Anna Szerb and Panos Kanavos
Health Technology Assessment of Cancer
Drugs in France and Germany: Commonalities
and Differences in the Value Assessment of
Medical Technologies
Working Paper No: 43/2015 January 2015 LSE Health
HealthTechnologyAssessmentofCancerDrugsinFranceandGermany‐
CommonalitiesandDifferencesintheValueAssessmentofMedicalTechnologies
AnnaSzerb
1
andPanosKanavos
1
1
LSEHealth,LondonSchoolofEconomicsandPoliticalScience
WorkingPaperNo.43/2015
FirstpublishedinJanuary2015by:
LSEHealth
TheLondonSchoolofEconomicsandPoliticalScience
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©AnnaSzerb,PanosKanavos
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ISSN2047‐8879
CorrespondingAuthor:
PanosKanavos
DepartmentofSocialPolicy
OldBuilding
LondonSchoolofEconomicsandPoliticalScience
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2
Abstract
Context Health Technology Assessment (HTA) plays an increasingly important role in the
process of allocating finite healthcare resources, especially in the context of innovative, high-
cost, specialized medicines. Recent reforms of the value assessment of pharmaceuticals in
both France and Germany provide the basis for a comparative analysis of the changing
market access landscape for cancer drugs in these two countries.
Objectives To examine the commonalities and differences in the recently reformed benefit
assessment processes of the two countries; to understand the priorities of each HTA agency
by focusing on the process and methodology of HTAs; and finally, to derive the effects
thereof on final outcomes, patient access to and list prices of cancer drugs.
Methodology A descriptive analysis and an in-depth comparison of cancer medications
appraised by both agencies was undertaken based on the publicly available databases of the
Federal Joint Committee (Gemeinsamer Bundesausschuss – G-BA) in Germany and the
National Authority for Health (Haute Autorité de Santé – HAS) in France between 2011 and
2014.
Results Similarities were observed in the process and evidence requirement of the HTAs
undertaken by the G-BA and the HAS but the clinical benefit ratings awarded for the same
drug-indication pair often differed; arguably, due to differing methods used to assess the
relevance of clinical endpoints in the submitted evidence. Sub-group analyses were very
common in the G-BA assessments, and clinical added benefit was often awarded for only a
subset of patients. The HAS emphasized unmet medical need and availability of therapeutic
alternatives in its reasoning for positive decisions. None of the agencies provided economic
evaluations for the appraisals. There was no direct correlation between the added benefit
ratings and the list prices.
Conclusion Increasing transparency of HTA processes and improving the quality of clinical
evidence submitted are shared goals for both HTA bodies and manufacturers. Therefore
detailed information on the determinants of certain levels of added clinical benefit and robust
guidelines for manufacturers on submission requirements are necessary. Furthermore,
economic evaluations of high-cost, innovative technologies are vital to make decisions about
the reimbursement status and pricing of such medications.
What this study adds:
Evidence on similarities in the process and some methodologies employed by the
agencies but divergence in the reasons and criteria prioritized when granting added
clinical benefit rating to new technologies
In-depth perspective of the very recent developments in the changing HTA processes and
requirements in France and Germany
Detailed description of the endpoints used and other reasons considered by the
evaluating bodies in all cancer drug assessments since 2011
Evidence on the lack of enforcement of economic evaluation requirements in the HTA
procedure of cancer drugs
3
Table of Contents
1. Background....................................................................................................................................4
2. Methodology...................................................................................................................................7
2.1 Data and Sample Selection..................................................................................................................7
2.2 Case Studies and Pricing.....................................................................................................................9
3. Results............................................................................................................................................11
3.1 HTA: Decision-making Process and Methods in Germany and France................................11
3.2 Comparison of the Outcomes and Methodologies for Common Appraisals.........................16
3.2.1. Overall Results..........................................................................................................................................16
3.2.2. Comparison of HTA Methods and Criteria for Common Appraisals......................................21
3.3. Case Studies.........................................................................................................................................25
3.3.1. Uniform Decisions....................................................................................................................................25
3.3.2. Divergent Decisions.................................................................................................................................30
4. Discussion......................................................................................................................................34
4.1 Process.................................................................................................................................................... 34
4.2 Methods.................................................................................................................................................34
4.2.1. Clinical evidence.......................................................................................................................................34
4.2.2. Sub-group analysis...................................................................................................................................35
4.2.3 Endpoints and recommendation............................................................................................................35
4.2.4 Economic evaluation and pricing..........................................................................................................35
4.3. Limitations...........................................................................................................................................36
5. Conclusion and Policy Recommendations............................................................................37
Figures...............................................................................................................................................39
Figure 1........................................................................................................................................................39
Figure 2........................................................................................................................................................40
Figure 3........................................................................................................................................................41
Figure 4........................................................................................................................................................42
References.........................................................................................................................................43
Appendix...........................................................................................................................................53
Appendix 1. Master database..................................................................................................................53
Appendix 2. Common appraisals - detailed comparison..................................................................59
Appendix 3. Endpoints defined..............................................................................................................62
Appendix 4: Common appraisals - information.................................................................................63
Appendix 5. HTA methods and criteria for common appraisals – full sample..........................64
4
1. Background
Economic sustainability of the pharmaceutical market is a global concern amid rapid
improvement in health technologies that enable patients to live longer with previously
untreatable diseases. While the desirability of new and improved health technologies is
uncontested, the scarcity of resources in healthcare necessitates rationing mechanisms and
prioritising to allocate finite healthcare budgets. Health technology assessments (HTAs) aim
to evaluate the added benefit of new technologies relative to their cost in order to derive their
opportunity cost, that is the health gain forgone by not reimbursing other medications.
Different evidence requirements, data interpretation techniques and country-specific
regulation in HTAs allow disparate value assessment outcomes for the same medicines in the
various pharmaceutical markets, giving rise to concerns about inequitable access to
medicines across countries.
Oncological diseases present a growing concern for payers and public health budget holders
due to increasing patient numbers and treatment costs. Rising incidence of cancer is
accompanied by increasing survival rates due to improvement in the effectiveness of
treatments; an estimated 32.5 million men and women were still alive in 2012, who were
diagnosed up to five years before that date. The most common diagnoses have been breast
(females only), bowel (including anus) and prostate cancer
1
. The improvement in survival
rates for cancer patients (see Figure 1.) implies longer treatment time and higher treatment
costs. From a health economic point of view, cancer types that can be controlled for years,
such as chronic lymphocytic leukaemia, and those that are recurrent, allowing patients to live
with cancer for years, can be treated as chronic illnesses
2
. Health technology assessments are
therefore necessary tools for policy-makers to decide which new technologies provide
greatest value for money, both on the individual and on the population level.
The notion of “value” provided by medicines varies in different country contexts but it
provides a key insight into country-specific priorities regarding new medicinal products. The
novelty of this paper lies in the evaluation of the German value assessments of cancer drugs
1
Ferlay et al. 2012
2
Cancer Research UK, 2013
5
since the recently passed Act on the Reform of Market for Medicinal Products
(Arzneimittelmarkt-Neuordnungsgesetz - AMNOG), the introduction of a comparative
clinical benefit assessment of products with new active ingredients. The act, which came into
force on the 1
st
of January 2011, obliges new pharmaceutical products to undergo an early
evaluation procedure by the Federal Joint Committee (Gemeinsamer Bundesausschuss – G-
BA). Evidence on comparative effectiveness plays a key role in this reformed benefit
assessment and therefore also in pricing and reimbursement (P&R) decisions. In France,
medical benefit (Service Médical Rendu – SMR) and improvement in medical benefit
(Amélioration du Service Médical Rendu – ASMR) granted by the National Authority for
Health (Haute Autorité de Santé – HAS) had already been the key drivers of P&R decisions
prior to 2011. The passing of two laws in the same year nevertheless altered the
pharmaceutical market access conditions for companies in France to a great extent; including
the requirement to submit comparative evidence for reimbursement. Given the recent
reforms of the appraisal processes, a comparative study of the two HTA procedures in the
context of cancer drugs has not been carried out in a depth similar to this paper.
The increasing public scrutiny surrounding cancer treatment costs coincides with a move
towards improved and more transparent HTA procedures in both Germany and France; in
particular, strengthening the comparative nature of evaluations to existing treatments. The
resulting similarities and differences can therefore be showcased through the in-depth
comparison of the cancer drug assessments that have taken place in both countries since the
passing of the AMNOG. This paper aims to inform both policy-makers and pharmaceutical
companies about the changing market access landscape for cancer drugs in the chosen
countries through the comparison of the process and methods of the reformed benefit
assessment procedures.
The objectives of this paper can therefore be summarized as follows:
Conduct an in-depth comparison of the early benefit evaluation process in Germany
to the medical benefit assessment in France through the analysis of common cancer
drug appraisals carried out in the period between 2011-2014
Examine the differences in the outcome of the appraisals of the same drug-indication
pairs with regards to the evidence used (randomized controlled trial – RCT – results
6
submitted), sub-group analyses, the general indicators and disease-specific endpoints
considered when reaching a final decision
Assess whether differences in the process, methods and criteria used by the two HTA
agencies could have given rise to different recommendation results for the same drug-
indication pairs; particular attention should be paid to cases where the same evidence
was used to determine added clinical benefit
Compare list prices of oncology treatments with regards to their added clinical benefit
rating to present the market access landscape in the two countries
Draw conclusion about general convergence or divergence of HTA practices in
France and Germany
Synthesize the information collected to arrive at policy-recommendations to increase
the transparency and efficiency of future HTAs
7
2. Methodology
The first part of this thesis provides a static review of the HTA processes of cancer drugs in
France and Germany since the passing of the AMNOG, in the period between 2011-2014
(section 3.1). This section includes an overview of the appraisal process and methodology
used by the two HTA agencies, including the decision-making process, the evidence
requirement, the appropriate comparator therapy, the endpoints and criteria used by the two
agencies, and the role economic evaluations play in the assessment process. The second part
(section 3.2) aims to highlight the most significant differences and similarities in the methods
and focus of HTAs, aided by a case study section (section 3.3.), including a comparison of
publicly disclosed list prices of cancer medicines to their added clinical benefit rating.
2.1 Data and Sample Selection
The reasons and levers for granting cancer medicines a specific SMR and ASMR status in
France, or a specific level and probability of additional clinical benefit status in Germany are
presented through the comparative analysis of cancer appraisals since 2011.
The publicly available online drug review databases were used to obtain appraisal documents
in original languages from the websites of the German G-BA and the French HAS. In
Germany, a further comparison was undertaken between the recommendation of the advisory
body of the G-BA, the Institute for Quality and Efficiency in Health Care (Institut für
Qualität und Wirtschaftlichkeit im Gesundheitswesen – IQWiG) and the final decision of the
G-BA.
The website of the European Medicines Agency (EMA) provides a list of cancer drugs that
were granted market authorization (MA) since 2011 through the central European procedure,
however, manufacturers can apply directly to national authorities as well, therefore, the EMA
website was not complete. Cancer drug assessments were collected separately from the HAS
and the G-BA websites, which were obtained by selecting drug appraisals with cancer
8
indication after 2011 that did not have orphan-indication
3
. The search function on the G-BA
website allowed all these criteria to be selected at the same time; this was unfortunately not
the case for the HAS website, therefore in this case all the different cancer indications had to
be screened separately.
A master database was created with all the drug-indication pairs that were appraised by either
the G-BA or the HAS (or both, see Appendix 1.). This database contains the name of the
active ingredient and the brand name of the drug and its general indication. SMR and ASMR
ratings granted by the HAS were recorded, if there were more than one assessment then the
most recent decision is indicated with the date of the decision. Outcomes produced by the
German HTA body were recorded as “Favourable”, “Favourable with restrictions” and “Non-
favourable”, including the specific level and probability of clinical added benefit in the most
favourable sub-group.
From this master database, the 15 commonly appraised drugs (and 16 drug-indication pairs)
were selected and detailed information on their value assessment was collected (see
Appendix 2., 4. and 5.). Each medicine was assessed for the same indication, therefore
comparisons of final added clinical benefit ratings could be made. Marketing authorization
(MA) dates and final appraisal dates were recorded for these drugs and they were compared
across the two agencies (See Figure 2). Only prescription drugs, including vaccines were
considered.
Section 3.2 gives an overview of the outcomes for these common assessments first,
describing the decision timeframe and the listings. Afterwards it aims to drill deeper in the
analysis by looking at the reasons and levers of the two agencies for arriving at specific
benefit ratings by providing information for all the 16 commonly appraised drug-indication
pairs on:
Comparative clinical evidence (or the lack thereof) used when assessing the medicine
Subgroup analyses (including those not used in the marketing authorization process)
Appropriate comparator (or the lack thereof) used in the clinical study
3
Orphan drugs have specific appraisal procedures that are different to the ones associated with non-orphan
drugs, therefore they are not considered in this paper.
9
Primary and secondary endpoints used in the clinical study to assess clinical
effectiveness, such as overall survival (OS), progression-free survival (PFS), time
until progression and quality of life (QoL)
Consideration of safety, such as adverse effects (AEs)
Any country-specific information that was relevant to the assessment outcome
The rationale behind the decisions on the added clinical value will largely depend on the
endpoints used in the clinical studies and their relative importance in the country-specific
HTA procedure. The manufacturers of drugs that were assessed by both agencies provided
the agencies with the same clinical evidence; therefore it is particularly relevant to study
uniform and divergent decisions. It is also crucial to analyse whether differences in the
priorities associated with the above mentioned criteria could lead to substantially disparate
ratings on added clinical benefit for the same drug-indication pairs. This study aims to
uncover how the divergence in the HTA processes, methods and criteria used in these two
countries could lead to a more favourable decision in one country for the same drug, which
could imply inequitable access to cancer drugs among German and French patients.
2.2 Case Studies and Pricing
The case study section (3.3) aims to complement the analysis by presenting the most
pertinent cases to show the similarities and differences between the newly reformed HTA
processes of Germany and France. This section draws on specific cases of appraisals where
1) the same evidence was used to arrive at the same added clinical benefit rating, or 2) the
added clinical benefit rating was granted to certain sub-groups of patients in Germany or 3)
the same evidence used resulted in different benefit rating decision for the same drug-
indication pair. Given that the official evidence requirement for pricing and reimbursement
has converged in the two countries, this section aims to highlight the key drivers behind
different HTAs, particularly how the importance attached to different analysis endpoints and
subgroup analyses can lead to different appraisal outcomes.
In order to bring a dynamic element into the analysis, publicly available list prices of
medicines were also recorded for each drug and have been compared to their benefit ratings.
The German list prices were readily available in the G-BA reports for the drug assessments,
10
with the detailed description of the prices after the deduction of the statutory discounts. Since
the passing of the AMNOG law such discounts are publicly disclosed alongside with the
amount of refund paid after medicines (”Erstattungsbetrag”) according to the §130b SGB
V
45
. In France, list prices were obtained from the website of the French National Agency for
Medicines and Health Products Safety (Agence Nationale de Sécurité du Médicament et des
Produits de Santé – ANSM), a public medicines regulator body under the supervision of the
Ministry of Health
6
. These prices bear limited meaning because further discounts may be
agreed upon and the final net prices are not publicly disclosed. In Germany the additional
clinical benefit rating is the basis for rebate negotiations but these rebates are not publicly
disclosed while list prices remain unchanged. These peculiarities make the German pricing
system particularly challenging to evaluate in this context. Nevertheless, a comparison of the
list prices (or prices after statutory discounts) to benefit ratings, and secondary research data
on net prices, provide a useful insight into consequences of HTAs on drug prices and
potential profit margins for pharmaceutical companies.
The methodology and structure of this paper can therefore be summarized as follows: an
overview of the decision-making procedure and assessment of added clinical benefit for
products with new active ingredients in France and Germany since 2011; an in-depth
assessment of the HTAs in the two countries focusing on the reasons and criteria for arriving
at certain decisions about the commonly appraised drug-indication pairs; three case studies of
the most pertinent cases that truly highlight the similarities and differences between the
procedures; finally, a comparison between the benefit rating of the medicines and their
published list prices within the case study section. Discussion and policy recommendations
will conclude.
4
According to §130 SGB V 2011 (5
th
Book of the Social Code, Germany), sickness funds receive a statutory
€2.05 discount after prescription drugs from pharmacies and according to § 130a SGB V sickness funds receive
a statutory discount on prescription drugs of either 7% or 16% of the list price from manufacturers.
5
According to § 130b SGB V 2011, the amount of refund will be negotiated directly between the National
Association of Statutory Health Insurance Funds (Die Gesetzliche Krankenversicherung – Spitzenverband –
GKV-SV) and the pharmaceutical company as a discount on the list price and will be publicly disclosed.
6
The ANSM website had a more comprehensive list of prices for medicines than the Ministry of Health
website.
11
3. Results
3.1 HTA: Decision-making Process and Methods in Germany and France
Since the passing of the AMNOG, every new medicine in Germany with a new active
ingredient is subject to an early assessment of additional clinical benefit by the G-BA, based
on IQWiG recommendation. If no additional benefit is proven compared to the appropriate
comparative therapy (ACT), the price of the medication will be set according to the price in
the reference group with comparable active ingredients
7
. If additional clinical benefit is
proven, the GKV negotiates a rebate with the manufacturer that will lead to a higher
reimbursement price than that of the comparator therapy. This central arrangement has ended
pricing freedom and the price monopoly of pharmaceutical manufacturers in Germany (see
Table 3.1. and Figure 3.)
In France, medicines post-MA undergo a scientific assessment by the Transparency
Committee (Commission de la Transparence – CT), when a request has been submitted for
the inclusion of the drug on the reimbursable drugs formulary. The CT makes a
recommendation regarding the efficacy and appropriate use of the drug and determines its
SMR and ASMR level. Reimbursement rate of the medicines is based on their SMR level and
is decided by the National Healthcare Insurances (UNCAM), the French equivalent of the
German GKV – SV (National Association of Statutory Health Insurance Funds). ASMR is a
key indicator in drug price negotiations between the Economic Committee on Healthcare
Products (CEPS) and the manufacturer
8
. Table 3.1. provides additional information on the
HTA processes in France and Germany.
France also followed suit after Germany and 2011 saw the passing of two legislations, which
obligate comparative evidence submission when a reimbursement request is made by a
manufacturer and imposed de-reimbursement for medicines with insufficient SMR ratings
9
.
Subsequently there has been a shift in the effect size that is required to achieve a given
ASMR level.
7
If no such reference group exists, it will be subject to reimbursement negotiations.
8
Rémuzat et al. 2013
9
The new drug safety law (Law no. 2011-2012 of 29 December 2011) and the Social Security Funding Law of
2012.
12
Table 3.1. Cancer drug review and decision-making processes since AMNOG
Table 3.2. Cancer drug review methods since AMNOG
Agency Role
Relations
h
ip to
government
Function Reimbursement Pricing Pricing decision
Germany
IQWiG Advisory Arms-length
Guidance on level of
added clinical benefit
Negotiation based on
dossier, IQWiG
assessment and G-BA
decision on added
clinical benefit
Negotiation
between GKV-
SV and
manufacturer
If addit
i
ona
l
benefit: re
b
ate
negotiated but higher reimb. than
comparator. If no additional benefit:
reference-priced group or negotiation -
net price to sick funds cannot exceed
cost of comparator therapy
France
HAS,
Transparency
Commission
(CT)
Advisory Integrated
SMR and ASMR
guidance
Based on SMR
Major:100%,
Major/Important:65%,
Moderate:30%,
Weak:15%,
Insufficient: 0%
Negotiation
between
CEPS and
manufacturer
Pricing based on ASMR: ASMR I, II,
III: price premium ASMR IV: context-
specific ASMRV: no price premium
R
eview Decision-maki
n
g
Drugs assessed
Cli
n
ical
evidence
Clinical assessment Choice of comparator
Pri
n
ciple outcome
measures
Costs Economic Evaluation
Germany
All new drugs
Compara
t
i
ve,
phase III RCT
required
Added c
l
i
nica
l
benefi
t
based on patient-
relevant endpoints
Defined by G-BA can be
non-medication
Mortality, Morbidity,
QoL, Adverse events
Direct costs
recorded
Required but not enforced
France
All new drugs
Comparative,
phase III RCT
required
Ac
t
ua
l
c
l
i
nica
l
benefi
t
(incl. public health
impact) and
improvement in actual
clinical benefit
Currently available
therapy
Mortality, Morbidity,
QoL, Adverse events
No costs
recorded in
appraisal
documents
Not required
M
ethods
13
3.1.1. Clinical Evidence
Both the HAS and the G-BA request pharmaceutical manufacturers to submit comparative
clinical evidence (evidence from phase III randomized controlled trials) for value
assessments, therefore non-inferiority of drugs has to be proven along with safety, quality and
efficacy
1011
.
3.1.2. Appropriate Comparator Therapy
The definition of an appropriate comparator therapy (ACT) has received much scrutiny both
from the public and the policy-making side, because defining the ACT has a substantial
impact on the added clinical benefit level: if a drug is compared to a medicine that is known
to be inferior, there will be greater added benefit than if it had been compared to the
appropriate comparator. Pharmaceutical companies often get accused of evaluating their
products to placebo or treatments known to be inferior to the tested drug, producing
unreasonably positive results on additional clinical benefit
12
.
In Germany, since the passing of the AMNOG, it is no longer the manufacturer, but the G-
BA, who defines what the appropriate comparator therapy (“zweckmäßige
Vergleichstherapie”) should be. The new pricing law also broadened the options of
comparators to non-medication therapies such as surgical interventions, physiotherapeutic
treatments and best supportive or palliative care (BSC)
1314
. Although the requirements for
selecting the ACT have been defined, the wording of the reform received criticism for not
precisely defining when and by whom the ACT should be set, only that the final decision is
taken by the G-BA
15
.
In France, the manufacturer sets the ACT and the chosen comparator has to be justified. The
appropriate comparator medicine has a rather vague definition in the CT report; the level of
improvement in medical benefit is evaluated to the currently available therapies (“traitements
10
Dr. Forstmeier Health Care Consulting, [Patient-relevant Added Benefit]
11
Rémuzat et al. 2013b
12
Goldcare 2013, p.182
13
Defined as treatment to control symtoms resulting from serious illness and imporving quality of life, in: Hui
et al., 2013
14
G-BA Code of Procedure 2014, p.112
15
BDI 2014
14
disponibles”), which can be the reference medicinal product (“médicament de référence”) or
the best mode of treatment (“meilleures modalités de prise en charge”)
16
.
3.1.3 Endpoints and Criteria
In both countries, the general parameters to evaluate the clinical benefit of medicines were
safety, quality, efficacy and potential effectiveness, including adverse effects and quality of
life indicators. The SMR in France also takes into account public health impact, which
considers the burden of disease or its impact on the healthcare system
17
.
According to the EMA guidelines of 2013, improvement in overall survival (OS) is the most
persuasive clinical study endpoint; thereby reimbursement status and a price premium should
only be granted to medications that can prove to increase length of survival for patients
18
.
However, it has been recognised that specifically for oncology treatments, prolonged disease-
free or progression-free survival (DFS/PFS)
19
should be considered as primary endpoint and
OS should only be considered as a subordinate endpoint. Furthermore, disease-free or
progression-free survival rates are also morbidity-related endpoints, which are particularly
relevant for complex diseases such as cancer.
The IQWiG requests the endpoints in the study to be relevant to the indication of the product
and to be “patient-relevant” (“patientenrelevant”); this means that the tested parameters
should have direct effect on the health status of the patient, and it should be possible to
observe and discern these parameters from the health status of the patient as well. Clinical
added benefit derived from surrogate endpoints, such as tumour response rate, have to be
validated by the manufacturer on case-by-case basis
20
.
3.1.4 Economic Evaluations
The “fourth hurdle”, or the pharmaco-economic evaluation of medicines is a formal
requirement in the clinical benefit assessment procedures of new medications in both France
and Germany
21 22
. However, explicit cost-effectiveness or cost-utility analyses were not
16
Presentation of the Transparency Commission 2014
17
Rémuzat et al. 2013a
18
EMA 2012
19
Defined as the time between randomization and disease progression or death; disease progression is usually
measured by a change in size of the tumour (Booth and Eisenhauer 2012, p.1030)
20
Dr. Forstmeier Health Care Consulting, [Patient-relevant Added Benefit]
21
Decree no. 2012-1116 of the 2
nd
of October 2012 in: HAS, Department of Economics and Public Health
Assessment 2012
22
§35a SGB V, Article 5a
15
conducted or reported in either country as part of the official benefit assessment reports
studied in this paper.
3.1.5 Country-specific factors affecting decisions – recommendation restrictions
Both agencies grant reimbursement status to medicines with restrictions to the approval
indication, sometimes to a subgroup of patients within the broader indication population and
based on product positioning. Only the HAS restricted the use of all medicines studied in this
paper to specialist prescription and to hospital use only. The HAS also explicitly states on the
appraisal report that some medications require special monitoring during treatment in case
severe adverse effects occur.
Table 3.3.
Recommendation restrictions GBA HAS
Restrictions based on approval indication ✓
✓
Restriction to specific subgroups of patients ✓
✓
Restrictions based on product positioning ✓
✓
Restrictions by type of prescriber (e.g. specialist only) apply ✓
Administration restricted (e.g. hospital use only) ✓
Special monitoring necessary while treatment is administered ✓
3.2 Co
m
3.2.1.
O
The m
a
agenci
e
apprais
e
ratings
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n
only a
receive
d
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Graph 3
Decisi
o
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on the
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(see Fi
g
decisio
n
23
Some
m
24
This ti
m
several a
A
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A
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France Germany
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parison
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verall Re
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ster datab
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e
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e
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(see Table
n
y were gr
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an ASM
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o
n timefram
raisal time
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linical be
n
gure 2.)
24
.
n
date in Fr
m
edicins wer
e
m
eline show
s
ssessments.
0
A
SMRI
A
SMRII
S
MRIII
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A
B
C
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ASMR
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t
ings
3
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o
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o
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ults
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se (Appen
d
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n
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h
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t
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nted adde
d
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rating I, I
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e
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r
n
efit of eac
h
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ance, and a
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appraised b
u
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r
I
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ancer
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d
ix 1.), wh
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a
h
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t
ailed descr
i
d
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on popula
t
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or III, mo
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r
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h
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ines on t
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cording to
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t did not rec
e
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sment of eac
h
5
r
ance
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R
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11 17
Drug
A
M
ethodolo
g
i
ch include
s
a
irs, 82 of
t
s
a graphic
d
i
ption of t
h
applied fo
r
tion. Out
o
st of them
c
u
strate the
d
c
onducted
b
o
p of the
t
their decis
i
e
ive an ASM
R
h
medicine u
n
10
R
ASMRV
22
A
ssess
m
g
ies for Co
m
s
all the dr
u
t
hem asses
s
d
isplay of
o
h
e possible
r
and nine
d
o
f the dru
g
c
ould prov
e
d
ifferences
i
b
y the Fren
t
imeline ar
e
i
on date in
G
R
rating.
n
dertaken by
t
15
AB
010
m
ents'
m
mon Ap
p
u
gs assesse
d
s
ed by HA
S
o
verall asse
s
r
atings). Ei
d
rugs prov
e
g
s appraise
d
e
no additio
n
i
n the time
f
c
h and Ger
m
e
arranged
G
ermany b
e
t
he relevant a
g
2
0
Germany
C
7
11‐'14
p
raisals
d by eithe
r
S
23
and 20
s
sments an
d
i
ght of the
d
e
d added
be
d
by the
H
o
nal benefit
f
rame for
d
m
an HTA
a
according
e
low the ti
m
g
ency, if ther
e
0
D
E
0
3
16
or both
of them
d
benefit
d
rugs in
e
nefit in
H
AS, 21
(ASMR
d
ecisions
a
gencies
to their
m
eline.
e
were
25
E
3
17
It can be seen from the timeline that decisions in Germany in many cases lagged behind
decisions made in France, although the clinical added benefit assessment is equally important
in the pricing and reimbursement decisions in both countries. There are several plausible
explanation for this phenomenon: whereas the CT is integrated in the HAS, IQWiG is an
arms-length institution to the G-BA, therefore the recommendation of the IQWiG has to be
formally appraised by the G-BA, which may be a less formal procedure in France.
Furthermore, as it will be shown in the case study section, in many instances the IQWiG
recommendation restricts the indication defined in the assessment dossier to a narrower
subgroup (“indication slicing”
25
). Therefore the appraisal procedure can be viewed as a more
thorough process in Germany than in France.
Listings
A very general overview of the appraisal results shows a tendency towards marginally more
favourable results for the same drug-indication pair in Germany than in France, when
comparing ASMR ratings to the added clinical benefit level in Germany. The next section
will present a thorough analysis of the appraisal results for the 15 drugs that were assessed in
both countries, aided by a case study section, to illustrate the similarities and the differences
in the appraisal processes and methods within the French and the German clinical benefit
assessment procedures of cancer drugs.
Although both countries conduct their added clinical benefit assessments using two rating
systems, the SMR and ASMR are not directly comparable to the German system, where the
quality of the evidence and the added clinical benefit level are evaluated (Table 3.4.)
26
.
25
Ecker + Ecker GmbH 2013
26
Translation of labels is based on the official English language translation of report documents published on
the websites of the respective HTA agencies.
18
Table 3.4.
G-BA HAS
Quality of
Evidence
Extent of Benefit SMR ASMR
1. Proof ("Beleg") A) Major ("Erheblich") Major ("Majeur") ASMR I (Major)
2. Indication
("Hinweis")
B) Considerable
("Beträchtlich")
Important ("Important") ASMR II (Important)
3. Hint
(“Anhaltspunkt")
C) Minor ("Gering") Moderate ("Modéré") ASMR III (Moderate)
4. Not proven
(“Nicht belegt”)
D) Not quantifiable
additional benefit
("Liegt vor, ist aber
nicht quantifizierbar”)
Weak ("Faible") ASMR IV (Minor)
E) No additional
benefit shown ("Kein
Zusatznutzen belegt")
Insufficient
("Insuffisant")
ASMR V (Non-
existent)
f) Benefit less than
alternative ("Nutzen
geringer als der Nutzen
der zweckmäßigen
Vergleichstherapie")
The SMR defines the severity of the illness targeted by the medicine, including factors such
as the public health benefit on top of safety, quality, efficacy and effectiveness, but it is not a
comparative effectiveness assessment. The ASMR rating reflects the degree of clinical
improvement of the new medicine relative to any existing treatments. In Germany, the quality
of the comparative evidence submitted is classified in one of the four categories, based on the
bias potential of the study that is evaluated on the level of the different endpoints used in the
study. The extent of added benefit can range from “major” to “less than therapeutic
alternative” on six different levels. Table 3.5. compares the criteria of each added clinical
benefit rating in the two countries.
19
Table 3.5.
27
In terms of comparing the ratings in the two countries, although both agencies employ a scale
of five possible added benefit levels, they are not directly comparable. Therefore, the author
of this paper suggests comparing the ASMR rating with the added clinical benefit rating in
Germany. The proposed method here is to group together medicines receiving either “major”
or “considerable” added clinical benefit in Germany to ASMR ratings I, II or III; pairing a
“minor” or “unquantifiable” added benefit rating in Germany to an ASMR IV; and finally,
equating “no additional benefit” to an ASMR V rating. This categorization, although fairly
arbitrary, can accommodate uncertainties surrounding the differences between each level of
added clinical benefit, which are not clearly specified in either country. However, there is a
clear difference in medications that prove no additional clinical benefit to the comparator (3),
some additional benefit (2) and that bring considerable added benefit (1, in Table 3.6.). This
27
Pfizer Germany Online, [AMNOG for Patients – Package Instruction Leaflet for the Law] and La Revue
Prescrire 2002
G
ermany France
Therape
u
tic Be
n
efit ASM
R
- curing of illness
- s
i
gnifican
t
increase in length of
survival
- long-
t
erm freedom from serious
symptoms
- fa
r
-reaching avoidance of serious
side-effects
- easing of serious symptoms
- modera
t
e increasein leng
t
h of
survival
- tangible alleviation of disease
- re
l
evan
t
avoidance of serious s
i
de
-
effects
- meaningful avoidance of o
t
her s
i
de
-
effects
- reduction of not serious side-effects
- pharmaceut
i
ca
l
equiva
l
ent
exists
- relevant avoidance of side-effects
- modera
t
e i
m
prove
m
en
t
in
terms of therapeutic efficacy
and/or in terms of reduction of
side-effects
-m
i
nor i
m
prove
m
ent in
t
erms of
efficacy and/or utility
- c
l
i
nica
l
l
y: accepta
b
i
l
i
t
y,
convenience of use, observance
- justified extension of range
- po
t
ent
i
a
l
advan
t
age lying in
pharmacokinetic properties or in
the lower risk of drug
interaction
5
No demonstrated added
therapeutic benefit (NB)
ASMR V
- no i
m
prove
m
ent but s
t
i
l
l
granted recommendation to be
listed
6
Less therapeutic benefit
than comparator
- nega
t
i
ve opinion in
t
erms of
inclusion on the reimbursement
list
4
Additional but
unquantifiable added
therapeutic benefit
ASMR IV
2
Significant (considerable)
improvement in efficacy or
side effects (CB)
ASMR II
- important improvement in
terms of clinical efficacy and/or
in terms of side effects
3
Slight (marginal) but not
minor improvement in
efficacy or side effects
ASMR III
G
BA/
I
Q
W
i
G
A
ssessme
n
t
Criteria
ASMR criteria
1
Major added therapeutic
benefit (MAB)
ASMR I - major therapeutic advance
20
comparison method forms the basis of the case study section, when classifying decisions
made by the G-BA and the HAS as “uniform” and “divergent” decisions.
Table 3.6.
G-BA HAS
(1) Substantial added benefit “Major” (A) or “Considerable” (B) ASMR I, II, or III
(2) Some minor added benefit
“Minor” (C) or “Unquantifiable”
(D)
ASMR IV
(3) No added benefit “No added benefit proven” (E) ASMR V
21
3.2.2. Comparison of HTA Methods and Criteria for Common Appraisals
Table 3.7. HTA methods and criteria for common appraisals – subset (full dataset in Appendix 5.)
Drug Brand Name Agency
Best ad
d
e
d
be
n
efit
rating
Clinical evidence Comparator Endpoints of clinical study
En
d
poi
n
ts
considered
Reason for decision
Axitinib Inlyta GBA 2C
S
ub-group ana
l
ys
i
s;
Open-label, parallel
group
Sorafenib
Mortality, Morbidity, QoL,
AEs, Progression
Morta
l
i
t
y,
Morbidity,
QoL, AEs
Benefit rating granted to sub-population
due to study design
HAS ASMR IV
Open-label, parallel
group
Sorafenib
Mortality, Morbidity, QoL,
AEs, Progression
A
l
l
endpoin
t
s
in study
considered
No comparative data on treatment after
sunitinib (compared to everolismus)
Crizotinib Xalkori GBA 3B
Sub-group analysis;
open-label
Chemotherapy
Mortality, morbidity, QoL,
AEs, Progression
Morta
l
i
t
y,
morbidity,
QoL, AEs
GBA grants added benefit in one sub-
group, against IQWIG recommendation
HAS ASMR III Open-label Chemotherapy
Mortality, morbidity, QoL,
AEs, Progression
A
l
l
endpoin
t
s
in study
considered
No therapeutic alternative available, also
considered phase II trials
Eribulin
Mesylate
Halaven GBA 3C
Sub-group analysis;
open-label
Trea
t
m
ent of
Physician's
Choice
Mortality, Morbidity, AEs,
Progression
Mortality, AEs No complex AEs data provided
HAS ASMR IV Open-label
Trea
t
m
ent of
Physician's
Choice
Mortality, Morbidity, AEs,
Progression
A
l
l
endpoin
t
s
in study
considered
S
m
a
l
l
num
b
er of pa
t
i
ents
t
rea
t
ed w
i
t
h
capecitabine chemotherapy agent -
standard practice in France
Ipilimumab Yervoy GBA 2B Direct comparison gp100 Mortality, QoL, AEs
Morta
l
i
t
y,
QoL, AEs
S
i
gnificant i
m
m
une-media
t
ed adverse
events
HAS ASMR IV Direct comparison gp100 Mortality, QoL, AEs
A
l
l
endpoin
t
s
in study
considered
Absence of alternative, choice of
comparator
Trastuzumab
emtansine
Kadcyla GBA 2B
Sub-group analysis;
Direct comparison
Lapatinib +
Capecitabin
Mortality, morbidity, QoL,
AEs, Progression
Mortality,
QoL, AEs
Com
p
ara
t
or only ACT for one sub-
population for which benefit rating 2B
granted
HAS ASMR II Direct comparison
Lapatinib +
Capecitabin
Mortality, morbidity, QoL,
AEs, Progression
A
l
l
endpoin
t
s
in study
considered
Based on PFS, OS and acceptable
tolerance profile
Vismodegib Erivedge GBA 3C
Sub-group analysis;
indirect comparison
-
Mortality, morbidity, QoL,
AEs, Progression
Morta
l
i
t
y,
morbidity,
QoL, AEs
Devia
t
i
on from G-BA defined ACT,
ORR as primary outcome is not patient-
relevant
HAS ASMR IV Indirect comparison -
Mortality, morbidity, QoL,
AEs, Progression
A
l
l
endpoin
t
s
in study
considered
Non-comparative study data but lack of
therapeutic alternative
22
Table 3.7. presents the detailed analysis of the outcomes and the methods, endpoints and
reasons behind clinical benefit ratings for the drugs commonly assessed by both agencies.
“Best rating” entails the most favorable rating in any sub-group, according to the latest
appraisal. Endpoints considered were categorised into mortality, morbidity, quality of life,
adverse events and progression endpoints, where the last one includes all the endpoints
related to disease progression and response to treatment (detailed description in Appendix.
3.). The “Reasons for decisions” coloumn recorded any case-specific justification for a
certain benefit rating stated explicitly by the corresponding agency in the report document.
3.2.2.1 Clinical Evidence
Clinical evidence submitted for appraisal is assumed to be a double-blind, comparative RCT
unless otherwise stated. Although both the HAS and the G-BA require comparative evidence
to be submitted, only phase II studies were available in the assessment dossier of two drugs.
It was only in the case of Tafinlar
©
(dabrafenib) that this lack of head-to-head trial data lead
to unfavourable decision from both agencies; in the case of Erivedge
©
(vismodegib), both the
HAS and the G-BA granted the medicine some added clinical benefit. Although the HAS
considered phase II studies alongside head-to-head trials as well, such as in the case of
Xalkori
©
(crizotinib), the pivotal study and the main driver of clinical benefit rating was
always the comparative RCT.
3.2.2.2. Appropriate Comparator Therapy
Given the importance attached to the ACT in the assessment process, most submitted trials
used the ACT in the control arm. Derivations from the ACT were rare; in case of Kadcyla
©
(trastuzumab emtansine), the comparator in the clinical study was only appropriate for one
sub-group of the indication population and therefore the G-BA only granted quantifiable
added clinical benefit to that subgroup
28
. Such analysis was not undertaken by the HAS,
rather, an ASMR IV was decided for the whole indication group. In the case of Erivedge
©
(vismodegib), although there was deviation from the ACT, and against the recommendation
of IQWiG, the G-BA and the HAS both appraised the medicine to have some added clinical
benefit. The HAS usually did not comment on the appropriateness of the comparator therapy,
except in the case of Yervoy
©
(ipilimumab), where concerns have been raised about the
28
Patients after treatment with anthracycline, taxane or trastuzumab.
23
gp100, a vaccination without MA. In the case of Halaven
©
(eribulin mesylate), the HAS
commented on the fact that only a small number of patients were treated with capecitabine
chemotherapy agent, which is the standard practice in France.
3.2.2.3 Endpoints and Criteria
The clinical studies submitted for evaluation provided measures on mortality, morbidity,
adverse events, quality of life and other measures related to the progression of the disease.
Mortality was mostly expressed by comparing overall survival rates in Germany in the
treatment arms; in France progression-free survival was also often considered a primary
endpoint in the appraisal process. It is interesting to note that even though it is argued in
section 3.1.3 that progression-free survival is an appropriate measure of mortality and
morbidity for complex diseases such as cancer, IQWiG tended to disregard PFS as a non-
patient-relevant endpoint. A detailed list of the different endpoints that have been assessed in
the RCTs can be found in Appendix 3.
The IQWiG consistently examines the patient-relevance of all included endpoints in the
analysis and disregards those endpoints for which this relevance cannot be proven. In the case
of vismodegib, the company claims objective response rate to be a patient-relevant outcome
but the IQWiG does not accept it as one. It is argued in the IQWiG report, that although the
size of the externally visible tumour in this case is burdensome for the patients, the actual
burden should manifest itself in a change of quality of life or the severity of symptoms
associated with the tumour. The IGWiG and the G-BA therefore did not consider objective
response rate (ORR) as a patient-relevant outcome. HAS considered all endpoints that were
included in the RCT.
Subgroup analyses were regularly undertaken by the IQWiG, especially in those cases where
the ACT or the endpoints were only relevant for a specific subset of patients. The IQWiG
considered sub-group analyses undertaken in the RCT itself if they were related to the
patient-relevant endpoints. In case of crizotinib, for example, the company provided sub-
group analyses on sex and age to surrogate endpoints only. Therefore these analyses were not
considered in the value assessments. In the case of Jevtana
©
(cabazitaxel), the IQWiG
assessed the added clinical benefit in three different sub-populations; the G-BA
recommendation contains two of them and awards an indication of minor added benefit to
cabazitaxel only compared to best supportive treatment.
24
Although much less frequently, but the HAS also conducted sub-group analyses, and in the
case of cabazitaxel, a re-assessment of the effectiveness in a specific sub-group
29
granted the
medicine an ASMR rating of III instead of IV.
3.2.2.4 Economic Evaluations
Economic evaluations have not been undertaken or made publicly available even though both
agencies request them. All G-BA reports contain estimates of medicine prices before and
after statutory discounts. Yearly therapy cost of the new medicine versus the old medicine per
patients is also provided. There were no economic evaluations in the publicly available
database of the HAS for the drugs studied in this paper.
3.2.2.5 Country-specific factors affecting P&R decisions
Although the SMR has not been the focus of this study, given its importance in P&R
decisions, it should be briefly discussed. Out of all the studied drugs, only regorafenib had a
“weak” SMR rating, justified by the lack of public health benefit it may bring. However,
eribulin could also not prove any public health benefit, but was granted “important” SMR
level. The availability of therapeutic alternative and the unmet medical need within the
therapeutic indication therefore seem to bear more relevance to the SMR rating, and
subsequently for the ASMR rating as well, than the public health benefit the medicine may
provide.
29
Those patients for whom docetaxel therapy was halted due to disease progression.
25
3.3. Case Studies
In order to move the analysis from the theoretical to the empirical level, this paper continues
with a case study section to present three cases of appraisals in detail from the commonly
assessed medicines. The axis of comparison between the two countries will be the scientific
evidence used and the final added clinical benefit rating the same drug received in both
countries.
The section is organized as follows: first of all, cases where the same clinical added benefit
rating was decided based on the method described in Table 3.6. will be presented. In the first
case study of Zelboraf
©
(vemurafenib), the added benefit rating was the same in both
countries based on the same clinical evidence.
The second case study will present a situation where the added clinical benefit rating was the
same based on the same clinical evidence, however, the recommendation is restricted to
specific sub-groups in Germany (eribulin mesylate).
The third case study presents a very critical part of this paper, showing that based on the
same clinical evidence divergent decisions are possible - Zytiga
©
(abiraterone) was granted
substantially different ratings in the two countries.
3.3.1. Uniform Decisions
3.3.1.1. Vemurafenib (Zelboraf ©) – 240mg, 56 tablets
Submission and recommendation timeframe
Vemurafenib was granted MA by the EMA on the 17
th
of February 2012 and was reviewed
by the HAS and the G-BA in the same year; recommendation of the CT was published on the
3
rd
October 2012. The G-BA decision was first published on the 6
th
September 2012, with a
limited mandate of one year. The manufacturer was required to submit further evidence by
the end date of the mandate, which was received by the IQWiG on the 5
th
September 2013.
Both agencies considered vemurafenib for the treatment of adult patients with BRAF V600
mutation-positive unresectable or metastatic melanoma.
26
Clinical evidence and comparator therapy
Both agencies based their decision on the BRIM-3 study, a randomized, open-label study,
comparing vemurafenib with dacarbazine in patients with BRAF V600 mutation-positive
unresectable stage IIIc or metastatic (stage IV) melanoma as a first-line treatment.
Dacarbazine was determined to be the appropriate comparator therapy by the G-BA.
Clinical effectiveness and safety
In the case of vemurafenib, the BRIM-3 study provided a statistically significant increase in
overall survival, which was the basis of granting added clinical benefit rating by both
agencies. IQWiG also considered other endpoints in the study, such as pain (in terms of
morbidity), quality of life and adverse effects. The HAS considered OS and progression-free
survival as joint primary endpoints and considered further secondary endpoints such as
tumour response rate (see Table 3.8). The IQWiG chose different patient-relevant outcomes
than the manufacturer, because progression-free survival and tumour response as outcomes
used in the dossier were not included in the added benefit assessment of vemurafenib by the
manufacturer, according to the assessment report.
Table 3.8
G-BA HAS
Mortality (OS) ✓
✓
Progression-free survival ✓
Percentage best overall response ✓
Delay in response ✓
Duration of response ✓
Morbidity (pain, VAS Pain
questionnaire)
✓
QoL (FACT-M questionnaire) ✓
Adverse events ✓
✓
Recommendation – criteria and concerns
Based on the increase in the overall survival rate but the substantial negative adverse effects,
the G-BA granted an “indication” (“Hinweis”) of “considerable” (“beträchtlichen“) added
clinical benefit to vemurafenib. The HAS determined the ASMR level of vemurafenib to be
“moderate” based on the same reasoning and the targeted nature of the medicinal product.
27
These two ratings can be viewed as belonging to the same category using Table 3.6., that is
considerable added benefit.
Table 3.9.
Criteria
G-BA HAS
Restriction based on indication ✓
✓
Product positioning ✓
✓
Prescriber (e.g. specialist only) ✓
Administration (e.g. hospital use only) ✓
Special monitoring necessary ✓
Economic Evaluations and Pricing
Although both the German and the French HTA body officially require economic evaluations
to accompany added benefit assessments, explicit cost-effectiveness or cost-benefit analyses
were not conducted alongside the appraisal procedures or were not made publicly available
for the studied medicines.
The price of Zelboraf
©
in Germany after statutory discounts was quoted to be €2516,55; and
the yearly therapy cost per patient €131.220,12 (plus necessary biannual mutation test, €100
p.a.) compared to €4.180,30 for dacarbazine.
The HAS did not publish economic evaluation for vemurafenib; the price of Zelboraf
©
on the
ASNM website is quoted as €2288,98, with a 100% reimbursement rate.
Table 3.10
Zelboraf
©
Rating Official List Price IMS Data
30
G-BA 2b €2888.2
Net price = 42% of list
price (€1213.04)
HAS ASMR III €2288,98
31
Assumed the same
32
Price difference (German
vs French price)
+20%
(higher price in Germany)
- 53%
(lower price in Germany)
30
Dehnen et al. 2013
31
ANSM Frane Online
32
Based on empirical testing of numbers from the IMS publication.
28
As table 3.10. presents, the officially published price of Zelboraf
©
is about 20% higher in
Germany than in France, which cannot be aligned with their similar added benefit levels.
However, it should be noted that the prices quoted here do not reflect additional discounts
and clawbacks negotiated on the wholesaler or pharmacy level, given that these are not
officially disclosed. Furthermore, IMS Consulting Group (IMSCG) published data on the
negotiated rebates in Germany, where they claimed the rebate negotiated on Zelboraf
©
to be
58% of the original list price. The percentage difference between the French and the
Germany price is stated as 53%, with the medicine being cheaper in Germany
3334
. Neither the
list prices nor the net prices according to the IMS publication bear any relevance to the very
similar added clinical benefit rating of Zelboraf
©
in the two countries.
3.3.1.2. Eribulin Mesylate (Halaven
©
) – 0.88mg/2ml
Submission and recommendation timeframe
Eribulin mesylate was given MA by the EMA on the 17
th
of March, 2011; was appraised by
the HAS on the 20
th
of July, 2011 and on the 19
th
of April, 2012 by the G-BA.
Both agencies considered eribulin mesylate for the treatment of locally advanced or
metastatic breast cancer, for patients who have had at least two chemotherapeutic regimens.
Prior therapy is supposed to include an anthracycline and a taxane unless patients were not
suitable for these treatments.
Clinical evidence and comparator therapy
Both agencies based their added clinical benefit rating on the open-label, randomized phase
III study EMBRACE, comparing eribulin mesylate with an active treatment, left to the choice
of the physician. The bias potential of the study was rated as low in the IQWiG report for
eribulin, both on the overall and on the endpoint level.
Clinical effectiveness and safety
G-BA considered overall survival as primary endpoint for Halaven
©
and adverse events as
secondary endpoints. The HAS also included progression-free survival, objective response
rate and the duration of the response in the analysis. In the HAS report the final secondary
33
IMSCG 2013, p. 15
34
The IMS publication claims its sources to be the ANSM Online, which is the source of the French medicine
prices in this study as well. The report also claims access to the Lauer Taxe Online, which is a German database
for pharmacist and doctors providing information on pharmaceutical prices; unofficial publication of that data
is, however, against the law. Therefore such data could not be included in this study.
29
endpoint is names as “tolerance”, which is later described by the occurrence of adverse
events, therefore, it is here included under “adverse events”.
Table 3.11.
G-BA HAS
Mortality (OS) ✓
✓
Progression-free survival ✓
Objective response rate ✓
Duration of response ✓
Adverse events ✓
✓
Recommendation – criteria and concerns
IQWiG recommends that eribulin has no proven added benefit compared to the ACT, neither
for patients for whom treatment with taxanes or anthracyclines is no longer an option, nor for
whom they still are, due to insufficient data provided by the manufacturer. The lack of
complex adverse data is disregarded in the final decision of the G-BA, which granted a hint
of minor added benefit to both sub-groups of patients.
The CT report of HAS also does not mention the lack of data on complex adverse effects, and
does not divide the eligible population into the subgroups IQWiG has. Eribulin mesylate is
granted a minor added benefit rating (ASMR IV) for patients who have received either
anthracycline or taxane therapy before, except if patients were not able to receive these
treatments. It is important to point out that the IQWiG report states that the differentiation
between the two subgroups must be made for the evaluation, and the enclosed clinical study
also makes the division between them.
Table 3.12.
Criteria
G-BA HAS
Restriction based on indication ✓
✓
Product positioning ✓
✓
Prescriber (e.g. specialist only) ✓
Administration (e.g. hospital use only) ✓
Special monitoring necessary ✓
Economic evaluation and pricing
The G-BA calculated the yearly therapy costs of eribulin to be €44.411,82; compared to the
yearly therapy cost of €7.438,08 for the ACT, capecitabine, and €7.439,12 for vinorelbine.
30
The comparison of the official list prices showed a rather large price difference, with an over
20% higher price in Germany than in France. However, according to IMS data, the difference
in net prices were a mere 8%, with prices lower in Germany, which is more in accordance
with the similar added clinical benefit ratings.
Table 3.13.
Halaven
©
Rating Official List Price IMS Data
35
G-BA 3C €435.41
36
Net price = 73%
37
of list
price (€317.85)
HAS ASMR IV €320
38
Assumed the same
Price difference (German
vs French price)
+26%
(higher price in Germany)
- 8%
39
(lower price in Germany)
3.3.2. Divergent Decisions
3.3.2.1. Abiraterone (Zytiga
©
) – 250mg, 120 tablets
Submission and recommendation timeframe
Abiraterone was granted MA by the EMA on the 5
th
of September 2011, and was given an
extension of indication on the 18
th
of December 2012, whereby it was approved for the
treatment of metastatic castration-resistant prostate cancer (mCRPC) before chemotherapy
treatment. For this particular indication, abiraterone was appraised by IQWiG and was
granted added benefit rating by the G-BA on the 4
th
of July 2013 and on the 12
th
of June 2013
by the HAS.
Clinical evidence and comparator therapy
Both agencies based their decision on the randomized, double-blind phase III study, COU-
AA-302, that compared the efficacy and safety of abiraterone acetate to placebo, combined
with both prednisone or prednisolone, in asymptomatic or mildly asymptomatic patients with
mCRPC.
35
Dehnen et al. 2013
36
The officially quoted list price of eribulin in the G-BA report is €2612,46 for 6 vials, the price in the table
corresponds to the price per vial.
37
IMSCG 2013, p.13
38
Vidal Online via http://www.vidal.fr/Medicament/halaven-106376-
prescription_delivrance_prise_en_charge.htm. Viewed August 2014
39
IMSCG 2013, p. 15
31
The IQWiG rated the study bias potential to be low on the overall level and also on the
endpoint level for OS and severe pain; the analyses of AEs were rated as highly biased
because of the “uncertainty of model assumptions”
40
, which is later explained to be the lack
of evaluable data on adverse events.
Clinical effectiveness and safety
The CT of the HAS considered all clinical effectiveness endpoints that were included in the
benefit assessment dossier submitted by the pharmaceutical company. The complete IQWiG
recommendation examines the patient-relevance of all endpoints included in the study and
considers only those that are deemed relevant, in section 2.7.2.4.3.4 of the IQWiG report (Nr.
160) of Zytiga
©
.
It is relevant to point out that although the IQWiG final report states that quality of life
measures were considered, the Institute did not consider the FACT-P and BPI-SF
questionnaires to be either valid or patient-relevant measures of quality of life, but used the
time until the need for opiate treatment to measure pain level
41
.
Table 3.14.
G-BA HAS
Mortality (OS) ✓
✓
Radiological progression-free survival ✓
✓
Time until need for treatment with
opiates
✓
✓
Time until the start of cytotoxic
chemotherapy
✓
Time until deterioration in ECOG
performance
42
✓
Time until PSA progression
43
✓
40
IQWiG Report, Commission No. A13-06, p. 2
41
It is argued that the BPI-SF questionnair has a not verifyable methodology and that the FACT-P questionnair
has an „anchor-based” system to measure quality of life, which is based on clinical tests or physician’s opinion,
which cannot be validated as patient-relevant outcome measures.
42
Defined as the time between randomisation and the date when ECOG PS (The Eastern Cooperative Oncology
Group Performance Status) deteriorated by at least 1point/grade subject to post-hoc analysis; HAS (2013)
“Transparency commission opinion – ZYTIGA (Extension of Indication)”, p.6
43
Defined as the time between randomisation and PSA (Prostate Specific Antigen) progression according to
PCWG2 (Prostate Cancer Working Group) criteria; ibid. p. 7.
32
G-BA HAS
PSA response rate
44
✓
Objective response rate ✓
Duration of response ✓
Time until an increase in need for
analgesics
✓
Quality of life (FACT-P and BPI-SF
questionnaires)
✓
Adverse events ✓
✓
Recommendation – criteria and concerns
The G-BA’s final decision regarding Zytiga
©
for this indication states that there is a hint of
considerable added clinical benefit versus ACT (watchful waiting while maintaining
conventional ADT [androgen deprivation therapy]).
The HAS granted a minor level of added clinical benefit to abiraterone acetate. It is relevant
to note that this is a fairly large difference to the considerable added benefit declared by the
G-BA for Zytiga
©.
The HAS does not specify any particular reason for the minor level of
added benefit granted.
These two ratings are viewed as divergent decisions under the proposed comparison method
of the two rating systems based on Table 3.6.
Table 3.15.
Criteria
G-BA HAS
Restriction based on indication ✓
✓
Product positioning ✓
✓
Prescriber (e.g. specialist only) ✓
Administration (e.g. hospital use
only)
✓
44
Defined as the proportion of patients showing a reduction in PSA by at least 50% compared with baseline
according to PCWG2 criteria; ibid.
33
Economic evaluation and pricing
The G-BA final report provides information on the yearly therapy cost of Zytiga
©
per patient,
which is €52.023,69; this sum is additional to the conventional androgen deprivation therapy
provided for the treatment of patients with mCRPC. The HAS document only states the CT’s
recommendation of 100% reimbursement for Zytiga
©
.
According to the IMS publication used for pricing data, abiraterone acetate had a 28% price
reduction through official and negotiated rebates in Germany, which was then used in IMS
report comparing French and German prices of Zytiga
©45
. The IMS report comparing French
and German prices of medicines does not include information on negotiated rebates on
French drug prices and empirical calculations of this paper confirms that the price differences
are equivalent to those between the price found on the ANSM France Online and the German
price after the official and negotiated rebates quoted by the IMS report.
Table 5.16.
Zytiga
©
Rating Official List Price IMS Data
46
G-BA 3B €4743,86
Net price = 72%
47
of list
price (€3415,58)
HAS ASMR IV €3612,58 Assumed the same
Price difference (German
vs French price)
+31%
(higher price in Germany)
- 4%
48
(lower price in Germany)
45
IMSCG 2013
46
Dehnen et al. 2013
47
IMSCG 2013, p.15
48
ibid.
34
4. Discussion
4.1 Process
France assessed a much larger sample of drugs than Germany, there were only three drugs
that were assessed by the G-BA and not by the HAS, but there were 62 drugs that were
appraised by the HAS but not by the G-BA.
The rigour of the process in France and Germany is slightly different based on the sub-group
analyses done and data interpretation presented in the appraisal documents. The HAS rarely
conducts sub-group analyses other than what is already determined in the indication, even if
the submitted clinical evidence would allow for such analysis to be made (see eribulin
mesylate case study, section. 3.3.1.2.). The IQWiG conducts a very thorough analysis, which
also includes detailed reasoning to why some study endpoints have and have not been
considered (see abiraterone case study, section 3.3.2.1.). The G-BA also collects evidence on
therapy costs, which is not the case in the HAS report documents. It can therefore be argued
that the rigour of the process and the information collection on costs play an important role in
the slightly longer evaluation process in Germany compared to France.
4.2 Methods
4.2.1. Clinical evidence
One of the most important finding of this paper is the relatively weak evidence used to assess
comparative clinical benefit of cancer treatments in France and Germany. For all the studied
medicines, both agencies had the same clinical evidence submitted to them for evaluation,
usually one phase III study. Although comparative effectiveness cannot be evaluated without
comparative evidence, in the case of vismodegib, certain circumstances lead to a favourable
decision in both countries despite of the lack of appropriate clinical evidence to test added
clinical benefit.
Missing evidence altered benefit ratings substantially in both countries. In the case of
Halaven
©
(eribulin mesylate), for example, the IQWiG recommended the G-BA not to grant
added clinical benefit status. It is argued in the report that even though there was a
statistically significant difference in overall survival in one of the sub-groups treated with
35
eribulin mesylate, the lacking data on complex adverse events prevented the exclusion of
possible greater harm.
4.2.2. Sub-group analysis
The German HTA body often considered the added clinical benefit of medicines in more sub-
groups than the HAS did, and added benefit was proven in many cases just for a specific
subset of the target population identified by the manufacturer. The HAS granted added
clinical benefit on overall level and never on a sub-group level; one exception was Jevtana
©
(cabazitaxel), where the re-assessment of the medicine in a specific sub-population of eligible
patients (put forward by the manufacturer) increased the benefit rating from ASMR IV to
ASMR III.
It is expected that sub-group analyses will form an increasing important part of assessments
in both countries as medicines are developed for ever more specialized indications, which
increases research and development costs. This will in turn lead to HTA bodies targeting
even narrower sub-groups of patients, for whom actual improvement in effectiveness can be
proven in order to control costs but not to hinder access to medicines.
4.2.3 Endpoints and recommendation
Both HTA agencies were consistent in their methods of considering endpoints in studies,
Germany focused on patient-relevant outcomes whereas the HAS tended to consider all
primary and secondary endpoints that were included in the assessment dossier submitted by
the manufacturer. Although there was usually a detailed explanation of why certain endpoints
were used by the IQWiG, the exact correlation between clinical effectiveness data and added
benefit level was not explicitly stated in the appraisal reports.
Overall the added clinical benefit levels granted to medicines were only marginally different
in the two countries. Safety, clinical efficacy and non-inferiority evidently play the most
important roles in determining added clinical benefit; France puts more emphasis on the need
for the medication or the availability of therapeutic alternatives whereas Germany focuses on
the quality of clinical evidence provided.
4.2.4 Economic evaluation and pricing
There were no economic evaluations published by the HTA bodies, although in Germany the
clinical benefit rating is stated alongside with the therapy costs for the evaluated treatment
36
and the ACT as well. It could be possible to develop a method that would combine the two
figures into a ratio showing the incremental costs relative to the added benefit, similarly to
the method employed by the English HTA body, the National Institute for Health and Care
Excellence.
Based on secondary research data on pricing, it can be concluded that there is currently no
correlation between the level of added clinical benefit provided by drugs and their list prices,
or net prices based on publicly available data. Ideally in the future, there should be a move
towards greater correlation between added clinical benefit rating and price premiums
awarded to new medications over existing treatments.
4.3. Limitations
This study has several limitations. It is possible that the construction of the master database
lacks drugs that were appraised by the HAS only, given that there was not a way to select for
cancer indication as a whole, rather all the different types of cancer indications had to be
screened separately. Given that the analysis was based on publicly available information, the
criteria and reasons agencies base their decisions on may lack some confidential information
that would have uncovered some subtleties in the decision processes. Finally, full reports of
assessments were only available in original languages, which may have resulted in
translational errors.
37
5. Conclusion and Policy Recommendations
Recent reforms point to convergence in the French and German HTA methods in terms of
strengthening the comparative nature of added clinical benefit assessment of new cancer
drugs. Decisions have subsequently been only marginally different both in terms of the
timing of the decisions and in terms of the added clinical benefit rating they received. An
overall inequity of access to medicines therefore cannot be observed. Disparities in decisions,
even if marginal, highlight differing priorities of HTA bodies regarding the criteria used to
award benefit levels and the consideration of different endpoints from the clinical study. In
pursuit of more efficient HTAs in the future, it will be increasingly important for HTA bodies
to establish a system in which the level of added clinical benefit corresponds to the net price
of the medication to ensure patient access to the most effective medicines across all markets.
The transparency and legitimacy of HTA processes is in the common interest of
manufacturers, HTA bodies and policy-makers. The implementation of certain measures
would help to overcome the weaknesses of current HTAs highlighted in this paper.
In order to improve the quality of the evidence submitted to HTA bodies and thereby
improve efficiency and reduce rejections, HTA agencies need to set explicit and
detailed guidelines on the clinical evidence that is required from manufacturers for
HTAs
To increase transparency in terms of methodology, HTA bodies should also provide
detailed information on their process indicators, how they define differences between
achieved levels of clinical added benefit, what are the determinants of such ratings
and what manufactures can do to achieve the highest possible rating
To reduce disparities, cancer drug assessments should be standardized across all HTA
bodies
In order to increase the uptake of new technologies and to maximize access and health
benefit, HTAs should take place as soon as possible alongside with economic
evaluations including budget impact analysis
There should be a correlation between clinical benefit ratings and price premiums
awarded to medicines; a methodology should also be developed to ensure a
transparent way of setting prices of new cancer drugs
38
HTA bodies should also consider improving their image in the media; assessment
agencies are often pictured as the entities that prevent patient access to life-saving
medicines. Greater collaboration with policy-makers and manufacturers could ensure
that the common goal of making the most effective medications available for people
is shared between the stakeholders and is effectively communicated to the public.
39
Figures
Figure 1.
40
Figure 2.
Eribulin Mesylate(FR)
Cabazitaxel(FR)
Ipilimumab(FR) Abiraterone(FR)
Abiraterone(D)
Cabazitaxel(D)
Eribulin Mesylate(D)
Vandetanib(FR)
Ipilimumab(D)
Vandetanib(D)
Vemurafenib(D)
Vemurafenib(FR)
Axitinib(FR)
Ruxolitinib(FR)
Ruxolitinib(D)
Axitinib(D)
Crizotinib(FR)
Crizotinib(D)
Abiraterone 2(FR)
Abiraterone 2(D)
Vismodegib(FR)
Vismodegib(D)
Aflibercept (FR)
Aflibercept (D)
Dabrafenib(D)
Dabrafenib (FR)
Radium-223-dichloride (FR)
Regorafenib (D)
Regorafenib (FR)
Trastuzumab
emtansine (D)
Trastuzumab emtansine (FR)
20/07/11 20/09/11 20/11/11 20/01/12 20/03/12 20/05/12 20/07/12 20/09/12 20/11/12 20/01/13 20/03/13 20/05/13 20/07/13 20/09/13 20/11/13 20/01/14 20/03/14 20/05/14 20/07/14
Radium-223-
41
Figure 3.
Source: Schoonveld et al. 2011
42
Figure 4.
Source: Ecker + Ecker GmbH 2013
43
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Federal Joint Committee – Radium-223-dichloride” [online] (Updated 19 June 2014)
Available at: https://www.g-ba.de/downloads/39-261-2007/2014-06-19_AM-RL-
XII_Radium-223_2014-01-01-D-094_BAnz.pdf. Viewed August 2014
5. Gemeinsamer Bundesausschuss, Federal Joint Committee (G-BA) (2014) “Decision of the
Federal Joint Committee – Regorafenib” [online] (Updated 20 March 2014) Available at:
https://www.g-ba.de/downloads/39-261-1948/2014-03-20_AM-RL-XII_Regorafenib_2013-
10-01-D-077_BAnz.pdf. Viewed August 2014
6. Gemeinsamer Bundesausschuss, Federal Joint Committee (G-BA) (2014) “Decision of the
Federal Joint Committee – Trastuzumab Emtansine” [online] (Updated 19 June 2014)
Available at: https://www.g-ba.de/downloads/39-261-2008/2014-06-19_AM-RL-
XII_Trastuzumab-Emtansin_2014-01-01-D-084_BAnz.pdf. Viewed August 2014
7. Gemeinsamer Bundesausschuss, Federal Joint Committee (G-BA) (2014) “Decision of the
Federal Joint Committee – Vemurafenib (New Assessment after Expiration of Deadline)”
[online] (Updated 6 March 2014) Available at: https://www.g-ba.de/downloads/39-261-
1943/2014-03-06_AM-RL-XII_Vemurafenib_2013-09-15-D-074_BAnz.pdf. Viewed August
2014
47
8. Gemeinsamer Bundesausschuss, Federal Joint Committee (G-BA) (2014) “Decision of the
Federal Joint Committee – Vismodegib”. [online] (Updated 6 February 2014) Available at:
https://www.g-ba.de/downloads/39-261-1922/2014-02-06_AM-RL-XII_Vismodegib_2013-
08-15-D-069_BAnz.pdf. Viewed August 2014
9. Gemeinsamer Bundesausschuss, Federal Joint Committee (G-BA) (2013) “Decision of the
Federal Joint Committee – Abiraterone acetate (New Therapeutic Indication)” [online]
(Updated 4 July 2013) Available at: https://www.g-ba.de/downloads/39-261-1765/2013-07-
04_AM-RL-XII_Abirateronacetat-neuesAWG_BAnz.pdf. Viewed August 2014
10. Gemeinsamer Bundesausschuss, Federal Joint Committee (G-BA) (2013) “Decision of the
Federal Joint Committee – Aflibercept” [online] (Updated 15 August 2013) Available at:
https://www.g-ba.de/downloads/39-261-1797/2013-08-15_AM-RL-
XII_Aflibercept_BAnz.pdf. Viewed August 2014
11. Gemeinsamer Bundesausschuss, Federal Joint Committee (G-BA) (2013) “Decision of the
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https://www.g-ba.de/downloads/39-261-1675/2013-03-21_AM-RL-XII_Axitinib.pdf.
Viewed August 2014
12. Gemeinsamer Bundesausschuss, Federal Joint Committee (G-BA) (2013) “Decision of the
Federal Joint Committee – Crizotinib” [online] (Updated 2 May 2013) Available at:
https://www.g-ba.de/downloads/39-261-1704/2013-05-02_AM-RL-
XII_Crizotinib_BAnz.pdf. Viewed August 2014
13. Gemeinsamer Bundesausschuss, Federal Joint Committee (G-BA) (2013) “Decision of the
Federal Joint Committee – Vandetanib (Second Assessment)” [online] (Updated 5 September
2013) Available at: https://www.g-ba.de/downloads/39-261-1807/2013-09-05_AM-RL-
XII_Vandetanib_BAnz.pdf. Viewed August 2014
14. Gemeinsamer Bundesausschuss, Federal Joint Committee (G-BA) (2012) “Decision of the
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XII_Abirateron_BAnz.pdf. Viewed August 2014
15. Gemeinsamer Bundesausschuss, Federal Joint Committee (G-BA) (2012) “Decision of the
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XII_Cabazitaxel_BAnz.pdf. Viewed August 2014
16. Gemeinsamer Bundesausschuss, Federal Joint Committee (G-BA) (2012) “Decision of the
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17. Gemeinsamer Bundesausschuss, Federal Joint Committee (G-BA) (2012) “Decision of the
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18. Gemeinsamer Bundesausschuss, Federal Joint Committee (G-BA) (2012) “Decision of the
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XII_Vandetanib_BAnz.pdf. Viewed August 2014
48
19. Gemeinsamer Bundesausschuss, Federal Joint Committee (G-BA) (2012) “Decision of the
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20. Haute Autorité de Santé, French National Authority for Health (HAS) (2014), “Transparency
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13453_KADCYLA_PIC_INS_Avis2_CT13453.pdf Viewed August 2014
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13240_STIVARGA_PIC_INS_Avis%203_CT13240.pdf Viewed August 2014
23. Haute Autorité de Santé, French National Authority for Health (HAS) (2014), “Transparency
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24. Haute Autorité de Santé, French National Authority for Health (HAS) (2014), “Transparency
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25. Haute Autorité de Santé, French National Authority for Health (HAS) (2013), “Transparency
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30. Haute Autorité de Santé, French National Authority for Health (HAS) (2013), “Transparency
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SGB-V.pdf. Viewed August 2014
44. Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, Institute for Quality and
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45. Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, Institute for Quality and
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46. Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, Institute for Quality and
Efficiency in Healthcare (IQWiG) (2013) “IQWiG Report – Nr. 198. Enzalutamid – Benefit
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https://www.iqwig.de/download/A13-33_Enzalutamid_Nutzenbewertung-35a-SGB-V.pdf.
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47. Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, Institute for Quality and
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https://www.iqwig.de/download/A13-37_Regorafenib_Nutzenbewertung-35a-SGB-V.pdf.
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48. Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, Institute for Quality and
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52
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53
Appendix
Appendix 1. Master database
Drug Brand Name ATC Code Drug Indication
France (HAS)☞
Germany (G-BA)
SMR ASMR HAS date
Overall
Decision*
Best
outcome
month/year
A Abiraterone
Zytiga L02BX03 mCRPC Important AMR III 29-Feb-2012 2 2B 29-Mar-2012
Abiraterone 2
Zytiga L02BX03
mCRPC before
chemotherapy
Important ASMR IV 12-Jun-2013 1 3B 4-Jul-2013
Afatinib
Giotrif L01XE13 Metastatic NSCLC -
2 2B 8-May-2014
Aflibercept
Zaltrap L01XX44 Colorectal cancer Important ASMR V 24-Jun-2013 1 2C 15-Aug-2013
Axitinib
Inlyta L01XE17 Renal cell carcinoma Important ASMR IV 9-Jan-2013 2 2C 21-Mar-2013
B Bendamustine
Levact L01AA09
Chronic lymphoid
leukaemia
Important AMSR III 6-Oct-2010 0
Bendamustine 2
Levact L01AA09 Multiple Myeloma Important ASMR V
0
Bevacizumab 1
Avastin L01XC07 Metastatic breast cancer Important ASMR V 25-May-2011 0
Bevacizumab 2
Avastin L01XC07
Metastatic carcinoma of
the colon or rectum
Important ASMR IV 4-Mar-2009 0
Bevacizumab 3
Avastin L01XC07 Renal cell cancer Important ASMR IV 3-Sep-2008 0
Bevacizumab 4
Avastin L01XC07 NSCLC Important ASMR V 14-May-2008 0
Bevacizumab 5
Avastin L01XC07 Metastatic breast cancer Important ASMR III 5-Dec-2007 0
Bexarotene
Targretin L01XX25 NHL Important ASMR V 28-Mar-2012 0
C Cabazitaxel
Jevtana L01CD04 Prostate cancer Important ASMR III 17-Nov-201
2
1 2C 29-Mar-2012
Chlorambucil
Chloraminophene L01AA02
Chronic Myeloid
Leukaemia
Important - 7-Nov-2012 0
Cladribine
Leustatine L01BB04 Leukaemia Important ASMR II 25-Jun-2014 0
Crizotinib
Xalkori L01XE16 NSCLC Important ASMR III 3-Apr-2013 2 3B 2-May-2013
Cyproterone
Androcur G03HA01 Prostate cancer (palliative) Important - 19-Dec-2012 0
54
Drug Brand Name ATC Code Drug Indication
France (HAS)☞
Germany (G-BA)
Cytarabine
Cytarabine Accord L01BC01
Acute Myeloid Leukaemia
(AML)
Important ASMR V 6-Nov-2013 0
Cytarabine
Aracytine L01BC01 AML, CML Important - 19-Jan-2011 0
D Dabrafenib
Tafinlar L01XE
Unresectable or metastatic
melanoma with BRAF
V600E mutation
Important ASMR V 7-May-2014 3 - 3-Apr-2014
Daunorubicine
Cerubidine L01DB02 Leukaemia Important ASMR V 2-Apr-2014 0
Denosumab 1
Xgeva M05BX04
Skeletal event prevention
by breast or prostate cancer
Important ASMRI V 11-Apr-2012 0
Denosumab 2
Prolia M05BX04
Bone loss in patients with
prostate cancer
Insufficient - 14-Dec-2011 0
Diethylstilbestrol
Distilbene G03CB02 Prostate cancer Weak - 21-Sep-2011 0
E Enzalutamide
Xtandi L01XX mCRPC Important ASMR III 20-Nov-2013 1 2B 20-Feb-2014
Eribulin Mesylate
Halaven L01XX41 Metastatic breast cancer Important ASMR IV 20-Jul-2011 1 3C 19-Apr-2012
Erlotinib 1
Tarceva L01XE03 Metastatic NSCLC Important ASMR IV 6-Jun-2012 0
Erlotinib 2
Tarceva L01XE03
Metastatic pancreatic
cancer
Insufficient - 19-Mar-2008 0
Erlotinib 3
Tarceva L01XE03
Metastatic NSCLC after
chemotherapy
Important
ASMR IV
(only as
3rd line)
15-Mar-2006 0
Everolimus 1
Afinitor L01XE10 Breast cancer Important ASMR V 3-Apr-2013 0
Everolimus 2
Afinitor L01XE10 pNET Important ASMR IV 28-Mar-2012 0
Everolimus 3
Afinitor L01XE10 Renal cell carcinoma Important ASMR IV 13-Jan-2010 0
55
Drug Brand Name ATC Code Drug Indication
France (HAS)☞
Germany (G-BA)
F Fentanyl
Breakyl N02AB03
Paroxysmal cancer-related
pain (palliative)
Important ASMR V 6-Sep-2012 0
Fotemustine
Muphoran L01AD05 Brain tumour Important ASMR V 9-Jul-2014 0
H Histrelin acetate
Vantas H01CA03 Prostate cancer (palliative) Moderate ASMR V 29-Feb-2012 0
I
Imatinib 1
Glivec L01XE01
ALL (with chemotherapy
for children)
Important ASMR I 28-May-2014 0
Imatinib 2
Glivec L01XE01
Gastrointestinal stromal
tumour
Important ASMR III 9-Sep-2009 0
Imatinib 3
Glivec L01XE01
Dermatofibrosarcoma
protuberans
Important ASMR IV 23-Jan-2008 0
Imatinib 4
Glivec L01XE02
Hypereosinophilic
syndrome
Important ASMR III 7-Nov-2007 0
Imatinib 5
Glivec L01XE04 ALL (monotherapy) Important ASMR II 14-Feb-2007 0
Imatinib 6
Gilvec L01XE06 ALL (with chemotherapy) Important ASMR I 14-Feb-2007 0
Ipilimumab
Yervoy L01XC11 Melanoma Important ASMR IV 14-Dec-2011 1 2B 2-Aug-2012
L Leuprorelin
Eligard L02AE02 Prostate cancer Important - 24-Jul-2013 0
M Medroxyprogesterone acetate
Depo-Prodasone L02AB02 Endometrial cancer Insufficient - 18-Sep-2013 0
Medroxyprogesterone acetate 2
Farlutal L02AB02 Endometrial cancer Insufficient - 16-Feb-2011 0
Melphalan
Alkeran L01AA03
Multiple Myeloma,
Ovarian Cancer
Important - 21-Sep-2011 0
Methyl
aminolevulinate
Metvixia L02BG04 Bowen's disease Important ASMR IV 5-Mar-2014 0
N Nilutamide
Anandron L02BB02 Prostate cancer Important - 15-May-2013 0
O Octreotide
Sandostatine H01CB02
Gastro-entero-pancreatic
endocrine tumour
Important - 6-Nov-2013 0
Oxycodone
Targinact N02AA55
Severe cancer-related pain
(palliative)
Insufficient - 7-Dec-2011 0
P
Paclitaxel
Paclitaxel AHCL L01CD01 Ovarian cancer Important ASMR V 9-Jul-2014 0
56
Drug Brand Name ATC Code Drug Indication
France (HAS)☞
Germany (G-BA)
Panitumumab 1
Vectibix L01XC08
Metastatic colorectal
cancer
Important ASMR V 17-Oct-2012 0
Panitumumab 2
Vectibix L01XC08
Metastatic colorectal
cancer (KRAS)
Important ASMR V 30-Apr-2008 0
Pazopanib 1
Votrient L01XE11 Soft-tissue sarcoma Important ASMR IV 9-Jan-2013 0
Pazopanib 2
Votrient L01XE11 Renal cell carcinoma Weak
ASMR V
(1st line
treatment)
26-Jun-2013 0
Pentostatine
Nipent L01XX08 Leukaemia Important ASMR II 25-Jun-2014 0
Pertuzumab
Perjeta L01XC13 Breast neoplasms - 2 3B 1-Oct-2013
Pixantrone dimaleate
Pixuvri L01DB11 NHL - 3 - 16-May-2013
Procarbazine
Natulan L01XB01
HL and NHL (ganglionic
and intestinal), brain
tumours
Important - 20-Jun-2012 0
Profimer sodium
Photofrin L01XD01 Lung cancer Weak ASMR V 9-Jul-2014 0
Propranolol
Hemangiol D11AX Hemangioma Important ASMR III 25-Jun-2014 0
R Radium-223-dichloride
Xofigo V10XX CRPC Important ASMR IV 2-Apr-2014 2 2B
19-Jun-2014
Raltitrexed
Tomudex L01BA03
Metastatic colorectal
cancer
Important ASMR V 9-Jul-2014 0
Regorafenib monohydrate
Stivarga L01XE21
Metastatic colorectal
cancer
Weak ASMR V 14-May-2014 1 3C
20-Mar-2014
Rituximab 1
Mabthera L01XC02 Follicular lymphoma Important ASMR II 18-Jul-2012 0
Rituximab 2
Mabthera L01XC02 CLL Important ASMR III 18-Jul-2012 0
Rituximab 3
Mabthera L01XC02
CLL (not previously
treated)
Important ASMR III 25-May-2011 0
S
Sunitinib 1
Sutent L01XE04 pNET Moderate ASMR V 21-Sep-2011 0
57
Drug Brand Name ATC Code Drug Indication
France (HAS)☞
Germany (G-BA)
Sunitinib 2
Sutent L01XE04
Metastatic renal cell
carcinoma
Important ASMR II 23-May-2007 0
Sunitinib 3
Sutent L01XE04
Metastatic renal cell
carcinoma (second-line)
Important ASMR III 20-Sep-2006 0
Sunitinib 4
Sutent L01XE04
Gastrointestinal stromal
tumour
Important ASMR II 20-Sep-2006 0
T Tamoxifen
Nolvadex L02BA01 Breast cancer Important - 7-Sep-2011 0
Tegafur/gimeracil/oteracil
Teysuno L01BC53 Advanced gastric cancer Insufficient N/A 3-Oct-2012 3 -
20-Dec-2012
Tegafur+ uracil
UFT L01BC53
Metastatic colorectal
cancer
Important - 11-Apr-2012 0
Temozolomide
Temozolomide Mylan L01AX03 Glioblastoma multiforme Important ASMR V 20-Nov-2013 0
Trastuzumab 1
Herceptin L01XC03 HER2+ early breast cancer Important - 9-Jan-2013 0
Expected
mid June
2014
Trastuzumab 2
Herceptin L01XC03 Metastatic gastric cancer Important ASMR IV 16-Feb-2011 0
Trastuzumab 3
Herceptin L01XC03
Breast cancer overexpress
HER2
Important ASMR V 19-Mar-2008 0
Trastuzumab 4
Herceptin L01XC03
Breast cancer overexpress
HER2 (second-line)
Important ASMR I 4-Oct-2006 0
Trastuzumab emtansine
Kadcyla L01XC HER2+ breast cancer Important ASMR II 19-Mar-2014 2 2B
19-Jun-2014
V
Vandetanib
Caprelsa L01XE12 Medullary thyroid cancer Important ASMR IV 20-Jun-2012 2 3C
5-Sep-2013
Vemurafenib
Zelboraf L01XE15 Melanoma Important ASMR III 3-Oct-2012 1 2B
6-Mar-2014
Vinorelbine
Navelbine L01CA04 Breast cancer and NSCLC Important - 6-Jun-2012 0
Vismodegib
Erivedge L01XX43 Basal cell carcinoma Important ASMR IV 18-Dec-2013 2 3C
6-Feb-2014
Medicinal products that are intended for rare diseases in Europe with European MA without orphan designation in Europe.
Medicinal products that have been removed or withdrawn from the European Community Register (ECR) of orphan medicinal products.
58
* If the medicine is only found to bring added clinical benefit for a specific subgroup of patients, or the medicine has not been compared to the ACT defined by the G-BA,
but certain circumstances lead to a favourable decision anyway, the decision by the GBA is recorded as “Favourable with restrictions”. If the medicine was approved for the
same indication and for the same target population as applied for, and was compared to the ACT, the decision was recorded as “Favourable”. When added clinical benefit
was not proven, the decision was “Not favourable”.
Key to overall G-BA decision: (0) Not appraised, (1) Favourable, (2) Favourable with restrictions, (3)Not favourable
☞Key from section 3.2.1:
G-BA HAS
Quality of Evidence Extent of Benefit SMR ASMR
1. Proof ("Beleg") A) Major ("Erheblich") Major ("Majeur") ASMR I (Major)
2. Indication ("Hinweis") B) Considerable ("Beträchtlich") Important ("Important") ASMR II (Important)
3. Hint (“Anhaltspunkt") C) Minor ("Gering") Moderate ("Modéré") ASMR III (Moderate)
4. Not proven (“Nicht belegt”) D) Not quantifiable additional benefit ("Liegt
vor, ist aber nicht quantifizierbar”)
Weak ("Faible") ASMR IV (Minor)
E) No additional benefit shown ("Kein
Zusatznutzen belegt")
Insufficient ("Insuffisant") ASMR V (Non-existent)
f) Benefit less than alternative ("Nutzen geringer
als der Nutzen der zweckmäßigen
Vergleichstherapie")
59
Appendix 2. Common appraisals - detailed comparison
Drug
Brand
Name
GBA HAS
G-BA
(overall)
Further subgroup
IQWIG
Rec.
Added
benefit
GBA date Clinical Study
HAS
Rating
Date Clinical Study
A Abiraterone
Zytiga 2 BSC 2B 2B 29-Mar-2012 COU-AA-301 ASMR III 29-Feb-2012 COU-AA-301
Docetaxel 4
Zytiga 1 3B 3B 4-Jul-2013 COU-AA-302 ASMR IV 12-Jun-2013 COU-AA-302
Aflibercept
Zaltrap 1
2C 2C 15-Aug-2013 VELOUR ASMR V 24-Jul-2013 VELOUR
Axitinib
Inlyta 2 Post cytokine-treatment 3B 2C 21-Mar-2013
AXIS
(A4061032)
ASMR IV 9-Jan-2013
AXIS study
(A4061032)
Post sunitinib treatment 4 4 ASMR V 8-Jan-2014
C Cabazitaxel
Jevtana 2 BSC over 65 2B 2C 29-Mar-2012
TROPIC STUDY
(EFC6193)
ASMRIII
17-Nov-2012
(first
assessment: 19-
Oct-2011)
TROPIC STUDY
(EFC6193)
BSC under 65 3D
Docetaxel 4
Crizotinib
Xalkori 2
Chemotherapy is
indicated
4 3B 2-May-2013 PROFILE 1007 ASMR III 3-Apr-2013
PROFILE 1007
(Phase III), Study
1001(Phase I), 1005
(Phase II)
Chemotherapy not
indicated
4 4
D Dabrafenib
Tafinlar 3
4 3-Apr-2014 BREAK-3 ASMR V 7-May-2014
BREAK-2, BREAK
3
E Enzalutamide
Xtandi 1 Visceral metastasis 3B 2B 20-Feb-2014 AFFIRM ASMR III 20-Nov-2013 AFFIRM
No visceral metastasis 3A
60
Drug
Brand
Name
GBA HAS
G-BA
(overall)
Further subgroup
IQWIG
Rec.
Added
benefit
GBA date Clinical Study
HAS
Rating
Date Clinical Study
Eribulin Mesylate
Halaven 1
Taxanes or
anthracyclines no
longer an option
4 3C 19-Apr-2012 EMBRACE AMSR IV 20-Jul-2011
EMBRACE and
Study 201, 211
(phase II)
Taxanes or
anthracyclines still
possible
4 3C
I Ipilimumab
Yervoy 1 2B 2B 2-Aug-2012 MDX010-20 ASMR IV 14-Dec-2011 MDX010-20
3
No prior therapy,
compared to
Dacarbazine
4 4 5-Jun-2014
Only indirect
comparison
submitted
ASMR IV
06-Nov-2013
(re-assessment)
R
Radium-223-
dichloride
2
Docetaxel is still
possible
4 19-Jun-2014
ASMR IV 2-Apr-2014
Docetaxel is not
possible
2B
ALSYMPCA
(BC1-06) – data
only for this sub-
group
ALSYMPCA (BC1-
06) – data only for
this sub-group
Regorafenib
Stivarga 1 3C 3C 20-Mar-2014 CORRECT ASMR V 14-May-2014 CORRECT
T
Trastuzumab
emtansine
Kadcyla 2
Inoperable breast
cancer
4 4 19-Jun-2014
Post anthracycline,
taxane or trastuzumab
treatment
2B 2B
EMILIA – data
only for this sub-
group
ASMR II 19-March-2014
EMILIA – data only
for this sub-group,
THERESA
After treatment not
with anthracycline
4
V Vandetanib
Caprelsa 2 4 3C 5-Sep-2013 ZETA/58 Study ASMR IV 20-Jun-2012 ZETA/58 Study
4 4 6-Sep-2012
Vemurafenib
Zelboraf 1 2B 2B
6-Mar-2014
(first: 06-Sep-
2102)
Study NO25026
(BRIM-3)
ASMR III 3-Oct-2012
Study NO25026
(BRIM-3)
61
Drug
Brand
Name
GBA HAS
G-BA
(overall)
Further subgroup
IQWIG
Rec.
Added
benefit
GBA date Clinical Study
HAS
Rating
Date Clinical Study
Vismodegib
Erivedge 2
Local advanced basal-
cell-carcinoma, neither
operation nor
radiotherapy is suitable
(smBCC)
4 3C 6-Feb-2014 ERIVANCE ASMR IV 18-Dec-2013
ERIVANCE (Phase
II), STEVIE (Phase
II)
Symptomatic metastatic
basal-cell carcinoma
(lsBCC)
4 4
62
Appendix 3. Endpoints defined
Endpoint Definition (HAS Reports)
Mortality /
Morbidity
rPFS (Radiological progression-
free survival) Time between randomisation and radiological progression or death.
VAS (Visual Analogue Scale)
Pain
Time to first skeletal-related event
Radiotherapy or bone surgery, a pathological fracture, spinal cord compression, a change in antineoplastic treatment,
in line with the protocol, to treat bone pain.
Time until need for treatment with
opiates Time between randomisation and the use of an opiate for the treatment of cancer pain.
FKSI-DRS FACT Kidney Symptom Index - Disease-Related Symptoms
PPI-Scores Palliative Prognostic Index (for pain)
EORTC QLQ-C30 European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30
Progression/
Response
Time until the start of cytotoxic
chemotherapy
Time between randomisation and administration of cytotoxic chemotherapy for the treatment of prostate cancer
(sometimes used as QoL indicator)
Time until deterioration in ECOG
performance
Time between randomisation and the date when ECOG PS (The Eastern Cooperative Oncology Group Performance
Status) deteriorated by at least 1point/grade subject to post-hoc analysis.
Time until PSA (Prostate Specific
Antigen) progression
Time between randomisation and PSA (Prostate Specific Antigen) progression according to PCWG2 (Prostate Cancer
Working Group) criteria.
PSA response rate
Proportion of patients showing a reduction in PSA by at least 50% compared with baseline according to PCWG2
criteria.
Objective response rate
Proportion of patients showing an objective response (i.e. a complete response [CR] or a partial response [PR])
identified with CT-CAT scan or MRI.
Duration of response Time between the first response and the appearance of progression identified with CT-CAT scan or MRI.
Time until an increase in need for
analgesics Time between randomisation and the date of an increase of ≥30% in score for analgesics used over a 4 week period.
Quality of
Life
FACT-P Functional Assessment of Cancer Therapy – Prostate
BPI-SF Brief Pain Inventory (Short Form)
FKSI-15 FACT Kidney Symptom Index
EQ-5D EuroQoL: quality of health-related life
63
Appendix 4: Common appraisals - information
Drug Brand Name MA holder Form Additional Monitoring MA date by EMA ATC code
A Abiraterone
Zytiga
Janssen-Cilag International
N.V.
250mg, 120tablets Yes 5-Sep-2011 L02BX03
Zytiga
Janssen-Cilag International
N.V.
250mg, 120tablets Yes
L02BX03
Aflibercept
Zaltrap Sanofi-Aventis Groupe 25mg/ml, 4 or 8ml vial, 1or 3 vials Yes 1-Feb-2013 L01XX44
Axitinib
Inlyta Pfizer Ltd. 5mg 56 tablets Yes 3-Sep-2012 L01XE17
D Dabrafenib
Tafinlar
Glaxosmithkline PLC 50/75mg, 120 tablets Yes 26-Aug-2013 L01XE
C Cabazitaxel
Jevtana
Sanofi-Aventis Groupe
S.A.
60mg/1.5ml, 1 vial of 1.5ml Yes 17-Mar-2011 L01CD
Crizotinib
Xalkori Pfizer Ltd. 200/250mg, 60 tablets
Yes and Conditional approval
23-Oct-2012 L01XE16
E Eribulin Mesylate
Halaven Eisai Europe Ltd. 0.88mg/2ml, 1/6 vials of 5ml with 2ml solvent Yes 17-Mar-2011 L01XX41
Enzalutamide
Xtandi
Astellas Pharma Europe
B.V.
40mg, 120tablets Yes 21-Jun-2013
I Ipilimumab
Yervoy
Bristol-Myers Squibb
Pharma EEIG
5mg/ml, 10ml/40ml vial Yes 13-Jul-2011 L01XC11
R
Radium-223-dichloride
Xofigo
Bayer Pharma AG 1000 kBq/ml, 6ml vial Yes 1-Nov-2013 V10XX03
Regorafenib
Stivarga
Bayer Pharma AG 40mg, 84 tablets Yes 26-Aug-2013 L01XE21
T Trastuzumab emtansine
Kadcyla Roche Registration Ltd 100/160mg, 1 vial of 15/20ml No 15-Nov-2013 L01XC14
V Vandetanib
Caprelsa AstraZeneca AB 300mg, 30tablets Yes and Conditional Approval 17-Feb-2012 L01XE18
Vemurafenib
Zelboraf Roche Registration Ltd. 240mg, 56 tablets Yes 17-Feb-2012 L01XE15
Vismodegib
Erivedge Roche Registration Ltd 150mg, 28 tablets Yes and Conditional Approval 12-Jul-2013 L01XX43
Conditional approval: approval based on non-comprehensible data, that nevertheless proves that the benefits of the medicine outweigh its risks; the medicine must address
“unmet medical need” and the company is required to fulfill certain obligations and the approval is re-evaluated on yearly basis (EMA website).
64
Appendix 5. HTA methods and criteria for common appraisals – full sample
Drug
Brand
Name
Agency
Best
added
benefit
rating
49
Clinical evidence
use
50
Comparator
Endpoints of clinical
study
51
Endpoints
considered
Reason for decision
Abiraterone
Zytiga
GBA 2B
Sub-group
analysis; Direct
comp.
Placebo + prednisolone + BSC
Mortality, Morbidity, QoL,
AEs, Progression
Mortality,
Morbidity, AEs
AEs data cannot prove less
harm, QoL not evaluable
HAS ASMR III Direct comp. Placebo + prednisolone +BSC
Mortality, Morbidity, QoL,
AEs, Progression
All endpoints in
study considered
Efficacy and tolerance
Zytiga GBA 3B Direct comp. Placebo + prednisone
Mortality, Morbidity, QoL,
AE, Progression
Mortality,
Morbidity
Bias potential of AEs data,
QoL not evaluable
HAS ASMR IV Direct comp. Placebo+ prednisone
Mortality, Morbidity, QoL,
AE
All endpoints in
study considered
Efficacy
Aflibercept
Zaltrap GBA 2C Direct comp. Placebo+FOLFIRI
52
Mortality, AEs, Progression Mortality, AEs
Possible greater harm due to
serious AEs
HAS ASMR V Direct comp. Placebo+FOLFIRI Mortality, AEs, Progression
All endpoints in
study considered
High frequency of treatment
discontinuation due to AEs
Axitinib
Inlyta GBA 2C
Sub-group
analysis; Open-
label, parallel
group
Sorafenib
Mortality, Morbidity, QoL,
AEs, Progression
Mortality,
Morbidity, QoL,
AEs
Benefit rating granted to sub-
population due to study
design
HAS ASMR IV
Open-label,
parallel group
Sorafenib
Mortality, Morbidity, QoL,
AEs, Progression
All endpoints in
study considered
No comparative data on
treatment after sunitinib
(compared to everolismus)
Cabazitaxel
Jevtana GBA 2C
Sub-group
analysis; Open-
label
Mitoxantrone
Mortality, Morbidity, QoL,
AEs, Progression
Mortality,
Morbidity, AEs
Benefit rating granted to sub-
population due to study
design
HAS ASMR III
Sub-group
analysis; Open-
label
Mitoxantrone
Mortality, Morbidity, QoL,
AEs, Progression
All endpoints in
study considered
ASMR III instead of ASMR
IV based on sub-group
analysis
49
The most favorable rating in any sub-group, according to the latest appraisal.
50
Assumed to be a double-blind, comparative RCT unless otherwise stated.
51
List of possible endpoints included in studies with definitions can be found in Appendix 3.
52
Irinotecan with fluorouracil (5FU) and folinic acid (FOLFIRI)
65
Drug
Brand
Name
Agency
Best
added
benefit
rating
49
Clinical evidence
use
50
Comparator
Endpoints of clinical
study
51
Endpoints
considered
Reason for decision
Crizotinib
Xalkori GBA 3B
Sub-group
analysis; open-
label
Chemotherapy
Mortality, morbidity, QoL,
AEs, Progression
Mortality,
morbidity, QoL,
AEs
GBA grants added benefit in
one sub-group, against
IQWIG recommendation
HAS ASMR III Open-label Chemotherapy
Mortality, morbidity, QoL,
AEs, Progression
All endpoints in
study considered
No therapeutic alternative
available, also considered
phase II trials
Dabrafenib
Tafinlar GBA 4
Indirect
comparison
Dacarbazine
Mortality, Morbidity, QoL,
AEs, Progression
Mortality,
Morbidity, QoL,
AEs
Methodological shortcomings
of study
HAS ASMR V
Indirect
comparison
Dacarbazine
Mortality, Morbidity, QoL,
AEs, Progression
All endpoints in
study considered
No direct comparison
between dabrafenib and
vemurafenib
Enzalutamide
Xtandi GBA 2B
Sub-group
analysis; Direct
comparison
Placebo
Mortality, Morbidity, QoL,
AEs, Progression
Mortality,
Morbidity, AEs
-
HAS ASMR III Direct comparison Placebo
Mortality, Morbidity, QoL,
AEs, Progression
All endpoints in
study considered
No active comparator data
Eribulin Mesylate
Halaven GBA 3C
Sub-group
analysis; open-
label
Treatment of Physician's Choice
Mortality, Morbidity, AEs,
Progression
Mortality, AEs
No complex AEs data
provided
HAS ASMR IV Open-label Treatment of Physician's Choice
Mortality, Morbidity, AEs,
Progression
All endpoints in
study considered
Small number of patients
treated with capecitabine
chemotherapy agent -
standard practice in France
Ipilimumab
Yervoy GBA 2B Direct comparison gp100 Mortality, QoL, AEs
Mortality, QoL,
AEs
Significant immune-mediated
adverse events
HAS ASMR IV Direct comparison gp100 Mortality, QoL, AEs
All endpoints in
study considered
Absence of alternative,
choice of comparator
Radium-223-
dichloride
Xofigo GBA 2B Direct comparison Placebo
Mortality, morbidity, QoL,
AEs, Progression
Mortality,
morbidity, AEs
Study only provides valid
data for BSC population
HAS ASMR IV Direct comparison Placebo
Mortality, morbidity, QoL,
AEs, Progression
All endpoints in
study considered
No active comparator data,
uncertain extrapolation
Regorafenib
Stivarga GBA 3C Direct comparison Placebo
Mortality, morbidity, QoL,
AEs, Progression
Mortality,
morbidity, AEs
Only patients with ECOG PS
0 or 1 in the study population
HAS ASMR V Direct comparison Placebo
Mortality, morbidity, QoL,
AEs, Progression
All endpoints in
study considered
Toxicity concerns
Trastuzumab
emtansine
Kadcyla GBA 2B
Sub-group
analysis; Direct
comparison
Lapatinib + Capecitabin
Mortality, morbidity, QoL,
AEs, Progression
Mortality, QoL,
AEs
Comparator only ACT for
one sub-population for which
benefit rating 2B granted
HAS ASMR II Direct comparison Lapatinib + Capecitabin
Mortality, morbidity, QoL,
AEs, Progression
All endpoints in
study considered
Based on PFS, OS and
acceptable tolerance profile
66
Drug
Brand
Name
Agency
Best
added
benefit
rating
49
Clinical evidence
use
50
Comparator
Endpoints of clinical
study
51
Endpoints
considered
Reason for decision
Vandetanib
Caprelsa GBA 3C Direct comparison Placebo
Mortality, morbidity, QoL,
AEs, Progression
Mortality,
Morbidity
High risk of study bias, no
evaluable data for most AEs
HAS ASMR IV Direct comparison Placebo
Mortality, morbidity, QoL,
AEs, Progression
All endpoints in
study considered
Limited effectiveness given
unrepresentative sample of
study population
Vemurafenib
Zelboraf GBA 2B Direct comparison Dacarbazine
Mortality, morbidity, QoL,
AEs, Progression
Mortality,
morbidity, QoL,
AEs
Potential greater harm
HAS ASMR III Direct comparison Dacarbazine
Mortality, morbidity, QoL,
AEs, Progression
All endpoints in
study considered
Safety concerns, negative
impact on QoL cannot be
excluded
Vismodegib
Erivedge GBA 3C
Sub-group
analysis; indirect
comparison
-
Mortality, morbidity, QoL,
AEs, Progression
Mortality,
morbidity, QoL,
AEs
Deviation from G-BA
defined ACT, ORR as
primary outcome is not
patient-relevant
HAS ASMR IV
Indirect
comparison
-
Mortality, morbidity, QoL,
AEs, Progression
All endpoints in
study considered
Non-comparative study data
but lack of therapeutic
alternative
For further information on this or any of the
Health publications contact:
Anthony Kelly
Managing Editor
LSE Health
The London School of Economics and Political Science
Houghton Street
London WC2A 2AE
Tel: + 44 (0)20 7955 7392
Fax: + 44 (0)20 7955 6090
Email: a.p.kelly1@lse.ac.uk
Website: www.lse.ac.uk/collections/LSEHealth/
