February 21, 2023

1. Surrogate Endpoints:
Are drug review processes flexible enough to
expedite patient access to new cancer medicines?
February 21, 2023
1pm EST

2. Hot Topics Expert Webinar Series
2
pCPA and provincial listings | Wednesday Nov. 23, 2022 @1pm Eastern
Why timelines for public reimbursement of cancer medicines are getting longer and how this impacts patients
If you missed a webinar or would
like to review them, please see our
YouTube and SlideShare pages
Funding algorithms | Tuesday Dec. 13, 2022 @1pm Eastern
What goes into decisions on what medicines patients can access across different lines of treatments?
QALYs | Tuesday Jan. 24, 2023 @1pm Eastern
How arbitrary decisions on cost-effectiveness impact patients’ access to some novel cancer treatments
Surrogate endpoints | Tuesday Feb. 21, 2023 @1pm Eastern
Are drug review processes flexible enough to expedite patients’ access to new cancer medicines?

3. 3
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4. Today’s panel
4
Speakers Moderator
Bill Dempster
CEO
3Sixty Public Affairs
Robert Bick
CanCertainty
Campaign Co-Lead
Kristian Thorlund
Sr. Strategic Advisor
Cytel
Tara Bourgoin
Sr. Consultant
IQVIA
Lorraine Hudson
Sr. Manager,
Patient
Engagement and
Policy Strategy
AstraZeneca

5. Surrogate Endpoints in
Cancer Clinical Research
What are they and how are they used?
Kristian Thorlund, PhD
McMaster University

6. If not survival, then what?
Overall survival is the gold standard clinical
outcome in cancer clinical trials
Early stage cancer clinical trials
would take over a decade to
complete to show survival benefit
Surrogate endpoint
Are there other clinical endpoints that may
reliably confer treatment benefit?

7. The Surrogate Endpoint
1Fleming & DeMets. Ann Int Med 1996. Surrogate Endpoints in Clinical trials. Are we being Misled?
2 Prentice RL. Stat Med 1989. Surrogate Endpoints in Clinical trials. Definition and Operational Criteria
Surrogate endpoint
‘the surrogate must be a
correlate of the true clinical
outcome and fully capture
the net effect of treatment
on the clinical outcome.’ 1,2

8. 1Fleming & DeMets. Ann Int Med 1996. Surrogate Endpoints in Clinical trials. Are we being Misled?
2 Prentice RL. Stat Med 1989. Surrogate Endpoints in Clinical trials. Definition and Operational Criteria
‘the surrogate must be a
correlate of the true clinical
outcome and fully capture
the net effect of treatment
on the clinical outcome.’ 1,2
The Surrogate Endpoint

9. What is NOT a good surrogate?
Not involving same pathological
process that results in outcome
Intervention only affects pathways of
the surrogate outcome
Intervention affects pathways
independent of the surrogate outcome
Intervention effect through intended pathways
offset by under-recognized mechanisms
Fleming & DeMets. Ann Int Med 1996. Surrogate Endpoints in Clinical trials. Are we being Misled?

10. What is NOT a good surrogate?
Fleming & DeMets. Ann Int Med 1996. Buyse M et al. The Oncologist 2022. Surrogacy beyond prognosis:…
Presence of prognostic factors (known
or unknown) correlated both with
surrogate and survival

11. What is NOT a good surrogate?
Fleming & DeMets. Ann Int Med 1996. Buyse M et al. The Oncologist 2022. Surrogacy beyond prognosis:…
Presence of surrogate outcome may
alter the treatment course, and thus the
outcome

12. Treatment effect and comparative effect
Surrogate
Outcome
Overall
Survival
New
Treatment
Surrogate
Outcome
Overall
Survival
Control
Treatment
50% better! 50% better?

13. Treatment effect and comparative effect
Buyse M et al. The Oncologist 2022. Surrogacy beyond prognosis:…
No surrogate endpoint is
perfect
Ideally, the surrogate itself
should capture some net
effect of the treatment

14. Poor post-approval data in late cancers
• < 20% of drugs approved on surrogate outcomes show long-term benefits
• Most post-approval studies use same unvalidated surrogate outcome
• Trial activity drops substantially after approval of drug
○ E.g. of 52 bevacizumab breast cancer trials, 10 (21%) were terminated
and results of 14 (29%) completed trials remain unknown.
Gyawali B et al. JAMA Intern. Med. 2019; 179(7): 906-913.
Schnog BBJ et al. Brit J Cancer 2021;15:1477-1485.
Spencer PH et al. JNCI J Natl Cancer Inst 2020; 12(4):djz211.

15. Sparse validation in early cancers
• Reviews of 200+ clinical trials in lung cancer and breast cancer
• Only 3 trials concentrated on ‘early stage’ cancer
• None reviewed Quality of Life
• All looked a ‘correlation’ only

16. The oncoming avalanche
These are important facts to
pay attention to…

17. 17
A retrospective evaluation of CADTH recommendations for oncology therapies
highlighted historic trends in submitted evidence across all indications
78
20
2
10
3 2
0
10
20
30
40
50
60
70
80
90
Conditional Negative Positive
Number
of
CADTH
Recommendations
(N=115)
115 CADTH recommendations from Jan 2017 – Dec 2021 were evaluated and included all indications and disease stages. Recommendations assessed did not include the following:
Resubmissions, submissions with 2nd pCPA attempt, non-manufacturer submissions, or those for gene therapies or biosimilars.
Recommendations – All oncology indications and disease stages
Source: IQVIA’s Market Access Metrics database & CADTH
Analysis conducted by IQVIA, and sponsored by AstraZeneca

18. 18
Conversely, recommendations for early-stage cancers demonstrates a
proportionally higher use of non-traditional endpoints
Traditional Surrogate
Type of
outcome
1 1 3 2
1 1 2
1
0
1
2
3
4
OS PFS ORR pCR DFS/EFS (d)MFS iDFS
Number
of
CADTH
Recommendations
(n=12)
Conditional Negative Positive
Abbreviations: DFS=disease-free survival; EFS=event-free survival; IDFS=invasive disease-free survival; (d)MFS= (distant) metastasis-free survival; ORR=Objective response rate; OS=Overall survival; pCR=Pathologic
complete response; PFS=Progress-free survival
Source: IQVIA’s Market Access Metrics database & CADTH
Analysis conducted by IQVIA, and sponsored by AstraZeneca
Recommendations – Early-stage solid tumours
12 CADTH recommendations from Jan 2017 – Mar 2021 were evaluated and included only solid tumours in
early-stage disease. Recommendations assessed did not include the following: Resubmissions, submissions
with 2nd pCPA attempt, non-manufacturer submissions, or those for gene therapies or biosimilars.
2
1
0
5
3
1
0
1
2
3
4
5
6
Conditional Negative Positive
Number
of
CADTH
Recommendations
(N=12)

19. 19
An independent study of clinical trials in early-stage disease for solid tumours was
conducted to estimate the potential impact of surrogate endpoints on future HTA
Total oncology clinical trials meeting selection
criteria (n=4,848)
Trials for indications of focus
(10 solid tumours)
Excluded
(2,518)
Trials for early-stage disease
Excluded
(1,932)
Trials for single-indication only
Excluded
(11)
Oncology Trials (387) (8.0%)
Traditional outcomes
47
109
6
0
50
100
150
200
250
300
Single Multiple None
Number
of
Clinical
Trials
(N=387)
Count of primary endpoints
Distribution of clinical trials for early-stage solid tumours by
number of primary endpoints
Surrogate outcomes
225
Trial type: Interventional clinical trials
Trial timing: Start date of Jan 2017 - Mar 2022
Sponsor: Industry
Study Phase: Phase 2 and 3
Status: not withdrawn, suspended or completed
Top 10 tumor types: Lung, Breast, Prostate,
Melanoma, Ovarian, Colorectal, Pancreatic,
Esophageal, Gastric, Bladder (single indication)
Disease stage: Early stage, non metastatic, non
invasive, localized, Stage I-III
Selection
Criteria
Source: clinicaltrials.gov
Analysis conducted by IQVIA, and sponsored by AstraZeneca

20. 20
Surrogate endpoints for early-stage cancers can be seen across tumour types, with
significant representation in breast and prostate
Source: clinicaltrials.gov
Analysis conducted by IQVIA, and sponsored by AstraZeneca
74
(97%) 41
(61%)
29
(91%)
19
(70%)
18
(90%)
15
(94%)
15
(94%)
6
(86%)
3
(60%)
5
(100%)
2
(3%)
26
(39%)
3
(9%)
8
(30%)
2
(10%) 1
(6%)
2
(13%)
1
(14%)
2
(40%)
0
10
20
30
40
50
60
70
80
90
100
Breast Lung Prostate Bladder Melanoma Colorectal Esophageal Pancreatic Ovarian Gastric
Number
of
Clinical
Trials
(n=272)
Surrogate outcomes Traditional outcomes
Notes: 1 trial with gastro-esophageal cancer was merged with esophageal cancer

21. 21
Looking towards the future, ~82% of clinical trials in early-stage disease with a single
primary endpoint include an array of surrogate outcomes
52
25 23
19
12 12 10 10 10 9
4 4 4 3 2 2 1
6 5 4
55
0
10
20
30
40
50
60
Number
of
Clinical
Trials
(N=272)
Type of primary endpoint
Distribution of clinical trials by type of primary endpoints
*only includes trials with single primary endpoint
Abbreviations: CR; complete response; DFS, Disease free survival; EFS, event free survival; IDFS, Invasive disease free survival; MFS, Metastasis free survival; MPR, major pathological
response; ORR, overall response rate; OS, overall survival; pCR, Pathologic complete response; PFS, progression free survival; QoL, quality of life; RFS (recurrence free survival); RFS (relapse free
survival) *Includes eight clinical trials for lung cancer and one for melanoma
Disease-specific
endpoints
Source: clinicaltrials.gov
Analysis conducted by IQVIA, and sponsored by AstraZeneca

22. 22

23. 23
Discussion

24. Hot Topics Expert Webinar Series
24
pCPA and provincial listings | Wednesday Nov. 23, 2022 @1pm Eastern
Why timelines for public reimbursement of cancer medicines are getting longer and how this impacts patients
If you missed a webinar or would
like to review them, please see our
YouTube and SlideShare pages
Funding algorithms | Tuesday Dec. 13, 2022 @1pm Eastern
What goes into decisions on what medicines patients can access across different lines of treatments?
QALYs | Tuesday Jan. 24, 2023 @1pm Eastern
How arbitrary decisions on cost-effectiveness impact patients’ access to some novel cancer treatments
Surrogate endpoints | Tuesday Feb. 21, 2023 @1pm Eastern
Are drug review processes flexible enough to expedite patients’ access to new cancer medicines?

25. Coalition Members
25