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Presentation Outline
• Regulatory background • Past endpoints in Oncology• Approvals for colon cancer (adjuvant, first-
line and second-line therapy)
• Studies supporting drug approval• Endpoints supporting approval in CRC
Requirements for Drug Approval
• Safety (FDAC, 1938)• Efficacy demonstrated in adequate and well
controlled studies (1962)• Basis for efficacy:
– Regular approval• Clinical benefit, or• Established surrogate for clinical benefit
– Accelerated approval• Surrogate (reasonably likely to predict CB)
How many trials?• Usually more than one trial is needed.
Substantial evidence: “Adequate and well-controlled investigations”
• Sometimes a single trial may suffice.– FDAMA (1997) single trial + other supportive evidence– 1998 FDA Effectiveness Guidance:
• Multicenter trial• Statistically strong evidence• Important clinical benefit• Additional trials not ethical
Established Surrogates
• Disease-free survival (selected settings)• Complete response rates in some
settings (e.g., acute leukemia)• Partial response rate in some settings
(e.g., hormonal treatment of breast cancer)
Endpoints other than Survival
Approvals not based on Survival (From 1/1/90 - 11/1/02)):
– 73% (48/66) of all approvals– 67% (37/55) excluding accelerated
approvals
Accelerated Approval (AA)
• Serious or life-threatening disease• Drug must provide benefit over available
therapy• Surrogate endpoint may be used• Surrogate endpoint must be reasonably likely
to predict clinical benefit• Post marketing studies must verify clinical
benefit
Agents ApprovedAdjuvant First-Line RefractoryLevamisole (+ 5FU)1990
-Leucovorin (with 5FU)1991
-Irinotecan (+ 5FU/LV)2000
-Capecitabine2001
-Oxaliplatin (+ 5FU/LV)2004
-Bevacizumab2004
-Irinotecan1996,1998
-Oxaliplatin(+ 5FU/LV)2002
-Cetuximab2004
Levamisole (Adjuvant Rx)
Arms NFollow
up (Yrs)
Reduction in Recurrence
%
Reduction in Death
%
Study 1Duke C Subset
5FU+lev262 5
36 27lev 28 28
Observe
Study 2
5FU+lev
929 2
41 33
lev 2 6
Observe
5FU+leucovorin (First-line Rx)
Study Arms N RR%
TTPmo
OSmo
P (one-sided)
1
5FU 70 10 2.9 7.75FU+LV(HD) 69 26 6.7 12.2 0.04
5FU+LV(LD) 73 44 6.7 12 0.05
2(Study 1 ext)
5FU+LV(HD) 149 31 12.7 0.04
5FU+LV(LD) 153 42 12.7 0.01
5FU+MTX+LV 155 14 8.4
Irinotecan (First-line Rx)
Study Arms N RR TTP OS P (one-sided)
1
CPT 11 wkly x 4 (q 6 wks)
226 18 4.2 12
CPT11 + 5FU/LV wkly x 4 (q 6 wks)
231 39 7 14.8<0.05
5FU/LVqd x 5 (q 6 wks)
226 21 4.3 12.6
2
CPT11 + inf 5FU/LV
198 35 6.7 17.4<0.05
5FU/LV 187 22 4.4 14.1
Capecitabine (First-line Rx)
Study Arms NRR (%)
TTP(mo.)
OS(mo.)
Hazard ratio
1Cap 302 21 4.3 12.7
1.000.84 – 1.18
5FU/LV 303 11 4.4 13.6
2Cap 301 21 4.6 13.5
0.920.78 – 1.09
5FU/LV 301 14 4.4 12.3
Oxaliplatin (First-line Rx)
Study Arms N RR* TTP* OS HR for OS
1
IFL 264 33 6.9 14.60.65
(0.53-0.8)FOLFOX4 267 45 8.7 19.4
IROX 264 35 6.5 17.6
* RR and TTP based on unblinded investigator assessment
Bevacizumab (First-line Rx)
Study Arms N RR (%)
PFS (mo.)
OS (mo.)
HR for OS
1IFL 411 35 6.4 15.6
0.66IFL + Bev 402 45 10.6 20.3
2
5FU/LV 36 17 5.2* 13.6
5FU/LV + Bev (5mg) 35 40 9* 17.7
5FU/LV + Bev (10 mg) 33 24 7.2 15.2
* Comparison statistically significant for Study 2
Irinotecan (Refractory; AA)
Study Arms NRR (%)
TTP(mo.)
OS(mo.)
Med Resp Duration
1 Wkly CPT 11 48 21 6.4 10.4
5.8 mo.(2.6-15.2)
2 Wkly CPT 11 90 13 5.9 8.1
3
Wkly CPT 11 125 mg/m2 64 14 5.6 10.7
Wkly CPT 11 100 mg/m2 102 9 6.4 9.3
Irinotecan (Refractory; reg. approval)
Study Arms NOS
(mo.)p
1CPT 11 189 9.2
0.0001Best Supportive Care 90 6.5
2CPT 11 127 10.8
0.0355FU-basedregimens
129 8.5
Oxaliplatin (Refractory; AA)
Study Arms N RR (%)
TTP (mo. with 95% CI)
P for RR
1
Oxaliplatin + 5FU/LV
(FOLFOX4)152 9
4.6 (4.2 – 6.1)
0.0002
5FU + LV 151 02.7
(1.8-3.0)
Oxaliplatin 156 11.6
(1.4-2.7)
Cetuximab (Refractory; AA)
Study Arms NRR(%)
TTP(mo)
HR
1CPT-11 + Cet 218 22.9 4.1
0.54 (0.42-0.71)
Cet 111 10.8 1.5
2 CPT-11 + Cet 138 15
3 Cet 57 9
Summary of FDA Requirements
FDA requirements– Evidence from Trials or Trial+– RA: Clinical Benefit or accepted surrogate– AA: Advantage over available therapy with
regard to a “reasonably likely surrogate”