Robin Markowitz and Elizabeth Lye from Lymphoma Canada discussed recent pCODR drug funding requests for innovative cancer therapies and how negative funding recommendations are affecting patient access to effective new treatments. To read the white paper discussed in this webinar, visit our website: http://bit.ly/2q8duxM

1. Improving Access to Innovative
Cancer Therapies in Canada
Robin Markowitz & Elizabeth Lye

3. Overview
1. The evolving landscape of cancer treatment
2. Drug approval and reimbursement in Canada
3. Recent trends in pCODR assessment of funding requests
submitted with non-RCT data
4. Impact of negative pCODR recommendations on patient
access
5. Recommendations to improve access to innovative cancer
therapies
6. 2018 – is change underway?

4. The evolving landscape
of cancer treatment
• Cancer is a diverse collection of diseases that have different
molecular composition, even within histological subtypes.
• Many new cancer drugs target discrete molecular aberrations or
pathways in tumor cells and consequently are active on smaller
subsets of the patients.
• Companion diagnostics that measure biomarkers are being
increasingly integrated with the drug-development and clinical
trials.
• Unique tumour characteristics and other health conditions of
individual patients are of increasing importance in treatment
selection.

5. From “one drug fits all” to a focused,
personalized approach
Towards rational, targeted drug design:
• Monoclonal antibodies & antibody-drug
conjugates
• Small molecule protein inhibitors
• Cellular immunotherapy
• Oncolytic virus therapy

6. Advances in the molecular
characterization of tumors
Science Translational Medicine 30 Oct 2013:
Vol. 5, Issue 209, pp. 209ra153

7. Drug access in Canada
Regulator
(Effect &
Safety)
CDR
(CADTH)
HTA
(Assess
Value)
Price
Negotiator
Decision
maker/
funder
pCODR
(CADTH)
QUEBEC
(INESSS)
HEALTH CANADA
Pan Canadian Pharmaceutical Alliance
(pCPA)
F/P/T Ministries of Health & Cancer
Agencies

8. Drug Access in Canada
• Not all drugs approved by Health Canada are publicly
funded.
• Each province and territory has their own publicly
funded prescription drug benefit program.
• The drug coverage provided by each of the provinces
can vary.
• Private insurance may be provided through
employers and/or purchased individually.

9. Accelerated approval of promising new
therapies for life-threatening diseases
• Priority review can be granted for promising new drug products.
• In such cases, an NOC with conditions (NOC/c) may be issued.
• An NOC/c is authorization to market a drug with the condition that
the manufacturer undertakes additional studies to verify the clinical
benefit or other conditions required by Health Canada.
• Manufacturers seeking an NOC/c often submit data from non-
comparative phase I and II clinical trials, while awaiting the results
of RCTs or other clinical studies.

10. Growing gap in access to innovative
cancer drug therapies
Health Canada has granted an NOC/c for several innovative
cancer therapies with limited clinical data, but where the clinical
benefit is promising:
• there is no alternative therapy available on the Canadian market; or
• the new drug represents a significant improvement in the benefit/risk
profile over existing treatments.
Between 2012-2017, pCODR increasingly recommended that
these therapies NOT be reimbursed.

11. pCODR recommendations: 2012-2017
• Between January 1, 2012 and December 31, 2017, pCODR issued
recommendations for 99 oncology drug funding requests.
• Submissions supported by limited data sets (i.e. non-comparative data) accounted
for 20% (20/99).
0
5
10
15
20
25
2012 2013 2014 2015 2016 2017
RCT non-RCT
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
2012 2013 2014 2015 2016 2017
RCT non-RCT

12. pCODR Recommendations: 2012-2017
Only non-comparative trial data (N=20) RCT data (N=79)
8.5
(42%)11.5
(58%)
Positive Negative
66.5
(84%)
12.5
(16%)
Positive Negative

13. pCODR Recommendations: 2012-2017
Only non-comparative trial data (N=20) RCT data (N=79)
0
2
1
4
0.5
11
0
0
2
6.5
2
0
1
2
3
4
5
6
7
8
2012 2013 2014 2015 2016 2017
NumberofDecisions
Date of Recommendation
Positive Negative
7
13.5
7
14 13 12
2
2.5
2
3
1 2
0
2
4
6
8
10
12
14
16
18
2012 2013 2014 2015 2016 2017
NumberofDecisions
Date of Recommendation
Positive Negative

14. Common conclusions in pERC
recommendations
• Positive recommendation
• Significant unmet need
• Lack of existing safe and/or effective treatment options
• Small patient population
• Infeasibility to conduct RCT in target population
• Negative recommendation
• Uncertainty of net clinical benefit due to non-comparative data (despite
acknowledgement of clinical efficacy, e.g. anti-tumour activity)
• Ongoing RCT or feasibility to conduct RCT in target population
• High potential budget impact (approx. 50%)

15. pCODR recommendations: 2012-2017
Drug Product Funding Request Recommen-
dation Date
Recommendation Reasons for decision
Crizotinib NSCLC, ALK-
positive, advanced
2012-10-04 *Negative  Not confident of net clinical benefit
due to limitations of evidence
 Ongoing RCTs
Brentuximab
vedotin
Hodgkin lymphoma,
3rd line
2013-08-29 Positive  Small population
 No other treatment options
 Infeasible to conduct a RCT
Brentuximab
vedotin
Systemic ALCL, 2nd
line
2013-12-05 Positive  Aggressive form of the disease
 No other effective, non-toxic
treatment options
 Infeasible to conduct a RCT
Vismodegib Basal cell
carcinoma,
advanced
2014-01-10 Positive  No standard treatment
 Small population
 Infeasible to conduct a RCT
Bosutinib CML, 2nd-line or
more
2015-04-21 Positive  Less toxic than existing treatments
 Decreased risk of exacerbating
comorbidities
 Infeasible to conduct a RCT
Romidepsin PTCL, 2nd-line,
transplant ineligible
2015-05-19 Positive  Aggressive form of the disease
 No other effective treatment options
 Small population
 RCT feasible, but uncertain it would
inform clinical value
Aldesleukin Melanoma,
metatstatic
2015-06-22 Positive  No standard treatment
 Toxicities of existing therapies
 Small population
Pertuzumab Breast Cancer, 1st-
line
2015-07-16 Negative  Uncertainty around net clinical benefit
due to validity of surrogate endpoint
 Ongoing RCT
Ponatinib CML / ALL 2015-10-01 Positive  No treatment options for the disease
sub-group
 Manageable toxicities
 Infeasible to conduct RCT
Ceritinib NSCLC, ALK-
positive,
relapsed/refractory
2015-12-03 *Negative  Not confident of net clinical benefit
due to limitations of evidence
 Ongoing RCT
Blinatumomab ALL, Adult,
relapsed/refractory
2016-04-01 *Negative
(2nd line)
Positive
(3rd
line)
 Not confident
of net clinical
benefit due to
limitations of
evidence
 Ongoing RCT
 Small
population
 Limited
treatment
options in this
setting
Palbociclib Breast Cancer,
ER+/her2-, 1st-line
2016-05-05 *Negative  Not confident of net clinical benefit
due to limitations of evidence
 Ongoing RCT
Olaparib Ovarian Cancer, 2nd-
line maintenance
2016-09-29 *Negative  Not confident of net clinical benefit
due to limitations of evidence
 Ongoing RCT
Idelalisib Follicular
Lymphoma, 3rd-line
2016-09-29 Negative  Not confident of net clinical benefit
due to limitations of evidence
 Feasible to conduct RCT
Ibrutinib WM lymphoma, 2nd-
line
2016-11-03 Negative  Not confident of net clinical benefit
due to limitations of evidence
 Feasible to conduct RCT
Daratumumab Multiple myeloma,
4th-line
2016-12-01 Negative  Not confident of net clinical benefit
due to limitations of evidence
 Feasible to conduct RCT
Venetoclax CLL, del(17p), 2nd-
line
2016-12-01 Negative  Not confident of net clinical benefit
due to limitations of evidence
 Feasible to conduct RCT
Alectinib NSCLC, ALK+, CNS,
relapsed
2017-03-03 Negative  Not confident of net clinical benefit
due to limitations of evidence
 Ongoing RCT
Blinatumomab ALL, pediatric, Ph-,
relapsed
2017-08-23 Positive  May be net clinical benefit
 Substantial need for treatment
options in small population
Dabrafenib +
trametinib
NSCLC, relapsed
with BRAF V600
mutation
2017-11-17 Negative  Not confident of net clinical benefit
due to limitations of evidence
 Feasible to conduct RCT
*The funding request received a positive funding recommendation after resubmission with results from a phase III RCT.
Abbreviations: ALL: acute lymphoblastic leukemia; ALK: anaplastic lymphoma kinase; CLL: chronic lymphocytic leukemia; CML:
chronic myelogenous leukemia; NSCLC: non-small cell lung cancer; PTCL: peripheral T cell lymphoma; RCT: randomized
controlled trial; WM: Waldenstrom’s macroglobulinemia

16. Feasibility & Applicability of RCTs
• RCTs considered “gold standard” of empirical medical knowledge – a
source of reliable evidence regarding which treatments will most benefit
patients
• RCTs not always appropriate, feasible or ethical for evaluation of new
therapeutic interventions:
– Rare diseases
– Distinct molecular subtypes
– Evidence of significant improvement in clinical endpoints in early trials
– Heavily pre-treated populations - lack of common comparator
– In rapidly-evolving therapeutic areas, results often outdated before
publication
– Lack of interest on part of manufacturers

17. Example 1
Ibrutinib for relapsed Waldenstrom’s Macroglobulinemia: Negative pCODR
Recommendation (November, 2016)
• pERC:
– Noted ibrutinib’s ability to control symptoms, with fewer toxic side effects than
available therapies, in an easy to take-at-home pill format that is extremely
important to patients.
– Not confident of net clinical benefit due to limitations of evidence.
– Believed phase III RCT is feasible in this population.
• CGP:
– WM has annual incidence of 5/million in Canada, making it difficult to recruit
enough patients to evaluate important clinical endpoints in an RCT.
– Treatment choice is largely guided by data from non-comparative phase II studies
and prior treatment history, therefore making comparisons between currently
available agents and new therapies challenging.
– No standard treatment for relapsed WM, limiting the feasibility of assessing
ibrutinib against a single comparator in this setting.

18. Example 2
Daratumumab (+ dexamethasone) for 4th-line Multiple Myeloma (December,
2016)
• pERC:
– Not confident of net clinical benefit due to limitations of evidence.
– Believed RCT would be feasible to determine efficacy compared with available
treatment options or best supportive care.
• CGP:
– RCT comparing daratumumab to best supportive care not feasible for pragmatic
and ethical reasons:
– Patients would likely decline participation in a study that may not provide them
with an active treatment and opt for one that ensures delivery of another
potentially efficacious agent.
– Unethical to enroll patients in a trial comparing daratumumab with best supportive
care when the toxicity and effectiveness of the suggested best supportive care had
proven detrimental to these patients

19. Impact of negative pCODR
recommendations on access
Funding requests that receive a negative recommendation from pCODR are
very unlikely to receive funding from public drug plans.
– All submissions which received negative recommendations and requested pCPA
negotiations resulted in pCPA deciding “not to negotiate collectively or individually
at the provincial-territorial level”
Private payers are increasingly relying on public HTA recommendations to
inform their reimbursement criteria for innovative, high-priced therapies.
As of December 31, 2017, only 5 funding requests that initially received
negative recommendations (based on non-comparative data), were
resubmitted with evidence from RCTs.
– All subsequently received positive recommendation; however resubmission
resulted in access delays up to 515 days.

20. Recommendations
1. Funding recommendations conditional on collection
of additional evidence.
Canadian Agency for Drugs and Technologies in Health, Recommendation Framework for CADTH
Common Drug Review and pan-Canadian Oncology Drug Review Programs, 2016

21. Recommendations
1. Funding recommendations conditional on collection
of additional evidence
2. Collection and sharing of real-world evidence

22. 2018 pCODR Recommendations
Drug product Funding Request Initial Recommendation Final Recommendation
Venetoclax CLL, 3rd-line or
more
Negative Positive/c: improvement in CE
in the form of a substantial
price reduction until more
robust clinical data are made
available for future assessment
Pembrolizumab Hodgkin
Lymphoma, 3rd-
line or more
Positive for 2 subsets/
Negative for 1
Positive for 2 subsets/ Negative
for 1
Nivolumab Hodgkin
Lymphoma, 3rd-
line or more
Positive for 1 subsets/
Negative for 1
Not yet available
Avelumab Merkel cell
carcinoma,
relapsed
Positive Positive
Olaratumab Soft-tissue
sarcoma
Positive/c: time-limited
reimbursement until more
robust clinical data can be
collected for future
assessment
Not yet available

23. Canadian Cancer Survivor Network
Contact Info
Canadian Cancer Survivor Network
1750 Courtwood Crescent, Suite 210
Ottawa, ON K2C 2B5
Telephone / Téléphone : 613-898-1871
E-mail jmanthorne@survivornet.ca or mforrest@survivornet.ca
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