Review the ICER Report of your drug

If your drug is not part of the ICER report,use one of the new therapies as a substitute for your drug. To accomplish this,you must:

a. Review the basic model description and methodology used by ICER

i. Key Comparative Clinical Effectiveness Parametersii. Methodology for Estimating QALYs, Costs, and other keyoutcomes of the review

b. Evaluate the findings ICER reported (both CUA and BIM)

i. Consider the WTP thresholds provided by ICER and the drugsability to achieve these thresholds. ii. What does the results of the BIM tell us that is useful? Howshould the manufacturer and payer interpret the BIM provided inICER? iii. Should the manufacturer think positively or negatively about thefindings of the ICER report? Provide rationale and direct examplesof concerns that exist in the ICER report. Targeted Immunomodulators for the Treatment
of Moderate-to-Severe Plaque Psoriasis:
Effectiveness and Value
Condition Update
Final Evidence Report
August 03, 2018
Prepared for:
Important note: Per ICER’s data in-confidence policy, this report was updated in October 2018 to
unredact data that were previously submitted in confidence and have subsequently been
published. We also updated the language regarding a preliminary vote taken during public
deliberation in July 2018 that was contingent on the publication of the confidential data in a peerreviewed journal.
©Institute for Clinical and Economic Review, 2018
ICER Staff/Consultants
University of Washington School of Pharmacy
Modeling Group*
Reiner Banken, MD, MSc
Senior Fellow
Institute for Clinical and Economic Review
David L. Veenstra, PharmD, PhD
Professor and Associate Director
Pharmaceutical Outcomes Research and Policy
Program
The Comparative Health, Outcomes, Policy, and
Economics Institute
Foluso Agboola, MBBS, MPH
Director, Evidence Synthesis
Institute for Clinical and Economic Review
Alexandra Ellis, MSc, AM
Senior Scientist, HTA and Economic Evaluation
Institute for Clinical and Economic Review
Rick Chapman, PhD, MS
Director of Health Economics
Institute for Clinical and Economic Review
Nathaniel Hendrix, PharmD
Pharmaceutical Outcomes Research and Policy
Program
The Comparative Health, Outcomes, Policy, and
Economics Institute
Celia Segel, MPP
Director of CER Policy Development
Institute for Clinical and Economic Review
Katherine Fazioli, BS
Research Assistant
Institute for Clinical and Economic Review
Daniel A. Ollendorf, PhD
Chief Scientific Officer
Institute for Clinical and Economic Review
Steven D. Pearson, MD, MSc
President
Institute for Clinical and Economic Review
DATE OF
PUBLICATION:
*The role of the University of Washington School of
Pharmacy Modeling Group is limited to the
development of the cost-effectiveness model, and the
resulting ICER reports do not necessarily represent
the views of UW.
August 03, 2018
Reiner Banken served as the lead author for the report. Foluso Agboola led the systematic review, network metaanalysis and authorship of the comparative clinical effectiveness section. Katherine Fazioli assisted with the
systematic review and network meta-analysis. Rick Chapman was responsible for oversight of the costeffectiveness analyses and developed the budget impact model. Celia Segel authored the section on coverage
policies and clinical guidelines. Alexandra Ellis, Daniel Ollendorf, and Steven Pearson provided methodologic
guidance on the clinical and economic evaluations. We would also like to thank Varun Kumar, Erin Lawler and
Matt Seidner for their contributions to this report.
©Institute for Clinical and Economic Review, 2018
Final Evidence Report: Plaque Psoriasis Condition Update
Page i
About ICER
The Institute for Clinical and Economic Review (ICER) is an independent non-profit research
organization that evaluates medical evidence and convenes public deliberative bodies to help
stakeholders interpret and apply evidence to improve patient outcomes and control costs.
The funding for this report comes from government grants and non-profit foundations, with the
largest single funder being the Laura and John Arnold Foundation. No funding for this work comes
from health insurers, pharmacy benefit managers, or life science companies. ICER receives
approximately 15% of its overall revenue from these health industry organizations to run a separate
Policy Forum program, with funding approximately equally split between insurers/PBMs and life
science companies. For a complete list of funders and for more information on ICER’s support,
please visit http://www.icer-review.org/about/support/
Through all its work, ICER seeks to help create a future in which collaborative efforts to move
evidence into action provide the foundation for a more effective, efficient, and just health care
system. More information about ICER is available at http://www.icer-review.org
About New England CEPAC
The New England Comparative Effectiveness Public Advisory Council (New England CEPAC) – a core
program of ICER – provides a public venue in which the evidence on the effectiveness and value of
health care services can be discussed with the input of all stakeholders. New England CEPAC seeks
to help patients, clinicians, insurers, and policymakers interpret and use evidence to improve the
quality and value of health care.
The New England CEPAC is an independent committee of medical evidence experts from across
New England, with a mix of practicing clinicians, methodologists, and leaders in patient engagement
and advocacy. All Council members meet strict conflict of interest guidelines and are convened to
discuss the evidence summarized in ICER reports and vote on the comparative clinical effectiveness
and value of medical interventions. More information about New England CEPAC is available at
http://icer-review.org/programs/new-england-cepac/.
The findings contained within this report are current as of the date of publication. Readers should
be aware that new evidence may emerge following the publication of this report that could
potentially influence the results.
This is an ICER update. The first report was issued in December 2016 and can be found here:
https://icer-review.org/material/pso-final-report/.
©Institute for Clinical and Economic Review, 2018
Final Evidence Report: Plaque Psoriasis Condition Update
Page ii
In the development of this report, ICER’s researchers consulted with several clinical experts, patients,
manufacturers and other stakeholders. The following clinical experts provided input that helped
guide the ICER team as we shaped our scope and report. None of these individuals is responsible for
the final contents of this report or should be assumed to support any part of this report, which is
solely the work of the ICER team and its affiliated researchers.
For a complete list of stakeholders from whom we requested input, please visit:
https://icer-review.org/material/psoriasis-stakeholder-list/
Expert Reviewers
Alexa B. Kimball, MD
Harvard Medical Faculty Physicians
Beth Israel Deaconess Medical Center
Conflict of Interest Declaration: Alexa B. Kimball is a consultant for Novartis, AbbVie, UCB, Lilly,
Janssen. Investigator to AbbVie, and UCB. Fellowship funding from Janssen and AbbVie. President
of the International Psoriasis Council.
Joseph F. Merola, MD MMSc
Assistant Professor, Director of the Center for Skin and Related Musculoskeletal Disease
Dept of Dermatology and Medicine Division of Rheumatology
Harvard Medical School, Brigham and Women’s Hospital
Conflict of Interest Declaration: J. F. Merola is a consultant and/or investigator for the following
relevant companies: AbbVie, Amgen, Eli Lilly, Novartis, Pfizer, Janssen, UCB, Celgene.
Leah McCormick Howard, J.D.
Chief Operating Officer
National Psoriasis Foundation
Conflict of Interest Declaration: The National Psoriasis Foundation works with all the manufacturers
that have a therapy in the psoriatic disease space, including AbbVie, Amgen, Boehringer Ingelheim,
Celgene, Eli Lilly, Janssen, Merck, Novartis, Ortho Dermatologics, Pfizer, Sandoz, Sun Pharma, and
UCB. A full list of their funders can be found in their Annual Report.
Bram Ramaekers, PhD
Senior Researcher Health Economics
Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA)
Maastricht University Medical Center
Conflict of Interest Declaration: Bram Ramaekers did consulting for Janssen, but the consulting fee
was 100kg:
45mg/90mg subcutaneously
at week 0 and 4, then every
12 weeks
100mg subcutaneously at
weeks 0, week 4, then every 8
weeks
adalimumab / Humira®
AbbVie
certolizumab pegol /
Cimzia®
UCB
80mg subcutaneously, then
40mg every other week
starting 1 week after initial
dose
IL 12/23
ustekinumab / Stelara®
Janssen
Reference Biologic
2009/09/25
Available
IL 23
guselkumab/ Tremfya®
Janssen
Reference Biologic
2017/07/13
Available
tildrakizumab-asmn /
Ilumya®
Sun/Merck
Reference Biologic
2018/03/20
Not yet launched
100 mg subcutaneously at
weeks 0, 4, then every twelve
weeks
risankizumab
AbbVie
Submitted to the FDA
on April 25, 2018
n/a
n/a
secukinumab / Cosentyx®
Novartis
Reference Biologic
2015/01/21
Available
300mg subcutaneously at
weeks 0, 1, 2, 3, 4 then 300mg
every 4 weeks
ixekizumab /
Taltz®
Eli Lilly
Reference Biologic,
2016/03/22
Available
brodalumab /
Siliq®
Valeant
Reference Biologic
2017/02/15
Available
160mg subcutaneously at
week 0, then 80mg at weeks
2, 4, 6, 8, 10, 12, then 80mg
every 4 weeks
210mg subcutaneously at
weeks 0, 1 and 2, then every 2
weeks*
Apremilast /
Otezla®
Celgene
Reference Biologic
2014/09/23
Available
IL 17
PDE-4
5-day titration then 30mg
orally 2x/day thereafter
1
This table includes all reference biologics approved or submitted for approval, but only the 2 biosimilars that are
currently available. Four other biosimilars have been FDA approved, but are not available mainly due to patent
litigation.19,20
©Institute for Clinical and Economic Review, 2018
Final Evidence Report: Plaque Psoriasis Condition Update
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For many of these agents, there is some suggestion of waning effectiveness with continued use,
known as biologic fatigue.21 To maintain effectiveness, physicians often prescribe increasing doses
of targeted immunomodulators. On the other hand, physicians occasionally prescribe lower doses
of effective medications to decrease out-of-pocket costs. Patients switching from one biologic to
another may have a slightly lower response rate, however this has not been consistently
demonstrated.22
General safety concerns for targeted immunomodulators primarily relate to effects on the immune
system: a range of infections, including tuberculosis, and malignancies, especially skin cancer and
lymphoma. Specifically, the use of TNFα agents is associated with increased risk of reactivation of latent
tuberculosis infections. But overall, registry studies have shown that increased risks of major adverse
cardiovascular events and cancer, especially lymphoma and nonmelanoma skin cancer, initially
attributed to biologic therapy, are most likely related to psoriasis itself and not to its treatment.23,24
Evidence on the safety of specific agents will be further discussed in Section 3.
Insights Gained from Discussions with Patients and Patient Groups
In the development of the 2016 report,25 ICER had conversations with and received input from
patient advocacy groups, including the National Psoriasis Foundation, and individual patients.26
These conversations highlighted the shortcomings associated with clinical trial outcomes in many
studies of psoriasis therapies, frustrations with the healthcare system, as well as the social,
emotional, and financial impact of psoriasis. These issues were presented by the National Psoriasis
Foundation at the ICER public meeting on the topic.27,25 A discussion of the shortcomings associated
with clinical trial outcomes in many studies of psoriasis therapies can be found in section 1.4 of this
report.
Stigma of disease
•
•
•
•
•
People seeing the lesions conclude the patient has a communicable disease.
Choices of clothing to hide psoriatic skin.
Avoidance of certain activities such as swimming.
Children with psoriasis, especially teens, face teasing, bullying, and shunning.
Psoriasis is associated with a higher likelihood of having depression, anxiety, and suicidal
ideation.
Difficulties with treatments
•
Time from onset to diagnosis averages two years, even more in patients with darker skin
tones.
©Institute for Clinical and Economic Review, 2018
Final Evidence Report: Plaque Psoriasis Condition Update
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•
•
•
Difficult to apply topical therapies, especially when the affected area involves the scalp or
covers a large part of the body.
Multiple injections on a daily or weekly basis, especially initially, during induction.
Time and travel for administration of phototherapy and infused therapy.
Problems with coverage
•
•
•
•
Requirements for “step therapy” forcing patients to start treatment with less efficacious
medications.
Lack of clarity in the exception process and timing for physicians and patients.
Patients have to “start over” with “step therapy” of previously-tried medications after
switching insurance.
High out of pocket costs hindering treatment or leading to undertreatment.
Potential Cost-Saving Measures in Psoriasis
As described in its Final Value Assessment Framework for 2017-2019, ICER will now include in its
reports information on wasteful or lower-value services in the same clinical area that could be
reduced or eliminated to create headroom in health care budgets for higher-value innovative
services (for more information, see https://icer-review.org/final-vaf-2017-2019/). ICER encourages
all stakeholders to suggest services (including treatments and mechanisms of care) currently used
for people with psoriasis that could be reduced, eliminated, or made more efficient.
We did not receive any suggestions in response to the final scoping document or draft report. We
also did not identify recommendations specific to the management of plaque psoriasis from
professional organizations such as Choosing Wisely, the American Academy of Dermatology, or the
US Preventive Services Task Force.
Comparative Clinical Effectiveness
To inform our analysis of the comparative clinical effectiveness of targeted immunomodulators for
moderate-to-severe psoriasis, we abstracted evidence from available clinical studies. We included
all articles from our 2016 review. We updated our previous search strategy to include new
evidence on the drugs in the 2016 review; and added in the four new drugs (guselkumab,
tildrakizumab, risankizumab and certolizumab pegol). Our updated literature search identified 17
RCTs. In addition, we included all 36 individual RCTs from the previous review, to make a total of 53
RCTs.
Trials were rated to be of good or fair quality using criteria from U.S. Preventive Services Task Force
(USPSTF).28 We did not assign a quality rating to two trials that were available only in the grey
©Institute for Clinical and Economic Review, 2018
Final Evidence Report: Plaque Psoriasis Condition Update
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literature (one placebo controlled trial of risankizumab and one head-to-head trial between
secukinumab and ustekinumab). Characteristics of the trials for the new agent are presented in
Table ES2 (See full report for characteristics of all Phase III trials).
Trial populations included patients with moderate-to-severe plaque psoriasis despite generally
having used topical treatments, older systemic treatments, phototherapy, or other targeted
immunomodulators. Trials required washout of prior therapies and participants not to use non-trial
treatments. Use of other treatments was prohibited in the interest of directly evaluating the
comparative effectiveness of targeted immunomodulators to placebo or to one another.
The primary outcome for all RCTs of targeted immunomodulator therapy was assessed at the end of
the induction period (between 10 and 16 weeks after initiation, depending on agent), after which
treatment crossover was typically allowed. Because of this, we could only confidently compare the
comparative efficacy of targeted immunomodulators at the end of the induction period. Long-term
effectiveness and safety data were variably reported by individual drug.
Table ES2. Certolizumab Pegol, Guselkumab, Tildrakizumab and Risankizumab Phase III Trials
Drug
Trials
Certolizumab
Pegol 29,30
CIMPASI 1
CIMPASI 2
CIMPACT†
VOYAGE 1†
VOYAGE 2†
RESURFACE 1†
RESURFACE 2†
UltIMMA 1†
UltIMMA 2†
IMMhance*
Guselkumab31,32
Tildrakizumab33
Risankizumab 34 35
Total
patie
nts
1,020
Induction
period
(weeks)
16/12
PASI,
(mean)
Age
(years)
Previous
biologics
,%
30
PsA,
%
46
Psoriasis
duration
(years)
18
20
1,829
16
22
44
18
21
19
1, 862
12
20
46
NR
17
NR
1,504
16
20
48
NR
42
NR
18
*Only available in the grey literature as of September 2018; †Placebo controlled trials with active comparators (others are
placebo controlled); See Table 3.1 in main report for complete list of all Phase III trials
Clinical Benefits
Psoriasis Area and Severity Index (PASI)
The Psoriasis Area and Severity Index (PASI) was reported as the primary measure of clinical benefit
in all trials. PASI is a measure of the percent body surface area with psoriatic lesions in each of four
regions (head, trunk, arms, and legs) as well as the degree of erythema, induration, and scale of the
lesions in each area. The primary endpoint for most trials was the proportion of patients achieving
PASI 75 (a 75% reduction in the PASI score) at the end of the induction period. However, five new
trials relating to guselkumab (VOYAGE 1 &2) and risankizumab (ULTIMMA 1 & 2, IMMHANCE); one
head-to-head trial between ixekizumab and ustekinumab (IXORA-S), and two head-to-head trials
©Institute for Clinical and Economic Review, 2018
Final Evidence Report: Plaque Psoriasis Condition Update
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between secukinumab and ustekinumab [CLEAR and CLARITY] specified PASI 90 as their primary
endpoint.
All targeted immunomodulators showed statistically-significantly higher PASI 75, PASI 90 and PASI
100 response rates in comparison to placebo at the end of induction. In individual placebocontrolled RCTs, the incremental proportion of patients achieving PASI 75 above placebo within
trials was 61% to 69% for certolizumab pegol (three trials); 36,37 78% to 85% for guselkumab (two
trials);31,32 56% to 60% for tildrakizumab (two trials);33 and 80% to 85% for risankizumab (three
trials).35,38 In direct comparative trials of the new agents, guselkumab was superior to adalimumab;
tildrakizumab and 400mg certolizumab pegol was superior to etanercept; and risankizumab was
superior to ustekinumab (see Table ES3). However, 200mg certolizumab pegol was not significantly
different from etanercept (see Table ES3).
Direct comparative trials of the older agents showed that ustekinumab, secukinumab, ixekizumab
and infliximab were superior to etanercept; secukinumab, ixekizumab, and brodalumab were
superior to ustekinumab (see report for details).
Given the paucity of head-to-head data comparing treatments, we performed indirect comparisons
of PASI response using Bayesian network meta-analyses (NMAs). Further details on these methods
are available in the full report. On relative effectiveness of the PASI measures (measured as relative
risk (RR) of achieving PASI 75 or 90 responses during induction), the result showed that two of the
IL-23 agents (risankizumab and guselkumab), all three IL-17 agents (ixekizumab, brodalumab and
secukinumab), and infliximab all had similar effectiveness on PASI response. These agents did not
differ statistically, as the likelihood of achieving PASI 75 or PASI 90 response included 1.0 (no
difference) in the 95% credible intervals (see Table ES4). These agents were statistically significantly
more effective in terms of PASI 75 and PASI 90 outcomes than adalimumab, ustekinumab 45/90 mg,
certolizumab pegol 200/400mg, tildrakizumab, etanercept and apremilast. Adalimumab,
ustekinumab 45/90 mg, certolizumab 200mg/400mg, and tildrakizumab did not differ significantly,
and all were significantly better than etanercept and apremilast.
©Institute for Clinical and Economic Review, 2018
Final Evidence Report: Plaque Psoriasis Condition Update
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Table ES3. Comparative Trials: PASI Responses
Trial
New Drugs
VOYAGE 1
VOYAGE 2
CIMPACT
RESURFACE 2
ULTIMMA 1
ULTIMMA 2
Treatment
PASI 75
p-value
PASI 90
p-value
PASI
100
p-value
Adalimumab
Guselkumab
Adalimumab
Guselkumab
Etanercept
Certolizumab 200mg
Certolizumab 400mg
73
91
69
86
53
61
67