Clinical Trial Endpoints in Oncology - Inclusion of Surrogate
Endpoints and Shorter Endpoints Will Ensure Faster Clinical
Trials in Oncology
Reference Code: GBIHC061MR Publication Date: March 2011
Survival – Primary Endpoint in Majority of the Marketed Products
The primary endpoint for The primary endpoint for the approval of drugs in the oncology markets, which included colorectal,
the approval of a majority ovarian, head, neck and prostate cancer, was survival. The other endpoints in these markets were
of oncology drugs was response rate (complete, partial, objective, overall response rate and so on). The major marketed
survival. Other endpoints drugs approved after 1990 in the colorectal cancer market were Camptosar (irinotecan), Xeloda
include progression free (capecitabine), Avastin (Bevacizumab), Erbitux (cetuximab), Vectibix (panitumumab) and Eloxatin
survival, disease free (oxaliplatin). The primary endpoint in all these drugs was survival, followed by median time to tumor
survival and time to progression, tumor response rate, progression-free survival, overall response rate and duration of
progression response. In the prostate cancer market, the major marketed products were Taxotere (docetaxel),
Casodex (Bicalutamide), Zoladex (Goserelin), Provenge (sipuleucel-T), Eligard (leuprolide acetate),
Prostap (leuprolide acetate), Firmagon (degarelix), Vantas (Histrelin), Novantrone (Mitoxantrone
hydrochloride), Trelstar (triptorelin). The primary and secondary endpoints in these included the
median survival rate, prostate specific antigen (PSA) response, overall tumor response rate,
disease-free survival, objective response, serum testosterone level and time to disease
progression.
The major marketed drugs after 1990 approved for head and neck cancer were Erbitux
(cetuximab), Taxotere (docetaxel), Oncorine (H101, Modified Adenovirus) and Gendicine
(Recombinant Human Ad-P53). The primary and secondary endpoints in these included median
and overall survival rate, progression-free survival and complete response rate. Similarly, the major
marketed drugs after 1990 approved for ovarian cancer were Altretamine (Hexalen), Gemcitabine
(Gemzar), Hycamtin (Topotecan hydrochloride) and Yondelis (trabectedin). The primary and
secondary endpoints of these drugs included overall and complete response rate, progression-free
survival, time to response and overall survival.
Survival Followed by Progression Free Survival, Disease Free Survival and Time to
Progression as Endpoints in Phase III Clinical Trials
The Phase III clinical trial endpoint was predominantly survival, followed by progression free
survival (PFS), disease free survival (DFS) and time to progression (TTP). Approximately 66% of
the colorectal cancer pipeline candidates in the Phase III have either survival or PFS as their
primary endpoint. Out of this 66%, 43% have survival and 23% have PFS as the endpoint. In
addition to survival and PFS, 11% of the molecules have DFS, 7% of molecules have response
rate and 5 % of the candidates have TTP as the endpoint.
Cancer Therapeutics Market – Clinical Pipeline Phase III by Primary Endpoints, 2010
PFS
28%
Others
39%
Overall survival
Testosterone
20%
level
4% PFS and Overall DFS
Survival 5%
4%
Source: GBI Research, Company Websites
Clinical Trial Endpoints in Oncology - Inclusion of Surrogate GBIHC061MR /Published MAR 2011
Endpoints and Shorter Endpoints Will Ensure Faster Clinical Trials in
Oncology Page 1
© GBI Research. This is a licensed product and is not to be photocopied
The Phase III clinical trial pipeline for prostate cancer was dominated with either survival or PFS for
endpoints, as approximately 45% of the total pipeline was contributed by them together. In addition
to survival and PFS, 14% of the molecules have testosterone level, 13% of molecules have tumor
response rate and 8 % of the candidates have others as endpoints. Also, approximately 29% of the
head and neck cancer pipeline candidates in Phase III trials have overall survival as the endpoint.
In addition to overall survival, 8% of the molecules have TTP and 4% of the candidates have PFS
are the endpoint. Approximately 44% of the ovarian cancer pipeline candidates in Phase III have
PFS as the endpoint. In addition to PFS, the molecules have overall survival as the major endpoint.
Response Rate as the Endpoint in Phase II Clinical Trials
Approximately 32% of the colorectal cancer pipeline candidates in Phase II trials have response
rate, which includes complete response rate, best response rate and tumor response rate, as the
endpoint. Of the remainder, 25% have PFS and 27% have other endpoints (safety, efficacy,
dosage, toxicity and tolerability). Approximately 35% of prostate cancer pipeline candidates in
Phase II trials have tumor response rate, which includes complete response rate, objective
response rate and PSA response rate, as the endpoint. Approximately 48% of the head and neck
cancer pipeline candidates in Phase II trials have response rate, which includes best overall
response rate and objective tumor response rate, as the endpoint. Approximately 37% of the
ovarian cancer pipeline candidates in Phase II trials have response rate, which includes best
overall tumor response, clinical response, and complete response rate, as the endpoint.
Safety Issues, Lack of Improvement in Survival Rates and Failure to Meet Primary Endpoints
Led to Discontinuation of Clinical Trials
In the colorectal cancer market, Vectibix treatment has been discontinued due to safety issues. A
study showed that there were issues with the safety of patients. The analysis revealed a statistically
significant difference in progression-free survival in favor of the control arm. Overall survival
demonstrated a statistically significant difference favoring the control arm. In 2009, Pfizer
discontinued a Phase III trial of the drug for the treatment of prostate cancer after it failed to offer a
significant progression-free survival benefit. This was followed by further failures in the treatment of
breast, liver and lung cancers, substantially curtailing its potential indications.
Iressa (gefitinib) failed to prolong survival and increased bleeding events, leading to discontinuation
of its clinical trial for the treatment of Squamous Cell Carcinoma of the Head and Neck (SCCHN).
In addition to this, clinical development of bivatuzumab mertansine was discontinued before
reaching its maximum tolerated dose. The main toxicity of bivatuzumab mertansine was directed
against the skin, most probably due to CD44v6 expression in this tissue. The majority of skin
reactions were reversible; however, one fatal drug-related adverse event occurred.
In the ovarian cancer market, Ovarex and Pemtumomab were discontinued due to failure to meet
the primary endpoint.
Clinical Trial Endpoints in Oncology - Inclusion of Surrogate GBIHC061MR /Published MAR 2011
Endpoints and Shorter Endpoints Will Ensure Faster Clinical Trials in
Oncology Page 2
© GBI Research. This is a licensed product and is not to be photocopied
1 Table of Contents
1 Table of Contents ........................................................................................................................ 3
1.1 List of Tables..................................................................................................................... 5
1.2 List of Figures ................................................................................................................... 6
2 Clinical Trials Endpoints In Oncology – Introduction.................................................................... 7
2.1 Introduction ....................................................................................................................... 7
2.2 GBI Research Report Guidance ....................................................................................... 8
3 Clinical Trials Endpoints In Oncology – Market Overview ........................................................... 9
3.1 Endpoints Used for Regular Approval ............................................................................... 9
3.1.1 Survival .................................................................................................................... 11
3.1.2 Progression-free survival ......................................................................................... 11
3.1.3 Tumor Response, Response Duration, and Time-to-Tumor Progression ................ 12
3.1.4 DFS ......................................................................................................................... 12
4 Clinical Trials Endpoints in Oncology – Therapeutic Analysis ................................................... 13
4.1 Colorectal Cancer ........................................................................................................... 13
4.1.1 Major Marketed Drug Analysis................................................................................. 13
4.1.2 Profiling of Major Marketed Products ....................................................................... 15
4.1.3 Phase III Molecules Analysis ................................................................................... 22
4.1.4 Most Promising Drugs’ Profiles................................................................................ 23
4.1.5 Phase II Molecules Analysis .................................................................................... 29
4.1.6 Terminated Trials..................................................................................................... 35
4.2 Prostate Cancer .............................................................................................................. 36
4.2.1 Major Marketed Drug Analysis................................................................................. 36
4.2.2 Profiling of Major Marketed Products ....................................................................... 38
4.2.3 Phase III Molecules Analysis ................................................................................... 50
4.2.4 Most Promising Drugs’ Profiles................................................................................ 51
4.2.5 Phase II Molecules Analysis .................................................................................... 58
4.2.6 Terminated Trials..................................................................................................... 63
4.3 Head and Neck Cancer Therapeutics ............................................................................. 63
4.3.1 Major Marketed Drug Analysis................................................................................. 63
4.3.2 Profiling of Major Marketed Products ....................................................................... 65
4.3.3 Phase III Molecules Analysis ................................................................................... 68
4.3.4 Phase II molecules Analysis .................................................................................... 73
4.3.5 Terminated Trials..................................................................................................... 76
4.4 Ovarian Cancer ............................................................................................................... 77
4.4.1 Major Marketed Drug Analysis................................................................................. 77
4.4.2 Profiling of Major Marketed Products ....................................................................... 78
4.4.3 Phase III molecules Analysis ................................................................................... 81
4.4.4 Phase II Molecules Analysis .................................................................................... 89
4.4.5 Terminated Trials..................................................................................................... 93
5 Clinical Trials Endpoints In Oncology – New Trends and Technologies .................................... 94
5.1 Microsatellite Instability (MSI) as a Diagnostic Tool in Colorectal Cancer ....................... 94
5.2 New Biomarker for Aggressive Prostate Cancer ............................................................. 94
6 Clinical Trials Endpoints In Oncology – Company Profiling ....................................................... 95
6.1 F. Hoffmann La Roche .................................................................................................... 95
6.1.1 Business Description ............................................................................................... 95
6.1.2 Financial Overview .................................................................................................. 95
6.1.3 Major Oncology Products ........................................................................................ 96
6.2 Bristol-Myers Squibb ....................................................................................................... 98
6.2.1 Business Description ............................................................................................... 98
6.2.2 Financial Overview .................................................................................................. 98
6.2.3 Major Oncology Products ........................................................................................ 98
6.3 Sanofi-Aventis ............................................................................................................... 100
6.3.1 Business Description ............................................................................................. 100
Clinical Trial Endpoints in Oncology - Inclusion of Surrogate GBIHC061MR /Published MAR 2011
Endpoints and Shorter Endpoints Will Ensure Faster Clinical Trials in
Oncology Page 3
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6.3.2 Financial Overview ................................................................................................ 100
6.3.3 Major Oncology Products ...................................................................................... 101
6.4 Merck KGaA.................................................................................................................. 103
6.4.1 Business Description ............................................................................................. 103
6.4.2 Financial Overview ................................................................................................ 104
6.4.3 Major Oncology Products ...................................................................................... 104
6.5 Pfizer Inc. ...................................................................................................................... 105
6.5.1 Business Description ............................................................................................. 105
6.5.2 Financial Overview ................................................................................................ 106
6.5.3 Major Oncology Products ...................................................................................... 106
6.6 AstraZeneca.................................................................................................................. 107
6.6.1 Business Description ............................................................................................. 107
6.6.2 Financial Overview ................................................................................................ 108
6.6.3 Major Oncology Products ...................................................................................... 109
6.7 Takeda Pharmaceuticals .............................................................................................. 111
6.7.1 Business Description ............................................................................................. 111
6.7.2 Financial Overview ................................................................................................ 111
6.7.3 Major Oncology Products ...................................................................................... 111
6.8 GlaxoSmithKline plc. ..................................................................................................... 113
6.8.1 Business Description ............................................................................................. 113
6.8.2 Financial Overview ................................................................................................ 113
6.8.3 Major Oncology Products ...................................................................................... 114
7 Clinical Trials Endpoints In Oncology – Appendix ................................................................... 115
7.1 Market Definitions ......................................................................................................... 115
7.2 Abbreviations ................................................................................................................ 115
7.3 Research Methodology ................................................................................................. 118
7.3.1 Coverage ............................................................................................................... 118
7.3.2 Secondary Research ............................................................................................. 118
7.3.3 Primary Research .................................................................................................. 119
7.3.4 Expert Panel Validation ......................................................................................... 119
7.4 Contact Us .................................................................................................................... 119
7.5 Disclaimer ..................................................................................................................... 120
7.6 Sources ......................................................................................................................... 120
Clinical Trial Endpoints in Oncology - Inclusion of Surrogate GBIHC061MR /Published MAR 2011
Endpoints and Shorter Endpoints Will Ensure Faster Clinical Trials in
Oncology Page 4
© GBI Research. This is a licensed product and is not to be photocopied
1.1 List of Tables
Table 1: Endpoints for Approval of Oncology Drug Marketing Applications, Global, 1990-2010 ... 9
Table 2: Colorectal Cancer Therapeutics Market – Approved Products, Global, 1990-2010 ....... 13
Table 3: Colorectal Cancer Therapeutics Market, Global, Efficacy, 2010 .................................... 14
Table 4: Colorectal Cancer Therapeutics Market, Global, Eloxatin, Efficacy, 2010 ..................... 20
Table 5: Colorectal Cancer Therapeutics Market, Phase III Molecules , Global, 2010 ................ 25
Table 6: Colorectal Cancer Therapeutics Market, Phase II Molecules , Global, 2010 ................. 30
Table 7: Discontinued Drugs for Colorectal Cancer, Global, 2010 ............................................... 35
Table 8: Prostate Cancer Therapeutics Market- Approved Products, Global, 1990-2010 ............ 36
Table 9: Prostate Cancer Therapeutics Market, Global, Efficacy, Global, 2010........................... 37
Table 10: Prostate Cancer Therapeutics Market, Phase III Molecules , Global, 2010 ................... 55
Table 11: Prostate Cancer Therapeutics Market, Phase II Molecules, Global, 2010 ..................... 59
Table 12: Discontinued Drugs for Prostate Cancer, Global, 2010.................................................. 63
Table 13: Head and Neck Cancer Therapeutics Market – Approved Products, Global, 1990-2010
....................................................................................................................................... 63
Table 14: Head and Neck Cancer Therapeutics Market, Global, Efficacy, 2010............................ 64
Table 15: Head and Neck Cancer Therapeutics Market, Phase III Molecules ,Global, 2010 ......... 71
Table 16: Head and Neck Cancer Therapeutics Market, Phase II Molecules , Global, 2010 ......... 74
Table 17: Discontinued Drugs for Head and Neck Cancer, Global, 2010 ...................................... 76
Table 18: Ovarian Cancer Therapeutics Market- Approved Products, Global, 1990-2010 ............ 77
Table 19: Ovarian Cancer Therapeutics Market, Global, Efficacy, 2010 ........................................ 77
Table 20: Ovarian Cancer Therapeutics Market, Phase III Molecules , Global, 2010 .................... 87
Table 21: Ovarian Cancer Therapeutics Market, Phase II Molecules , Global, 2010 ..................... 90
Table 22: Discontinued Drugs for Ovarian Cancer, Global, 2010 .................................................... 93
Table 23: Colorectal Cancer Therapeutics Market, Global, Eloxatin, Efficacy, 2010 ................... 102
Clinical Trial Endpoints in Oncology - Inclusion of Surrogate GBIHC061MR /Published MAR 2011
Endpoints and Shorter Endpoints Will Ensure Faster Clinical Trials in
Oncology Page 5
© GBI Research. This is a licensed product and is not to be photocopied
1.2 List of Figures
Figure 1: Colorectal Cancer Therapeutics Market – Clinical Pipeline Phase III by Primary
Endpoints, 2010 ............................................................................................................. 22
Figure 2: Colorectal Cancer Therapeutics Market – Clinical Pipeline Phase II by Primary
Endpoints, 2010 ............................................................................................................. 29
Figure 3: Prostate Cancer Therapeutics Market – Clinical Pipeline Phase III by Primary Endpoints,
2010 ............................................................................................................................... 50
Figure 4: Prostate Cancer Therapeutics Market – Clinical Pipeline Phase II by Primary Endpoints,
2010 ............................................................................................................................... 58
Figure 5: Head and Neck Cancer Therapeutics Market – Clinical Pipeline Phase III by Primary
Endpoints, 2010 ............................................................................................................. 68
Figure 6: Head and Neck Cancer Therapeutics Market – Clinical Pipeline Phase III by Primary
Endpoints, 2010 ............................................................................................................. 73
Figure 7: Ovarian Cancer Therapeutics Market – Clinical Pipeline Phase III by Primary Endpoints,
2010 ............................................................................................................................... 81
Figure 8: Ovarian Cancer Therapeutics Market – Clinical Pipeline Phase II by Primary Endpoints,
2010 ............................................................................................................................... 89
Clinical Trial Endpoints in Oncology - Inclusion of Surrogate GBIHC061MR /Published MAR 2011
Endpoints and Shorter Endpoints Will Ensure Faster Clinical Trials in
Oncology Page 6
© GBI Research. This is a licensed product and is not to be photocopied
2 Clinical Trials Endpoints In Oncology – Introduction
2.1 Introduction
Endpoint refers to an The aim of cancer treatment is to improve Survival (SUR) and Quality