Regulatory Background and Past FDA Approvals in Colorectal

Cancer

Amna Ibrahim M.D

DODP, FDA

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

Regular Approval Endpoints in Oncology

Clinical Benefit Endpoints

• Survival

• Improvement in tumor-related symptoms

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 Refractory

Levamisole

(+ 5FU)1990

-Leucovorin

(with 5FU)1991

-Irinotecan

(+ 5FU/LV)2000

-Capecitabine2001

-Oxaliplatin

(+ 5FU/LV)2004

-Bevacizumab2004

-Irinotecan1996,1998

-Oxaliplatin

(+ 5FU/LV)2002

-Cetuximab2004

Historical Endpoints for Approval

• OS

• TTP & RR

• Superiority

• Noninferiority

Agents for Adjuvant Therapy

Levamisole (Adjuvant Rx)

Arms NFollow

up (Yrs)

Reduction in Recurrence

%

Reduction in Death

%

Study 1Duke C Subset

5FU+lev

262 5

36 27

lev 28 28

Observe

Study 2

5FU+lev

929 2

41 33

lev 2 6

Observe

Agents for First-line Therapy

5FU+leucovorin (First-line Rx)

Study Arms N RR%

TTPmo

OSmo

P (one-sided)

1

5FU 70 10 2.9 7.7

5FU+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/LV198 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

1

Cap 302 21 4.3 12.71.00

0.84 – 1.185FU/LV 303 11 4.4 13.6

2

Cap 301 21 4.6 13.50.92

0.78 – 1.095FU/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 NRR (%)

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

Agents for Refractory Cancer

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

1

CPT 11 189 9.2

0.0001Best Supportive Care

90 6.5

2

CPT 11 127 10.8

0.0355FU-based

regimens129 8.5

Oxaliplatin (Refractory; AA)

Study Arms NRR (%)

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

1

CPT-11 + Cet 218 22.9 4.10.54

(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”

Basis of Approval

Adjuvant Therapy(1 reg approval)

Superiority in Survival (1)

First-line Therapy

(5 reg approvals)

Superiority in Survival (4)

Non-inferiority in Survival (1)

Therapy for Refractory Disease(3 AA, 1 reg)

Survival (1 reg for CPT-11)

RR and/or TTP (3 AA)