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TRANSCRIPT
Interpreting Cost-Effectiveness Analyses in
the Context of Product Listing Agreements:
NIHB’s Reanalysis of CADTH’s Hepatitis C
Therapeutic Review
Andrew Portolesi, Biostatistician, Non-Insured Health Benefits Program,
First Nations & Inuit Health Branch, Health Canada
CADTH Symposium
Apr 12, 2016
Outline
• Introduction
– The Non-Insured Health Benefits (NIHB) Program
– Chronic hepatitis C infection (CHC)
– CADTH’s Therapeutic Review: Drugs for Chronic Hepatitis C Infection
– Product Listing Agreements (PLAs)
• Problem
– How can CDR/CDEC make cost-effectiveness recommendations when actual (PLA) pricing is confidential?
• Solution
• Considerations
• Worked Example
• Conclusion
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The Non-Insured Health Benefits (NIHB) Program is Health Canada's national, medically necessary health benefit program that provides coverage for benefit claims for a specified range of drugs, dental care, vision care, medical supplies and equipment, short-term crisis intervention mental health counselling and medical transportation for eligible First Nations people and Inuit.
Costs: • NIHB provides benefit coverage to over 824,000 eligible clients • Total benefit expenditures in 2014/15 were $1.03B • Pharmacy expenditures $422M
In order to determine whether or not to cover new medications, NIHB receives recommendations from the Canadian Drug Expert Committee (CDEC, part of the Common Drug Review – CDR – run by the Canadian Agency for Drugs & Technologies in Health – CADTH), the national cost-effectiveness expert review body for public drug plans in Canada and an international leader in cost-effectiveness analysis.
Overview of the NIHB Program
Source: NIHB Annual Report 2014/15
What is hepatitis C?
• Hepatitis C (HCV) infection is a blood-borne disease, often chronic, and can result in severe liver disease, cirrhosis, and cancer
• Chronic Hepatitis C infection (CHC) develops in 74% those that become infected with HCV who fail to naturally clear the virus
• CHC disproportionately high in Aboriginal populations (prevalence of 2-4% vs. 0.6% for the general Canadian population)
• Aboriginal CHC represents 10-20% of CHC in Canada (25,000-50,000 out of 244,000)
• With HC’s approval of the new Direct-Acting Antiviral Agents (DAAs), CHC can now be reliably treated
• Treating all CHC in the entire Canadian CHC population with the new DAAs would cost approx. $15B (1% of GDP)
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Previous Treatments (PegIFN-based) New Treatments (PegIFN-free DAAs)
• Low cure rates
• Severe side effects
• Long treatment (24-48 weeks)
• Require daily injections
• $10K-$40K per treatment
• High cure rates (up to 90%)
• Mild side effects
• Shorter treatment (8-24 weeks)
• Administered orally (pills)
• $45K-$134K per treatment
Sources: PHAC, Product Monographs
1999: Peginterferon/Ribavirin (“PegIFN/RBV” or “PR”)
Injection (PegIFN), low cure rates, bad side effects, long
treatment duration
2011: 1st-generation DAAs (Victrelis & Incivek)
Oral (i.e. tablets/capsules), increased cure rates, similar or
worse side effects since used in combination with
PegIFN/RBV, same treatment duration
2013: 2nd-generation DAAs (Sovaldi & Galexos*)
Oral, same or higher cure rates as 1st-gen, less side effects
since still used in combination with PegIFN/RBV but with a
shorter treatment duration
2014: 3rd-generation DAAs (Harvoni & Holkira Pak**)
Oral, high cure rates, low side effects, no PegIFN (only
sometimes RBV), short treatment duration
2015: Additional treatments (Daklinza & Technivie)
Add-on therapies & products for rarer genotypes
2016: Pan-Genotypic DAAs *Marketed as “Olysio” in the US
**Marketed as “Viekira Pak” in the US
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Treatments for CHC: Timeline
Source: Product Monographs
• CADTH has performed their own independent Therapeutic Review of treatments for Chronic Hepatitis C (CADTH CHC TR):
• Comprised of a clinical review (systematic review & meta-analysis), pharmacoeconomic review (economic modeling) and patient group input of drugs for CHC
• Update of the 2014 Therapeutic Review to include all current evidence for new therapies (i.e. adding Harvoni, Sovaldi, Holkira Pak, Daklinza) and cover all genotypes
• The CADTH CHC TR pools together all available evidence for these new drugs, comparing their effectiveness, safety and cost-effectiveness (using retail pricing)
• Uses the best methodology for Systematic Reviews, Network Meta-Analysis (NMA) and economic modeling for Cost-Utility Analysis (CUA)
• Compared to CDR reviews for individual drugs, which rely on reviewing individual manufacturers’ economic models
• Recommendation report published in Nov 2015
• A gold standard in HTA
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CADTH Therapeutic Review: Drugs for CHC
Source: CADTH TR: Drugs for Chronic Hepatitis C
What are Product Listing Agreements (PLAs)?
• A Product Listing Agreement (PLA) is a negotiated agreement between a drug plan and a drug company that allows the plan to cover a specific drug at a reduced price through the use of a rebate
• PLAs allow drug plans to cover medications that otherwise would not be considered cost-effective or affordable
• NIHB and other federal drug plans have recently joined the pan-Canadian Pharmaceutical Alliance (pCPA), the national initiative for provincial/territorial public drug plans to collectively negotiate PLAs
• Product Listing Agreements (PLAs) have become a de facto tool in the management of public drug plans in Canada
• The result of a PLA is a negotiated net price that is confidential between a drug plan and a drug company (i.e. cannot be disclosed to CADTH)
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Problem
With the actual price each plan pays for a given drug being confidential and
thus unknown (and cannot be disclosed to) to CADTH, the usefulness of the
CDR has ben called into question as its recommendations apply to what may
be entirely different sets of prices. This issue is especially impactful when the
comparator(s) in a review are already under PLAs:
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Retail Price
Retail Price
CDR Confidential
Price
PLA Price*
0
5
10
15
20
25
30
35
40
45
50
0 5 10 15 20 25 30
To
tal C
osts
Effectiveness (Total QALYs)
Current Scenario: CDEC Recommends “List at a Reduced Price”
Retail Price
Retail Price
CDR Confidential
Price
PLA Price*
PLA Price*
0
5
10
15
20
25
30
35
40
45
50
0 5 10 15 20 25 30
To
tal C
osts
Effectiveness (Total QALYs)
Emerging Scenario: Comparator PLA Pricing Unknown to CADTH
02
0 5 10 15 20 25 30
Comparator Intervention Not Cost-Effective Cost-Effective (?)
*PLA pricing unknown to CADTH
No Treatment
PR 48
Holkira Pak 12
Harvoni 12
Victrelis Galexos Incivek
Holkira Pak + RBV 12 Sovaldi + PR 12
Sovaldi 12 + PR RGT
Sovaldi + Galexos 12
Sovaldi + Galexos + RBV 12
Sovaldi + RBV 24
*Harvoni 8
*Daklinza + Sovaldi 12 *Daklinza + Sunvepra 24
$100,000
$120,000
$140,000
$160,000
$180,000
$200,000
$220,000
9.5 10.0 10.5 11.0 11.5 12.0
To
tal
Co
st
Effectiveness (Total QALYs)
Figure: CADTH CHC 2015 TR: Cost-Effectiveness Plane Genotype 1 Treatment-Naïve Non-Cirrhotic (G1TNNC)
Source: CADTH TR: Drugs for Chronic Hepatitis C
Less Effective
More
Costly
More
Effective
Less
Costly
NIHB’s Solution
• For the CADTH CHC Therapeutic Review, following the advice of CADTH
experts, the NIHB Program reanalyzed the cost-effectiveness results by
subtracting the applicable PLA discount for each regimen to determine its
own incremental cost-utility ratios (“Net Price ICUR”), to which it applied
CDEC's decision-making rationale
• This methodology is justified since treatment costs are direct costs which
can be subtracted from the CU tables without re-running the
pharmacoeconomic model as every patient in model receives treatment.
Significant discounts on indirect costs (e.g. drugs to treat significant side-
effects) would require re-running of model
• Applying PLA discount also considered for modeled discontinuation rate
(e.g. CADTH model assumed discontinuing halfway through, so removed
half of discontinuation rate)
• Specific to this Therapeutic Review, NIHB also excluded PegIFN/RBV (PR)
from the cost-effectiveness analysis by considering it dominated by new
treatments by patient values
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NIHB’s Methodology
1. Understand Cost-Utility Analysis (CUA) and CDEC’s use of CUA in this
review (i.e. economic model, ICURs and sensitivity analysis)
2. Extract CUA Tables (Total Costs, Total QALYs, ICURs) used by CDEC
3. Determine plan-specific discount amount for each modeled medication
regimen
4. Reduce discounts according to modeled discontinuation rates (e.g. 5%
discontinuing halfway through = reduce discount by 2.5%)
5. Additional considerations (e.g. removal of non-applicable comparators)
6. Recalculate CUA table to obtain plan-specific cost-effectiveness: the “Net
Price ICUR”
7. Apply CADTH’s decision-making rationale (including sensitivity analysis)
using new ICURs
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Considerations
• Technically, this is a post-hoc analysis, so we have to avoid arbitrary
methodologic decisions
Requirements:
• High-quality HTA
• Reporting of detailed cost-utility tables (Totals Costs & Total QALYs, not
just incremental costs)
• Understanding of pharmacoeconomic model (e.g. how to apply
discontinuation rates)
• Knowledge of ICUR algorithm and CUA in general (but don’t be beholden
to the algorithm)
• Knowledge of CDEC’s decision-making rationale (not just the rationale for
their final decision), including interpretation of sensitivity analysis
• Model where fundamental unit is a patient who received treatment
• Can’t disclose Net Price ICURs to drug companies as that could reveal
competitors’ products’ PLA discounts
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CHC TR: Removing PR as “Dominated by Patient Values”
• Specific to the CADTH CHC TR, CDEC excluded PR from consideration
based on patient values (i.e. with the new DAAs, it’s unethical to consider
recommending treating someone with PR anymore).
• In its reanalysis, NIHB listed PR as “dominated by patient values.” This
“dominated” isn’t the more-costly-less-effective domination in the usual
CUA sense, but dominated in the sense that you’d never recommend PR
when a new DAA is an option (i.e. not using the usual cost & effectiveness
set of values, but using a different set of values: namely, patient values).
Example, table 19 (Genotype 2 Treatment-Naïve Non-Cirrhotic): Treatment Total Cost Total QALYs Sequential ICUR
(70) PR24 $99,904 11.532 reference
(3) SOF12 + RBV12 $143,955 11.749 $203,282
(0) No Treatment $104,904 9.734 dominated by (70)
(40) So12 PR12 $145,731 11.698 dominated by (3)
Treatment Total Cost Total QALYs Sequential ICUR
(0) No Treatment $104,904 9.734 reference
(3) SOF12 + RBV12 $143,955 11.749 $19,380
(70) PR24 $99,904 11.532 dominated by (3) using patient values
(40) So12 PR12 $145,731 11.698 dominated by (3) Cost-Effectiveness Analysis Table 19, adjusted: G2 TN NC using No Treatment as a reference since PR cannot be recommended
Cost-Effectiveness Analysis Table 19: G2 TN NC using PR as a reference
Source: CADTH TR: Drugs for Chronic Hepatitis C
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ICURs by
Subgroup Genotype 1 Genotype 2 Genotype 3 Genotype 4
TN TE TN TE TN TE TN TE
F0 $31,148 $30,154 $31,195 $33,037 $66,549 $69,205 $94,660 $96,056
F1 $25,873 $25,067 $27,522 $27,370 $53,746 $55,946 $77,415 $78,634
F2 $18,227 $17,698 $19,311 $19,209 $38,481 $40,082 $52,880 $53,784
F3 $13,109 $12,749 $13,812 $13,741 $29,179 $30,413 $36,723 $37,410
F4 (Cirrhotic) $17,816 $18,646 $18,542 $18,226 $34,372 $43,292 $35,996 $37,303
F0: No liver damage, F4: Liver cirrhosis, TN: Treatment-Naïve ,TE: Treatment-Experienced (with PegIFN/RBV)
Retail ICURs with PegIFN/RBV removed (CADTH TR, Retail, No PR):
ICURs by
Subgroup Genotype 1 Genotype 2 Genotype 3 Genotype 4
TN TE TN TE TN TE TN TE
F0 $47,066 $30,154 $320,829 $33,037 $247,949 $69,205 $369,661 $96,056
F1 $40,192 $25,067 $276,590 $27,370 $205,679 $55,946 $315,469 $78,634
F2 $29,242 $17,698 $203,052 $19,209 $151,071 $40,082 $227,554 $53,784
F3 $21,332 $12,749 $146,489 $13,741 $115,513 $30,413 $161,766 $37,410 F4 (Cirrhotic) $23,047 $17,669 $58,659 $18,226 $92,117 $43,292 $59,492 $37,303
Incremental Cost-Utility Ratios (ICURs) for new DAAs for CHC (CADTH TR, Retail)
Removing PR and recalculating
ICURs
Recalculation of all ICURs with PR Dominated by Patient
Values
Worked Example (CHC TR with Fictitious Discounts)
• Using Genotype 1 Treatment-Naïve Non-Cirrhotic (Table 15), with fake
discounts:
• Calculation of discount amount is non-trivial: calculate component costs of
each regimen (not shown), then apply discounts according to
discontinuation rates:
• e.g. PR 48w: Net Price = $19,000 x (1 – 0.15 x (1 – 0.173 / 2 ) )
15 Source: CADTH TR: Drugs for Chronic Hepatitis C, with made-up discounts
Harvoni Holkira Pak Sovaldi Galexos Incivek Victrelis RBV PR 21% 13% 20% 12% 14% 20% 11% 15%
Regimen Retail Price Discontinuation Rate Discount Net Price No Treatment $0 0.0% $0 $0
PR 48w $19,000 17.3% -$2,603 $16,397
Victrelis + PR RGT $40,020 21.2% -$6,493 $33,527
Galexos + PR RGT $47,342 7.0% -$5,796 $41,546 Incivek + PR RGT $47,822 9.2% -$6,510 $41,312 Sovaldi + PR 12w $55,000 10.8% -$10,406 $44,594
Holkira Pak 12w $55,860 0.5% -$7,244 $48,616 Sovaldi + Galexos + RBV 12w $58,350 1.8% -$11,266 $47,084
Holkira Pak + RBV 12w $59,210 1.5% -$7,573 $51,637
Sovaldi + PR RGT $65,840 10.6% -$11,957 $53,883
Harvoni 12w $67,000 4.4% -$13,760 $53,240 Sovaldi + Galexos 12w $91,502 3.3% -$15,126 $76,376 Sovaldi + RBV 24w $116,700 5.4% -$22,123 $94,577
Worked Example (CHC TR with Fictitious Discounts)
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Treatment Total Cost Total QALYs Sequential ICUR
No Treatment $104,904 9.734 ref
Holkira Pak 12w $143,379 11.835 $18,313
Harvoni 12w $152,762 11.857 $426,500
PR 48w $114,105 10.839 dominated by pt values
Victrelis + PR RGT $135,218 11.370 ext. dominated
Galexos + PR RGT $136,770 11.449 ext. dominated
Incivek + PR RGT $137,381 11.400 dominated
Holkira Pak + RBV 12w $146,021 11.841 ext. dominated
Sovaldi + PR 12w $146,140 11.651 dominated
Sovaldi + PR RGT $150,969 11.589 dominated
Sovaldi + Galexos 12w $178,356 11.700 dominated
Sovaldi + Galexos + RBV 12w $182,383 11.655 dominated
Sovaldi + RBV 24w $201,979 11.497 dominated
Treatment Total Cost Discount Net total Cost Total QALYs Net Price Sequential ICUR
No Treatment $104,904 $0 $104,904 9.734 ref
Holkira Pak + RBV 12w $146,021 -$7,573 $138,448 11.841 $15,920
Harvoni 12w $152,762 -$13,760 $139,002 11.857 $34,601
PR 48w $114,105 -$2,603 $111,502 10.839 dominated by pt values
Victrelis + PR RGT $135,218 -$6,493 $128,725 11.370 ext. dominated
Incivek + PR RGT $137,381 -$6,510 $130,871 11.400 dominated
Galexos + PR RGT $136,770 -$5,796 $130,974 11.449 ext. dominated
Sovaldi + PR 12w $146,140 -$10,406 $135,734 11.651 ext. dominated
Holkira Pak 12w $143,379 -$7,244 $136,135 11.835 dominated
Sovaldi + PR RGT $150,969 -$11,957 $139,012 11.589 dominated
Sovaldi + Galexos 12w $178,356 -$15,126 $163,230 11.700 dominated
Sovaldi + Galexos + RBV 12w $182,383 -$11,266 $171,117 11.655 dominated
Sovaldi + RBV 24w $201,979 -$22,123 $179,856 11.497 dominated
Source: CADTH TR: Drugs for Chronic Hepatitis C
Treatment Total Cost Total QALYs Sequential ICUR
No Treatment $104,904 9.734 ref
PR 48w $114,105 10.839 $8,353
Holkira Pak 12w $143,379 11.835 $29,534
Harvoni 12w $152,762 11.857 $435,528
Victrelis + PR RGT $135,218 11.370 ext. dominated
Galexos + PR RGT $136,770 11.449 ext. dominated
Incivek + PR RGT $137,381 11.400 dominated
Holkira Pak + RBV 12w $146,021 11.841 ext. dominated
Sovaldi + PR 12w $146,140 11.651 dominated
Sovaldi + PR RGT $150,969 11.589 dominated
Sovaldi + Galexos 12w $178,356 11.700 dominated
Sovaldi + Galexos + RBV 12w $182,383 11.655 dominated
Sovaldi + RBV 24w $201,979 11.497 dominated
PR Dominated by Patient Values: Original CUA Table:
CUA Table with
PLA Discounts:
Conclusion
• NIHB was able to determine its own cost-effectiveness (the “Net Price
ICUR”) under its PLA pricing for the new DAAs for CHC without additional
work by CADTH
• NIHB also demonstrated that several subgroups recommended for listing
by CDEC but not reported as cost-effective are actually cost-effective upon
dominating PegIFN/RBV due to patient values
• While the usefulness of CDR has been called into question in the context
of Product Listing Agreements, with sufficient cost-effectiveness
information supplied by CDEC and an understanding of cost-effectiveness
analysis, public drug plans are able apply CDEC recommendations to their
own pricing context
• By phasing out the CDR Confidential Price (phased out Apr 1, 2016) and
using retail pricing in its reviews, CADTH will continue to be provide
relevant analysis and recommendations to plans in the new management
paradigm of Product Listing Agreements
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