AMNOG Seven Learnings Strategic Access Germany

AMNOG: Seven Learnings for Strategic Market Access Decisions in Germany

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An IMS Consulting Group White Paper on the impact of the AMNOG reforms based on the evidence of early benefit assessments

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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)

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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.

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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


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/

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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


Smaller benefit than comparator

Source: GBA (2012): Verfahrensordnung http://www. g-ba.de/downloads/62-492-598/VerfO_2012-01-19.pdf


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)

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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)


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.

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