Upload
samfabri
View
105
Download
1
Tags:
Embed Size (px)
DESCRIPTION
AMNOG
Citation preview
AMNOG: Seven Learnings for Strategic Market Access Decisions in Germany
TM
An IMS Consulting Group White Paper on the impact of the AMNOG reforms based on the evidence of early benefit assessments
TM
32 Copyright © IMS Consulting Group 2012Copyright © IMS Consulting Group 2012
THE AMNOG LAWThe price setting procedure for new drugs in Germany
changed on 1 January 2011 with the introduction of the
AMNOG law, which added a reimbursement price to the
existing manufacturer-set list price. While the list price
remains unchanged, the reimbursed price will be set at
the latest 12 months after a new product’s launch, based
on discount negotiations or reference pricing following
an assessment of the clinical benefits provided by the
manufacturer (see Figure 1).
Additional benefitFor every new product launched in Germany (excluding
generics and hospital-only products), manufacturers
are now required to submit a benefit dossier for
assessment to the Federal Joint Committee (GBA).
The GBA usually commissions the Institute for Quality
and Efficiency in Health Care (IQWiG), which operates
as a GBA support function, to evaluate the evidence
provided by the manufacturer.
The result – whether the drug offers an additional
benefit or not against a GBA selected comparator –
is published on the internet within three months
(see Figure 2).
The manufacturer then has the opportunity to
comment on the decision at a hearing, after which
the GBA will reach a final decision within a further
three months.
For new products with orphan drug status, a simplified
submission process applies. The manufacturer has
only to submit an extract of the dossier and the
GBA will only decide on the level of additional
benefit, as the additional benefit in general is
considered demonstrated by the orphan designation.
This exception applies to orphan drugs as long as
anticipated peak sales stay below the threshold of €50
million a year. If the threshold is exceeded after the
GBA decision, a complete dossier has to be submitted
by the manufacturer.
The reimbursement price of products with no
additional benefit is set based on a reference price or
in price negotiations, while manufacturers of products
with additional benefit enter price negotiations with
the lead association of the German sick funds
(GKV-SV). Should negotiations fail, the reimbursed
price is set by an arbitration panel based on
international prices in 15 EU countries (Austria,
AMNOG: Seven Learnings for Strategic Market Access Decisions in Germany
The introduction of a mandatory benefit assessment process in early 2011 – the Act
on the Reform of the Market for Medicinal Products (AMNOG) – radically changed the
market access environment for products with a new active ingredient in Germany. The
act created new requirements for comparator-driven evidence in clinical trials and
significantly altered the pricing process to include discount negotiations. In addition,
although the focus has so far been on new products, the law also covers products
already on the market, opening up the possibility of cuts to the reimbursed prices
of both new and existing products. Following publication of the first early benefit
assessments in January 2012, IMS Consulting Group’s Justus Dehnen and Michael
Schmoeller review the results and present the key learnings to date.
Figure 1 The AMNOG process in summary
Source: IMS Consulting Group FRP = reference price
Figure 2 What does ‘additional benefit’ mean?
If the drug is considered to offer no additional benefit,
it will be given a reimbursement price in relation to
the price of the comparator used during the benefit
assessment. Should that comparator belong to an
existing reference price group (festbetragsgruppe),
the new drug will be classified immediately into that
group if possible. If there is no existing reference
price group, the GBA will consider the possibility of
creating a new group. If a new group cannot be set
up, the reimbursement price will be discounted from
the list price to the price level of the comparator. The
reimbursement price will be effective at the latest from
the beginning of the 13th month after launch.
If the new drug is considered to offer an additional
benefit (there are different levels of additional benefits
possible: major, important, slight or non-quantifiable
additional benefits) then a discount will be negotiated
between the manufacturer and the lead association of
the German sick funds (GKV-SV) based on the reimbursed
price of the comparator and the additional benefit
demonstrated. Any discounts will be taken from the
list price set by the manufacturer. The new reimbursed
price will be effective at the latest from month 13 after
launch, while the original manufacturer-set list price
stays unchanged.
No additional benefit Additional benefit
Source: IMS Consulting Group
Institute for Quality and Efficiency in
Health Care(IQWiG)
Benefit assessment
Market launch
Dossier
Commission possible
Report
Additionalbenefit
No additionalbenefit
Reference price not possible
Hearing No agreement
Agreement Decision Decision
Valid until the end of the process
RetroactiveDiscounted ‘net’ price
Discounted ‘net’ price
FRP reference
price
Manufacturer’s price
(set freely)
Not accepted
3 months 6 months 12 months 15 months
Manufacturer Manufacturer Head association of the
SHI scheme(GKV)
Arbitration Panel Institute for Quality
and Efficiency in Health Care
Rebate negotiations
Federal Joint Committee (GBA)
Federal Joint Committee (GBA)
Market launch
Benefit assessment(internet
publication)
Benefit assessment(Decision) Cost/benefit
assessment
Decision(e.g. based
on international prices)
TM
54 Copyright © IMS Consulting Group 2012Copyright © IMS Consulting Group 2012
LEARNING 1: SELECT THE RIGHT CLINICAL COMPARATOR Choice of comparator has been shown to be the single most important factor in AMNOG benefit assessments with head-to-head evidence against the comparator key for a positive assessment.
IQWiG and GBA have underlined several times that they
will not consider evidence based on comparators that do
not meet their definition of the appropriate comparator.
Arguments for the use of other comparators have been
rejected and products that used the wrong comparator
ruled by the GBA to have no additional benefit. This has
direct implications on the achievable price in Germany
because products with no additional benefit are priced
via a reference price group or a more challenging price
negotiation – with the benchmark set at the level of
comparable products in the market.
Alignment with the GBA on choice of comparator is
therefore essential to a positive outcome and price
negotiation – the earlier, the better as it helps to
shape appropriate trials. On the evidence of completed
assessments, IQWiG and GBA fully accepted the
manufacturer’s choice of comparator in just three of the
12 completed assessments so far (Halaven, Victrelis,
Zytiga). In another five cases, the comparator was only
accepted for a specific sub-population, but not for all
defined sub-populations (Brilique, Esbriet, Gilenya,
Incivo, Jevtana). The comparator was rejected for a
further four products that were consequently found to
have no additional benefit (Rasilamlo, Trajenta, Trobalt,
Xiapex).
Alongside the right choice of comparator, manufacturers
must also provide compelling evidence to support the
positioning of their product against the comparator.
Available benefit assessments demonstrate that head-to-
head evidence against the right comparator was included
in all positive outcomes, while indirect comparison versus
Belgium, Czech Republic, Denmark, Finland, France,
Greece, Ireland, Italy, Netherlands, Portugal, Sweden,
Slovakia, Spain, UK).
Benefit dossierThe benefit dossier supplied by the manufacturer is
critical to the benefit assessment and the negotiation
process. The dossier is comparable to the kind of health
technology assessments (HTAs) previously undertaken
by IQWiG and must be structured according to the
GBA’s code of practice. At its core, it must present
evidence of the drug’s additional benefit over the
appropriate comparator – defined as the clinically
appropriate standard of care in the indication. Where
more than one such product is available, the lowest
price comparator should be selected. If there is no
drug alternative, the comparator can be a non-drug
treatment.
Additional benefit should ideally be demonstrated on
the basis of head-to-head trials with the appropriate
comparator. There are opportunities throughout the
a second comparator was accepted – but only with a
convincing and objective rationale. However, the use of
indirect trial data limited a product’s achievable level of
additional benefit. In the case of Brilique, for example,
the GBA showed that it will accept indirect comparison
but that it considers the evidence of limited value.
IMPLICATIONManufacturers should engage early with the GBA to choose the right comparators against which to present high quality evidence to give their products the best chance of achieving a positive outcome.
LEARNING 2: FOCUS ON HARD ENDPOINTSEvidence based on hard endpoints is strongly preferred by IQWiG and GBA to ensure acceptance of an additional benefit.
Soon after the AMNOG law was passed, and long before
the first benefit assessments were published, IQWiG
and GBA made it clear that they would consider trial
outcomes on four patient relevant hard endpoints:
mortality, morbidity, quality of life and side effects.
Benefit assessments containing these hard endpoints
would therefore have a greater chance of demonstrating
an additional benefit.
Surrogate parameters, on the other hand, are not
generally defined as appropriate endpoints though they
are considered as long as their use is well justified. In
the case of Victrelis, for example, sustained virologic
response (SVR) was accepted as a surrogate endpoint for
two reasons. First, because the percentage of patients
with complications (e.g. hepatocellular carcinoma)
in following years under the patients with SVR was
significantly lower than the percentage in patients
without SVR. Second, the percentage of patients with
SVR relapsing was very low. In effect, SVR was seen as a
surrogate for curing subsequent complications. But while
IQWiG and GBA will accept surrogate endpoints
GBA procedures (status of 11th May 2012)
Early benefit assessment procedure
started
2
Exemption from early benefit assessment 1
No status 1
Hearing procedure started 3
Final decision making in preparation 6
Early benefit assessment procedure completed
16
Total 29
Available GBA assessments
BRILIQUE HALAVEN
ESBRIET RASILAMLO
GILENYA TRAJENTA
INCIVO TROBALT
JEVTANA XIAPEX
VICTRELIS EDARBI
ZYTIGA LIVAZO
RAPISCAN
YELLOX
Restricted add. benefit granted
No additional benefit granted
No dossier submitted
Figure 3 AMNOG evaluations to date (1 Jan 2011 – 11 May 2012)
Source: GBA (2012): Übersicht der Wirkstoffe; in: http://www.G-BA.de/informationen/nutzenbewertung
THE SEVEN AMNOG LEARNINGSdrug development process for manufacturers to consult
the GBA, with approaches especially welcome before
starting phase III. The dossier must contain all clinical
trial data known to the manufacturer, including both
published and unpublished data for aborted and
investigator-driven trials. Dossiers will be judged
incomplete and not qualify for an additional benefit if
clinical data is missing. The same applies to products
that do not include a comparator and products for
which no dossier is submitted.
EVALUATIONS TO DATEThe first early benefit assessment was published in
January 2012, just over a year after the AMNOG law
came into effect. A total of 29 assessment procedures
had been initiated at the time of writing (April 2012),
of which results from IQWiG were available for 25. Of
this number, the GBA had reached a final decision on
16 new drugs, four of which were not supported by
their manufacturers with dossiers and were therefore
deemed of no additional benefit (see Figure 3).
On the basis of the evaluations to date, it is possible to draw seven early learnings on
the implications of AMNOG on strategic market access decisions for companies planning
to launch new molecular entities in Germany.
TM
76 Copyright © IMS Consulting Group 2012Copyright © IMS Consulting Group 2012
in cases like Victrelis, they still consider this type of
evidence as inferior to hard endpoints.
A further consideration for manufacturers is the way
in which IQWiG and GBA use hard endpoints in their
assessments. In the evaluation, they select a limited
number of high quality hard endpoints, ignoring the
rest gathered by the manufacturer. As with the choice
of comparator, this suggests that manufacturers consult
early with the GBA on the choice of relevant endpoints
in clinical trials. This will give the manufacturer the
best opportunity to gather and develop evidence that
meets the IQWiG and GBA’s rigorous standards – and
the best chance of securing an additional benefit.
IMPLICATIONManufacturers should focus their demonstration
of additional benefit on a limited number of hard
endpoints and/or well justified and accepted
surrogate endpoints developed in conjunction
with IQWiG and the GBA, rather than presenting a
broader range of endpoints that might be judged
irrelevant.
LEARNING 3: ANTICIPATE PATIENT SEGMENTATION BY IQWiG/GBACompleted assessments indicate that IQWiG and GBA have often segmented the patient population into different sub-populations to those defined by the
manufacturer, with the effect of reducing the overall level of additional benefit granted to a product.
In eight of 12 assessed benefit dossiers, IQWiG and GBA
have defined additional or new sub-populations to those
presented by manufacturers. In such cases, evidence
designed to support a different sub-population has been
deemed insufficient to warrant an additional benefit in
the newly defined GBA sub-population. As a result, the
overall additional benefit for the product as a whole,
defined as a combination of the additional benefit in
each patient segment, has been diluted – and found to
be lower than that claimed by the manufacturer.
The message for manufacturers is once again to plan
early and engage with the GBA on the definition of
the patient sub-populations for their product. For each
potential sub-population, manufacturers should then
identify the appropriate comparator (Learning 1) and
the patient relevant endpoints (Learning 2) to obtain
the best chance of demonstrating an additional benefit
for their product in development.
IMPLICATIONManufacturers should identify and consider all potential sub-populations in a risk assessment prior to the submission of the dossier – ideally in the planning phase of the clinical trials – in order to anticipate segmentation by IQWiG and the GBA after submission of the dossier.
LEARNING 4: PREPARE WITHOUT RELYING ON QUALITY OF LIFE OUTCOMESQuality of life outcomes are rarely considered in the benefit assessments of IQWiG and in the final decisions of the GBA.
Despite public pronouncements to the contrary, there
is little evidence that patient-oriented quality of life
measures hold as much weight in IQWiG/GBA assessments
as hard endpoints related to mortality, morbidity and side
effects. Of the total AMNOG assessments to date that have
demonstrated additional benefit, none has done so on the
basis of quality of life related evidence. While quality of
life data was taken into account on a case-by-case basis,
in most instances it was found statistically insignificant
or the methodology was considered inappropriate to
demonstrate an additional benefit on this endpoint.
The apparent contradiction between theory and
practice relates to IQWiG/GBA’s failure to map out and
communicate a viable methodology for producing quality
of life outcomes. Unlike the other three endpoint types
identified by IQWiG/GBA, in the absence of a viable
methodology, quality of life remains a work in progress.
It has yet to be seen whether IQWiG and GBA will address
this gap proactively by presenting guidelines, or whether
they will gradually accept manufacturer-submitted
methodologies.
In the meantime, manufacturers face a dilemma over
how to leverage quality of life endpoints in their
submissions. Once more, the best advice is to open an
early dialogue with the GBA on generating acceptable
quality of life outcomes for inclusion on dossiers. It
might be a long term investment but it could lead
to the eventual acceptance by IQWiG and GBA of
methodologies and standards that have proven their
use in practice.
IMPLICATIONManufacturers are advised in the current environment not to be over-reliant on quality of life endpoints in their benefit assessments but to work with IQWiG/GBA on the longer term development of acceptable methodologies and standards.
LEARNING 5: ASSUME THE GBA WILL NOT REFERENCE INTERNATIONAL CLINICAL BENEFIT AND ACCESS DECISIONSThe AMNOG process operates relatively independently of international price comparisons and reimbursement decisions, despite the inclusion of a reference price solution for products with an additional benefit that fail in price negotiations.
A comparison of products assessed under AMNOG that
have already undergone HTA evaluations in other
Ticagrelor (BRILIQUE)
Indication Brilique is indicated for the prevention of atherothrombotic events in adult patients with Acute Coronary Syndromes (unstable angina, non ST elevation Myocardial Infarction [NSTEMI] or ST elevation Myocardial Infarction [STEMI])
MNF dossier Patient population Total ACS population
Comparator Clopidogrel + ASA
IQWiG assessment
Patient population(s)Unstable Angina and MI w/o ST segment elevation (IA/NSTEMI)
MI with ST elevation (STEMI) in patients on medication
MI with STEMI in patients with previous Percutaneous Coronary Intervention (PCI)
MI with STEMI in patients with previ-ous Coronary Artery Bypass Graft (CABG)
Comparator choice Clopidogrel + ASA Clopidogrel + ASA Prasugrel + ASA ASA monotherapy
(Additional) benefit Evidence for important additional benefit No additional benefit No additional benefit No additional
benefit
GBA decision (Additional) benefit Evidence for important
additional benefitNo additional benefit
No additional benefit Exception: Weak indicator for not quantifiable additional benefit for (1) patients >75 inappropriate for Prasugrel (2) patients with transi-toric ischemic attacks/stroke
No additional benefit
AMNOG case study 2: Brilique
Source: GBA (2012): Nutzenbewertungsverfahren zum Wirkstoff Ticagrelor: http://www.g-ba.de/informationen/nutzenbewertung/18/
Cabazitaxele (JEVTANA)
Indication In combination with prednisone or prednisolone treatment of patients with hormone refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen
MNF dossier Patient population Grown up patients with mHRPC having been treated with docetaxel
Comparator Best supportive care
IQWiG assessment
Patient population(s) Best supportive care population (no further docetaxel therapy possible) Docetaxel-retherapy population
Comparator choice Palliative treatment with dxamethason, prednisone, prednisolone or methylprednisolone as well as best supportive care
Docetaxel in combination with prednisone or prednisolone
(Additional) benefitIndicator for important additional benefit for patients >65Weak indicator for not quantifiable additional benefit for patients <65 years
No additional benefit
GBA decision (Additional) benefit Indicator for slight additional benefit No additional benefit
AMNOG case study 1: Jevtana
Source: GBA (2012): Nutzenbewertungsverfahren zum Wirkstoff Cabazitaxel: http://www.g-ba.de/informationen/nutzenbewertung/10/
TM
98 Copyright © IMS Consulting Group 2012Copyright © IMS Consulting Group 2012
between the two and the IQWiG recommendation
features prominently in the GBA’s decision making.
In total, 6 out of 12 completed GBA decisions did not
follow exactly the IQWiG recommendations (see Figure
6). For example, IQWiG recommended in its report
on Brilique to split the patient population into four
different sub-populations, from which only one received
a label of additional benefit. In its decision, the GBA
granted evidence for an important additional benefit
and a weak indicator for a non-quantifiable additional
benefit for a further sub-population.
Additionally, the GBA does not always follow IQWiG in
its definition of sub-populations. In the case of Victrelis,
the GBA did not follow IQWiG’s advice to split the
patient population into four different sub-populations,
accepting only the distinction of two sub-populations.
For manufacturers, this could well mean that there
is scope beyond the initial submission of evidence
to shape and influence IQWiG and GBA thinking with
supporting evidence. While the dossier will always be
the bedrock of the submission, manufacturers should
make the most of these additional opportunities.
IMPLICATIONIQWiG’s recommendations are not final and
manufacturers should see the hearing after the
Institute’s assessment as a key step in discussing
the extent to which IQWiG’s scientific view is
applicable when treating patients in the real world.
IMPLICATIONIn the absence of quantitative definitions of benefit levels, the most reliable source of information on the AMNOG process is the back catalogue of publicly available benefit assessments, which can help manufacturers stratify risk and estimate the potential outcomes of benefit assessments.
LEARNING 7: NEGOTIATE WITH THE GBA AFTER PUBLICATION OF IQWiG’s RESULTSThe GBA represents the highest authority in the benefits assessment process and has demonstrated its independence by not always following recommendations from the IQWiG; this opens up opportunities for manufacturers to present additional arguments in the hearing before the GBA takes its final decision.
IQWiG is exclusively commissioned by the GBA and has a
very specific mandate to draw clinical conclusions on the
basis of scientific evidence. The GBA, on the other hand,
has a more pragmatic approach that applies clinical
data in actual medical practice – hence the inclusion of
payers, providers and patients on the GBA.
Just as the AMNOG process as a whole has not always
followed European precedents, so the GBA has shown a
degree of self-confidence in rejecting some of IQWiG’s
recommendations on the level and likelihood of
(additional) benefit for a new product (see Figure 5). At
the same time, there is a certain degree of dependency
The AMNOG law and the GBA Verfahrensordnung define
the general methodology for benefit assessments by
IQWiG and the GBA (see Figure 4). The main elements
of that methodological standard include the definition
of the level of benefit (major, important, slight, not
quantifiable, no additional benefit or smaller benefit
than comparator) and the definition of the likelihood
of additional benefit (evidence, indicator, weak
indicator). The clarity of these definitions increases the
transparency and, in theory at least, the predictability of
the IQWiG evaluation and GBA decision making process
(Lesson 5).
In contrast, specific details on how trial outcomes
per endpoint translate into the level of additional
benefit have not been defined. The first proposal on
the quantitative definition of the different levels of
additional benefit was provided by IQWiG in the first
benefit assessment on Brilique. It defined for each of
the main endpoints different thresholds for confidence
intervals and relative risks, and linked expected clinical
outcomes to one of the levels of additional benefit.
The GBA did not accept or comment on IQWiG’s proposal,
instead stating that the issue would have to be resolved
by an expert panel – which has not yet been convened.
It remains uncertain whether the GBA is willing to
define quantitative thresholds for each of the additional
benefit levels in each endpoint. On the one hand,
it would improve transparency and predictability for
manufacturers; on the other, it would burden IQWiG and
the GBA with another layer of procedure.
countries shows a high level of deviation – partly
owing to IQWiG/GBA’s unique methodologies. For
Brilique, the European Medicines Agency (EMA) granted
marketing authorization for the total acute coronary
syndrome (ACS) patient population and accepted the
comparison of ticagrelor with clopidogrel demonstrated
in one trial. Brilique had already been assessed in
England, Scotland, Wales and Denmark before the
benefit assessment in Germany and was granted full
access and reimbursement – also for the total ACS
patient population.
In Germany, however, IQWiG and GBA defined four sub-
populations and for each of these identified appropriate
comparators. In its final decision, the GBA accepted
evidence for an important additional benefit in just
one sub-population, while in the other three it found
no additional benefit (with the exception of a weak
indicator for a non-quantifiable additional benefit in a
segment of one of the four sub-populations).
In further examples of the AMNOG process not
following other EMA/health technology assesments in
Europe, Gilenya, Halaven, Incivo, Jevtana, Victrelis and
Zytiga were all granted full access and reimbursement
in France, but only limited or no additional benefit in
Germany.
In all cases, IQWiG and the GBA explained their
positions on the basis of the new AMNOG legal
framework in Germany. Further, by adopting a high
degree of transparency and sticking to its clearly
defined procedures, standards and rules, Germany has
been able to go its own way and justify its deviation
from other European markets.
IMPLICATIONFor manufacturers, the best predictors of benefit assessments are AMNOG’s own defined procedures, as German pricing and reimbursement decisions do not automatically follow the label, HTA or market access decisions of other European countries.
LEARNING 6: CLARIFY WHAT IS MEANT BY ADDITIONAL BENEFITThe general methodologies outlined in the legal documentation and implemented in the first AMNOG benefit assessments remain in use, though specific guidance on different benefit levels has yet to be defined.
7% 6% 7%
13% 14%
19%
71%
63%
major additional benefit important additional benefit
slight additional benefit
not quantifiable additional benefit
no additional benefit
IQwiG
GBA
Level of additional benefit
Quality of additional benefit
Major additional benefitEvidence for additional benefit
Important additional benefit
Indicator for additional benefit
Slight additional benefitWeak indicator for additional benefit
Not quantifiable additional benefit
No additional benefit
Smaller benefit than comparator
Source: GBA (2012): Verfahrensordnung http://www. g-ba.de/downloads/62-492-598/VerfO_2012-01-19.pdf
Source: GBA (2012): Übersicht der Wirkstoffe; in: http://www.G-BA.de/informationen/nutzenbewertung
Figure 4 AMNOG definition of level and quality of additional benefit
Figure 5 Differences in IQWiG and GBA decisions on level of additional benefit (N = 16)
10
TM
11Copyright © IMS Consulting Group 2012Copyright © IMS Consulting Group 2012
International launch sequencesOne recurring feature of the new process has been its
unrelenting focus on cost savings – sometimes at odds
with international HTA and market access decisions.
As a consequence, the evidence requirements in more
independent-minded Germany might not be suitable
for a global pricing and market access strategy, and
manufacturers might want to rethink their global
launch strategy. Tailoring trial designs to meet specific
requirements defined by IQWiG and the GBA might well
be counter-productive in other countries. Manufacturers
should therefore think through the entire commercial
opportunity across regions – USA included – when
considering the merits of a GBA-driven approach
internationally.
In the case of Trajenta, for example, Boehringer
Ingelheim (BI) and Lilly decided not to launch their oral
anti-diabetic Trajenta in Germany because of the GBA’s
choice of comparator. The manufacturers were concerned
that the therapeutic benefit of Trajenta would not be
properly demonstrated, resulting in a low price that other
countries could reference. The Trajenta case demonstrates
how AMNOG is already changing the way manufacturers
have to consider their launch strategy in Germany – and
how that is having ramifications internationally.
CONCLUSIONAlthough the pricing and market access environment
has become more regulated and more evidence-based
since the introduction of AMNOG, Germany remains one
of the world’s most attractive markets for innovative
new products. By mitigating the risks and learning from
their experience of the new process, pharmaceutical
manufacturers can continue to launch their innovative
new products successfully in Germany.
It is still very early in the evolution of the AMNOG reforms
to reach robust conclusions. But on the evidence of
benefit assessments to date, it is possible to draw some
preliminary learnings for the pharmaceutical industry to
action as it works with the new process to secure the best
outcomes for its new products (see Figure 7).
Several common themes emerge. First and foremost, it
is vital to engage constructively with the GBA at the
earliest possible opportunity – ideally before starting
phase III clinicals. This affords the greatest opportunity
to choose the appropriate comparator in the right patient
populations with the endpoints of most interest to IQWiG
and the GBA. Second, be prepared to switch courses as
the AMNOG process has thrown up a few surprises. The
GBA in particular has demonstrated a self-confidence
and independence of mind by apparently ignoring such
factors as quality of life data and such institutions
as EMA, international HTA agencies and even the
recommendations of IQWiG. Finally, given that AMNOG is
working to its own unique standards and procedures, the
best guide to what it might do in the future is what it
has done in the past.
But many questions remain unanswered. The first step
of the new process has been completed for selected new
products and the GBA’s initial decisions will form the
basis of phase two – price negotiations and arbitration.
However, that takes longer and there is so far little
evidence on the final outcomes for the first wave of
products going through the negotiations. As a result, cuts
to reimbursement prices remain a distinct possibility and
would seem to be in line with AMNOG’s overall objectives.
Other definition of the patient population (n=3)
Other definition of the extent of additional benefit (n=3)
GBA follows IQWiG(n=10)
GBA did not follow IQWiG(n=6)
Source: GBA (2012): Übersicht der Wirkstoffe; in: http://www.G-BA.de/informationen/nutzenbewertung
Figure 7 AMNOG: Seven learnings for market access (summary)
Learning Commentary Implication
1: SELECT THE RIGHT CLINICAL COMPARATOR
Choice of comparator has been shown to be the single most important factor in AMNOG benefit assessments with head-to-head evidence against the comparator key for a positive assessment
Manufacturers should engage early with the GBA to choose the right comparators against which to present high quality evidence to give their products the best chance of achieving a positive outcome
2: FOCUS ON HARD ENDPOINTS
Evidence based on hard endpoints is strongly preferred by IQWiG and GBA to ensure acceptance of an additional benefit
Manufacturers should focus their demonstration of additional benefit on a limited number of hard endpoints and/or well justified surrogate endpoints developed in conjunction with IQWiG and the GBA, rather than presenting a broader range of endpoints that might be judged irrelevant
3: ANTICIPATE PATIENT SEGMENTATION BY IQWiG/GBA
Completed assessments indicate that IQWiG and GBA have often segmented the patient population into different sub-populations to those defined by the manufacturer, with the effect of reducing the overall level of additional benefit granted to a product
Manufacturers should identify and consider all potential sub-populations in a risk assessment prior to the submission of the dossier – ideally in the planning phase of the clinical trials – in order to anticipate segmentation by IQWiG and the GBA after submission of the dossier
4: PREPARE WITHOUT RELYING ON QUALITY OF LIFE OUTCOMES
Quality of life outcomes are rarely considered in the benefit assessments of IQWiG and in the final decisions of the GBA
Manufacturers are advised in the current environment not to be over-reliant on quality of life endpoints in their benefit assessments but to work with IQWiG/GBA on the longer term development of acceptable methodologies and standards
5: ASSUME THE GBA WILL NOT REFERENCE INTERNATIONAL CLINICAL BENEFIT AND ACCESS DECISIONS
The AMNOG process operates relatively independently of international price comparisons and reimbursement decisions, despite the inclusion of a reference price solution for products with an additional benefit that fail in price negotiations
For manufacturers, the best predictors of benefit assessments are AMNOG’s own defined procedures, as German pricing and reimbursement decisions do not automatically follow the label, HTA or market access decisions of other European countries
6: CLARIFY WHAT IS MEANT BY ADDITIONAL BENEFIT
The general methodologies outlined in the legal documentation and implemented in the first AMNOG benefit assessments remain in use, though specific guidance on different benefit levels has yet to be defined
In the absence of quantitative definitions of benefit levels, the most reliable source of information on the AMNOG process is the back catalogue of publicly available benefit assessments, which can help manufacturers stratify risk and estimate the potential outcomes of benefit assessments
7: NEGOTIATE WITH THE GBA AFTER PUBLICATION OF IQWiG’s RESULTS
The GBA represents the highest authority in the benefits assessment process and has demonstrated its independence by not always following recommendations from the IQWiG; this opens up opportunities for manufacturers to present additional arguments in the hearing before the GBA takes its final decision
IQWiG’s recommendations are not final and manufacturers should see the hearing after the Institute’s assessment as a key step in discussing the extent to which IQWiG’s scientific view is applicable when treating patients in the real world
REFERENCESFederal Joint Committee (G-BA). Frühe Nutzenbewertung (§35 a SGB V), in: http://www.g-ba.de/informationen/nutzenbewertung/ Institute for Quality and Efficacy in the Health care system (IQWiG). Projekte, in: https://www.iqwig.de/projekte-ergebnisse.915.html
Figure 6 Differences in IQWiG and GBA decisions on definition of patient population and extent of additional benefit
Source: IMS Consulting Group
IMS Consulting Group is the world’s leading, specialized advisor on critical strategic and commercial issues in life sciences.
With a global presence and local expertise across five continents, we know the pulse of the market – anticipating change, understanding its impact and resolving the challenges it brings. From pricing and market access and marketing issues to product, portfolio and geographic investment decisions – our life sciences consulting teams offer insights that drive results. All backed by the strongest evidence and analytics.
Additional information is available at http://www.imsconsultinggroup.com
GERMANYJustus Dehnen, Engagement Manager [email protected] +49 89 457912 6418
Michael Schmoeller, Consultant [email protected] +49 89 457912 6416
UKKatia Berg, Principal [email protected] +44 203 075 4000
EDITORNeil Turner, Senior Manager [email protected] +44 1223 273430
If you have questions about this white paper or related issues you would like to explore, please contact our Pricing and Market Access group.
TM