4 RCT 11 (55%) 19 (68%) 2 Note: Ongoing applications excluded Abbreviations: OS overall survival, PFS progression-free survival, RCT randomized controlled trial 0 1995 2000 Submission (Year) DIA Annual Meeting 2005. 10
Rejected / withdrawn indications (N=13) / withdrawn indications (N=13) Rejected Design Endpoint n Reason for rejection Design Endpoint n Reason for rejection non randomised non randomised Phase II RR 5 AND Phase II RR 5 AND no outstanding activity no outstanding activity - low level of response low level of response - - inadequate control - inadequate control RR RR 6 6 - target /size of population - target /size of population Phase III Phase III - dose justification - dose justification - no effect no effect - OS 2 OS 2 - wrong comparator wrong comparator - - dose justification - dose justification Eur J Clin Pharmacol. 2002 Dec;58(9):573-80. 11
FDA experience FDA experience � What endpoints have been used in oncology What endpoints have been used in oncology � registration studies? registration studies? � Presentation/Publication: Presentation/Publication: � J Clin Clin Oncol Oncol. 2003 Mar 15;21(6):1066 . 2003 Mar 15;21(6):1066- -73 73 J 12
Primary Endpoints for New Molecular Entities Primary Endpoints for New Molecular Entities Proportion of clinical studies used to support approval using various endpoints Accelerated Regular Response Rate 93% 53% Survival 0 % 12% Time to Progression 7% 20% Symptom benefit 0% 12% Other 7% 32% Note: Totals are not 100% due to multiple endpoints. S. Hirschfeld, presentation to the CBER Office of Cellular Tissue and Gene Therapy seminar on November 16 Talarico, et al. ASCO 2005 13
EU oncology guideline EU oncology guideline “Guideline on Evaluation of Anticancer “Guideline on Evaluation of Anticancer Medicinal Products in Man” (July 2003) Medicinal Products in Man” (July 2003) http://www.emea.eu.int/pdfs/human/ewp/020595en.pdf http://www.emea.eu.int/pdfs/human/ewp/020595en.pdf
Non- -cytotoxic compounds cytotoxic compounds Non ⇒ Very heterogeneous cytotoxic compounds ⇒ � Non Non- -cytotoxic compounds Very heterogeneous � group group � Antihormonal Antihormonal agents, agents, antisense antisense compounds, compounds, � signal transduction, angiogenesis or cell signal transduction, angiogenesis or cell cycle inhibitors, immune modulators … … cycle inhibitors, immune modulators � Toxicity may not be an appropriate endpoint in Toxicity may not be an appropriate endpoint in � dose and schedule finding trials dose and schedule finding trials � ORR: may not be an appropriate measure of anti ORR: may not be an appropriate measure of anti- - � tumor activity activity tumor � Use of predefined PD targets Use of predefined PD targets � � Biological validation Biological validation � � Confirmation of PD Confirmation of PD- -efficacy efficacy � 15
Revision 3 of the anticancer guideline Revision 3 of the anticancer guideline � Non Non- -cytotoxic Compounds: cytotoxic Compounds: Focus on exploratory studies Focus on exploratory studies � � Phase I, dose and schedule finding trials Phase I, dose and schedule finding trials � – Endpoints, healthy subjects studies – Endpoints, healthy subjects studies � Phase II, therapeutic exploratory studies Phase II, therapeutic exploratory studies � – Use of TTP instead of response rate – Use of TTP instead of response rate – Randomised phase II studies – Randomised phase II studies – Within patient comparisons – Within patient comparisons � Phase III, confirmatory studies (all types of agents) Phase III, confirmatory studies (all types of agents) � � Interim analyses / data maturity Interim analyses / data maturity � � OS as primary endpoint, not RR OS as primary endpoint, not RR � � Possible: Possible: PFS when clinically relevant, s PFS when clinically relevant, symptom control ymptom control � 16
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