Supplementary material (appendix)

Supplementary table 1: Definitions of appraisal outcome categories

Agency / Definition /
Recommended / Restricted / Not recommended
NICE / Recommended for use within the NHS, with no restrictions / Optimised – i.e. restriction placed on the eligible patient population
Also includes appraisals recommended ‘only in research’ / Not recommended for use within the National Health Service
CADTH / Recommendation that the drug be listed, with no conditions placed / Recommendation that the drug be listed, with one or more conditions placed on the eligible patient population or requirement for improved cost-effectiveness / Recommendation that the drug not be listed
IQWiG / Added benefit in all subgroups / Added benefit in at least one subgroup, and no added benefit in at least one subgroup / No added benefit in any subgroups

CADTH: Canadian Agency for Drugs and Technologies in Health; IQWiG: Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen; NICE: National Institute for Health and Care Excellence

Supplementary table 2: Definitions of non-comparative study types

Study type / Classification
Single arm study / Clinical trial with only one treatment arm (i.e. all participants receive the same intervention)
Single arm extension study of a comparative trial / Extension phase of a comparative trial, with only one treatment arm
Randomized, dosing study / Study in which different doses of an intervention are evaluated in separate treatment arms, but no other comparators are evaluated
Other / Any non-comparative study not falling into the categories above, including registry data, retrospective audits, case series, case reports, and compassionate use studies

Note: indirect comparisons were not considered within the analysis.

Supplementary table 3: Drugs that were appraised solely on the basis of non-comparative evidence

Drug / Indication / ICD-10 category / Date / Recommendation / Clinical evidence base / Reason for consideration of evidence
NICE (n=5/118)
Fulvestrant / Locally advanced or metastatic progressive breast cancer in postmenopausal women / Neoplasms / Dec-11 / Not Recommended / One phase III study investigating 2 doses of fulvestrant and 2 dose-ranging studies / ·  Unmet need for new treatment options
Ledipasvir-sofosbuvir / Chronic hepatitis C / Infection / Nov-15 / Restricted / 10 non-comparative studies investigating ledipasvir-sofosbuvir for different treatment durations and different genotypes / ·  Anticipated large magnitude of treatment effect
·  Unmet need for new treatment options, especially in GT4
Ofatumumab / Chronic lymphocytic leukaemia refractory to fludarabine and alemtuzumab / Neoplasms / Oct-10 / Not Recommended / One prospective uncontrolled trial / ·  Lack of treatment alternatives
·  Small patient population
·  Short life expectancy
Peginterferon alfa and ribavirin / Hepatitis C (children and young people) / Infection / Nov-13 / Recommended / PegIFNα-2b/RBV: One uncontrolled observational study and one single-arm study / ·  Lack of treatment alternatives
·  Anticipated large magnitude of treatment effect
PegIFNα-2a/RBV: five single-arm studies
Trabectedin / Advanced soft tissue sarcoma / Neoplasms / Feb-10 / Recommended / One phase III study investigating 2 doses of trabectedin and 3 uncontrolled studies / ·  Lack of treatment alternatives
·  Small patient population
CADTH (16/262)
Aldesleukin (IL-2) / In-transit Melanoma / Neoplasms / Jul-15 / Recommended / Two single arm studies / ·  Small patient population
·  Lack of treatment alternatives
Brentuximab vedotin / Systemic Anaplastic Large Cell Lymphoma / Neoplasms / Dec-13 / Restricted / One single arm study / ·  Small patient population
·  Unmet need for new treatment options
·  Short life expectancy
Brentuximab vedotin / Hodgkin Lymphoma / Neoplasms / Sep-13 / Restricted / One single arm study / ·  Small patient population
·  Lack of treatment alternatives
·  Short life expectancy
Bosutinib / Chronic Myeloid Leukemia / Neoplasms / Jun-15 / Restricted / One single arm study / ·  Unmet need for new treatment options
·  Small patient population
Ceritinib / Metastatic Non-Small Cell Lung Cancer / Neoplasms / Dec-15 / Not recommended / Two single arm studies / ·  Unmet need for new treatment options
Crizotinib / Advanced Non-Small Cell Lung Cancer / Neoplasms / Oct-12 / Not recommended / Two single arm studies / ·  Unmet need for new treatment options
Darunavir / HIV infection (Pediatric) / Infection / Jun-10 / Recommended / One single arm study / ·  Anticipated large magnitude of treatment effect (due to approved adult indication)
·  Unmet need for new treatment options
Eculizumab / Atypical Hemolytic Uremic Syndrome / Blood / Jul-13 / Not recommended / Two uncontrolled prospective studies / ·  Small patient population
·  Unmet need for new treatment options
Pasireotide diaspartate / Cushing’s Disease / Endocrine/ metabolic / Feb-15 / Not recommended / One dose-ranging study / ·  Unmet need for new treatment options
Ledipasvir/ Sofosbuvir / Chronic Hepatitis C / Infection / Mar-15 / Restricted / Various trials looking at sofosbuvir/ledipasvir for 12 or 24 weeks, with or without RBV / ·  Anticipated large magnitude of treatment effect
·  Unmet need for new treatment options
Darunavir/ cobicistat / HIV Infection / Infection / Mar-15 / Restricted / One single arm study / ·  Anticipated large magnitude of treatment effect
Daclatasvir / Chronic Hepatitis C (genotype 3) / Infection / Sep-15 / Restricted / Two uncontrolled trials, with or without RBV / ·  Anticipated large magnitude of treatment effect
·  Unmet need for new treatment options
Ponatinib / Chronic Myeloid Leukemia/ Acute Lymphoblastic Leukemia / Neoplasms / Oct-15 / Restricted / One single-arm study / ·  Unmet need for new treatment options
·  Small patient population
Romidepsin / Peripheral T-Cell Lymphoma / Neoplasms / Jun-15 / Restricted / Two single-arm studies / ·  Unmet need for new treatment options
Taliglucerase alfa / Gaucher disease / Inborn and other disorders of metabolism / Oct-15 / Not recommended / Two studies evaluating two doses of taliglucerase alfa, and two single-arm studies, one with an extension phase / ·  Lack of treatment alternatives
Vismodegib / Advanced Basal Cell Carcinoma / Neoplasms / Jan-14 / Restricted / One single arm study / ·  Lack of treatment alternatives
IQWiG* (6/169)
Vismodegib / Basal cell carcinoma / Neoplasms / 15/11/2013 / Not recommended / Four single-arm studies / ·  Not considered relevant
ipilimumab, addendum / Melanoma / Neoplasms / 05/06/2014 / Not recommended / Individual patient-level data, used to inform an indirect comparison / ·  Not considered relevant
x 2 / ·  Not considered relevant
simeprevir addendum / Chronic Hepatitis C / Infection / 21/11/2014 / Not recommended / Single-arm study used to inform an unadjusted indirect comparison / ·  Not considered relevant
Ledipasvir/sofosbuvir / Chronic Hepatitis C / Infection / 02/03/2015 / Restricted / Multiple studies including ledipasvir/sofosbuvir for different durations and with/without RBV / ·  Anticipated large magnitude of treatment effect
Lomitapide / homozygous familial hypercholesterolaemia / Circulatory / 15/09/2015 / Not recommended / Single-arm study plus its extension / ·  Not considered relevant

* Only the evidence for sofosbuvir/ledipasvir was considered relevant for the benefit assessment. Non-comparative evidence was presented but not considered relevant for assessment by IQWiG in the other listed appraisals.

Note: ‘unmet need’ was cited as a reason for consideration when defined as such by the HTA agency. This usually referred to scenarios in which there were no treatment alternatives, as well as scenarios in which treatment alternatives were available but are lacking in efficacy, safety, or quality of life attributes.

CADTH: Canadian Agency for Drugs and Technologies in Health; HCV: hepatitis C virus; ICD-10: International Classification of Diseases, 10th revision; IQWiG: Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen; pegIFN: pegylated interferon; NICE: National Institute for Health and Care Excellence; RBV: ribavirin