The impact of rarity on oncology health technology assessment (HTA) - - PowerPoint PPT Presentation

Advancing Health Economics, Services, Policy and Ethics

The impact of rarity on oncology health technology assessment (HTA) and funding in Ontario: A review of pCODR recommendations from 2012 - 2017

CADTH Symposium 2019 Presenters: James Keech & Wei Fang Dai Authors: James Keech, Wei Fang Dai, Jaclyn Beca, Kelvin Chan

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• We have no conflicts of interests of declare
• The views expressed in this presentation are solely those of

the authors and do not reflect the views of Cancer Care Ontario

Conflicts of Interests

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1. Oncology HTA in Canada (pCODR Expert Review Committee framework) 2. What is rarity in cancer? 3. Study objectives 4. Rarity and Canadian HTA/funding in Ontario 5. Conclusions & future directions

Overview

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Oncology Drug Funding in Canada

Regulatory approval Health Canada HTA review & recommendation pCODR/CADTH & INESSS Pricing Negotiations pCPA Public Formulary Listing F/P/T Ministries of Health and Provincial Cancer Agencies 4

The pERC Deliberative Framework

Overall Clinical Benefit Alignment with patient values Cost-effectiveness Feasibility of adoption into the health system Funding Recommendation

pCODR expert review committee (pERC) considers 4 criteria when making funding recommendations:

Source: pCODR Expert Review Committee Deliberative Framework. March 2016

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• pERC’s framework does not explicitly address rarity

– Available evidence must suggest drug under review could substantially ↓ morbidity and/or mortality of disease

Evaluating Rare Indications

Significant Unmet Need Rarity of Condition

• Affects small # of patients
• Often genetically based
• Heavy burden on health system
• Difficult to study

Population

• Need identified on a population basis

Absence of Alternatives

• Absence of effective alternatives
• Substantial morbidity/mortality

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Source: Recommendation Framework for CADTH CDR and pCODR programs. March 2016

• Challenges of evaluating drugs for rare indications include:

1. High unmet need 2. Uncertainty in clinical evidence – Lack of RCTs and comparative data – No appropriate comparator/standard of care – Uncertainty in burden of illness 3. High costs/challenges with pharmacoeconomic evaluations 4. No universal definition of rarity

Evaluating Rare Indications

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Source: Nestler-Parr et al. Challenges in Research and Health Technology Assessment of Rare Disease Technologies: Report of the ISPOR Rare Disease Special Interest Group

11,547 • New Cases of Lung Cancer in Ontario 9815

• Non-small cell lung cancer (NSCLC)
• 85% of cases

6870

• Stage III/IV at diagnosis (advanced)
• 70% of cases

137

• ROS1 mutation
• 2% of cases

What is considered rare in cancer?

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Source: 2017 statistics from the Canadian Cancer Society

1. How often are positive funding recommendations made for rare indications by pCODR? 2. How many rare indications are submitted to pCODR with an RCT? In how many instances is conducting an RCT feasible? 3. Are drugs for rare indications less cost-effective (higher ICER)? 4. What is the time to funding for rare indications in Ontario?

Research Questions

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• No universal definition of rarity
• Incidence is one approach to operationalize rarity

– Definition 1 (less stringent): Incidence < 5/10,000 diagnoses per year – Definition 2 (more stringent): Incidence < 1/100,000 diagnoses per year

Methods

Source: Recommendation Framework for CADTH CDR and pCODR programs. March 2016

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• pCODR submissions with final recommendations (2012-2017)

× 2018/19 recommendations × Submissions that were withdrawn, suspended or requests for advice

• Incidence rates for each indication were extracted from:
• 1. pCODR Final Recommendations or Final Clinical

Guidance Reports

• 2. Canadian Cancer Society Statistics
• 3. Pivotal Trials

Methods

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Methods

Total pCODR Reviews

2012 - 2017

N =104 (100%) Excluded Reviews

(Withdrawn, suspended, RFA)

N=8 (7.7%)

• Pos. Recommendation

N=75 (78%)

• Neg. Recommendation

N=21 (22%) With Conditions N=66 (88%) Without Conditions N=9 (12%) Included Reviews N=96 (92.3%) Definition 1: Incidence < 5/10,000 All recommendations (positive and negative) were rare

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How often are positive recommendations made for rare and non-rare indications (definition 2)?

Rare (<1/100,000) Non Rare (>1/100,000) Positive Recommendation (n = 75) 12 (75%) 63 (78.8%) Negative Recommendation (n = 21) 4 (25%) 17 (21.2%) Odds Ratio = 0.67 (95% CI: 0.19, 2.4); P-value = 0.5*

16% 31% 44% 9% 19% 33% 24% 24%

0% 10% 20% 30% 40% 50% 60% <1 1 to 4 5 to 9 10 to 45 % of Recommendations Incidence rate (diagnoses/100,000 in Ontario)

The frequency of positive recommendations for rare and non-rare indications were similar (75% vs 78.8%; p-value = 0.5).

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*Fischer’s Exact Test Source: pCODR Website - Find a Review; https://www.cadth.ca/pcodr/find-a-review

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Does Biomarker Status affect the definition of rarity?

10 20 30 40 50 60

Incidence Rate (diagnoses/100,000 in Ontario) Indication with Biomarker Status Incidence - Biomarker Incidence - not accounting for biomarker Definition 1 Definition 2

2 indications changed from rare → non rare using definition 1 (<5/10,000). There were no changes in rarity status for definition 2 (<1/100,000).

Source: pCODR Website - Find a Review; https://www.cadth.ca/pcodr/find-a-review

How many rare indications are submitted to pCODR with a RCT?

83.3% 90.0% 50.0%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Total Non-Rare Rare

% of Submitted Requests with RCT

80/96 72/80 8/16 Rare indications appear to have fewer submissions with RCTs conducted

Rare (<1/100,000) Non Rare (>1/100,000) No RCT Conducted (n = 16) 8 (50%) 8 (50%) RCT Conducted (n = 80) 8 (10%) 72 (90%) Relative Risk = 5 (95% CI: 2.2, 11.35); Odds Ratio = 9 (95% CI: 2.7, 30.6); P-value <0.01 15

Source: pCODR Website - Find a Review; https://www.cadth.ca/pcodr/find-a-review

% of Positive Recommendations with RCTs

6 60 66

6 3 9

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Rare (N=12) Non-Rare (N=63) Total (N=75)

Frequency of Positive Recommendations

RCT No RCT

For positive recommendations without an RCT, pERC did not consider future RCT trials to be feasible for majority of the indications.

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1 feasible 1 feasible 2 feasible

Source: pCODR Website - Find a Review; https://www.cadth.ca/pcodr/find-a-review

2 12 14 2 5 7

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Rare (N=4) Non-Rare (N=17) Total (N=21)

Frequency of Negative Recommendations RCT No RCT

% of Negative Recommendations with RCTs

For negative recommendations without an RCT, pERC deemed it feasible to conduct an RCT for all indications.

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All feasible All feasible All feasible

Source: pCODR Website - Find a Review; https://www.cadth.ca/pcodr/find-a-review

5 10 15 20 25 30 35 40 45

• 200,000

200,000 600,000 1,000,000 1,400,000 1,800,000 Incidence rate (diagnoses/100,000 in Ontario) Incremental Cost-effectiveness Ratio ($/QALY)*

Positive - rare (n = 12) Positive - non rare (n = 62) Negative - rare (n = 3) Negative - non rare (n = 16)

Are drugs for rare indications less cost-effective?

Drugs for rare indications do not appear to be less cost-effective than drugs for non-rare indications.

Mean (SD) P-value Negative – Rare (n = 3) 370,001 (188,507) 0.81 Negative – Non-Rare (n = 16) 312,096 (395,001) Positive – Rare (n = 12) 324,493 (292,220) 0.49 Positive – Non-Rare (n = 62) 269,055 (248,478) 18

*The upper range of the ICER was plotted for submissions where the range of ICER was provided; Note: Two submissions without ICERs reported were excluded; One submission with the ICER upper range of ~4 million was excluded Source: pCODR Economic Guidance Panel Report;

Time to Funding in Ontario

282.85 322

100 200 300 400 500 600 700 800 900

Non-rare Rare

Time to Funding (Days)

Mean (days)

N = 62 N = 10

P-value = 0.45* There appears to be no significant differences in time to funding between rare and non-rare indications.

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*Calculated from Wilcoxon-Mann-Whitney test **3 reviews were excluded from the analysis as they were not funded at the time of data extraction Source: pCODR Website - Find a Review; https://www.cadth.ca/pcodr/find-a-review

Time to Funding = Date of Notice of Implement to Funding Date

• 1. Line of therapy or previous treatment(s) not factored in to

incidence calculation

• 2. Limited number of rare indications submitted to pCODR
• 3. No universal definition of rarity
• 4. Incidence calculated from multiple data sources and often

using best estimates

• 5. Did not control for multiple factors contributing to funding

recommendations and decisions

Limitations

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• 1. Rarity does not significantly impact positive or negative

funding recommendations

• 2. Rare indications appear to have fewer submissions with

RCTs conducted

• 3. Drugs for rare indications do not appear to be less cost-

effective than drugs for non-rare indications

• 4. There appears to be no significant differences in time to

funding between rare and non-rare indications.

Conclusions

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• Evaluate real-world utilization/public expenditures on

drugs for rare oncology indications

• Conduct a sensitivity analysis for the limitations described

in our incidence calculations

• Further examine how rarity should be incorporated into
• ncology HTA in Canada

Future Directions

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Advancing Health Economics, Services, Policy and Ethics

Acknowledgements

• We would like to acknowledge the helpful

contributions of CCO’s PDRP unit.

• Funding in support of this work was provided

by Canadian Centre for Applied Research in Cancer Control.

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