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Oncology drugs under AMNOG

Part 1: Segmentation and comparator choice - lessons for cancer drug market access in Germany
The AMNOG early benefit assessment process in Germany is now over three years old and as tweaks are made to regulations and manufacturers gain more familiarity with the process we look at what can be learned from its oncology drug benefit assessments. 

Drugs coming to the German market no longer have free pricing. Instead, they are reimbursed at the manufacturer’s price only during the first year on the market, while the Federal Joint Committee (G-BA) assesses the new product or indication for a benefit relative to comparator/s selected by the G-BA. Usually the G-BA also seeks the advice of expert Health Technology Assessment (HTA) body IQWiG (the Institute for Quality and Efficiency in Healthcare), to determine the level of added benefit of a drug relative to comparators. This benefit can be at one of four positive levels - major, considerable, minor or unquantifiable added benefit - or there can be a finding of no benefit or of increased harm. The G-BA also rules on the strength of evidence of the added benefit. If any positive level of added benefit is found, for any patient subpopulation, the drug can go forward to the next step of price negotiation with the payers, the federal association of sickness funds (GKV). If ‘no benefit’ is found for all patient groups across all comparators, the drug should be priced at the level of other available options - often cheap generics. This is not an acceptable option for manufacturers of novel, expensive cancer therapies, meaning that for oncology manufacturers, gaining a positive benefit level against the right comparator in the right population is critical to market success. 

Prepare for segmentation

One of the major themes in the AMNOG early benefit assessments is that the G-BA will look to segment patients - commonly on the basis of clinical practice (suitability for chemotherapy, or what prior treatment the patient has received). 

This often means that manufacturers will only have trial data for part of the label population (based on a single phase 3 trial). There is also a risk that if the trial population is segmented and data has not been collected for the relevant segments with sufficient rigour, the trial data may lose statistical significance and leave the manufacturer at risk of having no benefit found in any group. 

Pixuvri: Polycomparator segmentation by the G-BA removes statistical power

Cell Therapeutics gained European approval for Pixuvri (pixantrone) in non-Hodgkin’s B-cell lymphoma, on the basis of a trial against ‘treatment of physician’s choice’ (TPC) or any of a range of older chemotherapies. The G-BA and IQWiG restricted these options to therapies with approval in the same treatment line in Germany, and then further ruled out some of the comparators because they were used in the trial as monotherapies but were only approved in Germany in combinations. This exclusion of trial data from other countries with different clinical practice left only four patients in the Pixuvri trial who had been treated with a G-BA-recognised comparator treatment - as a result, there was no suitable evidence and no benefit was found. 

Inlyta: Added benefit in minority of patients enough for price negotiation

Pfizer’s Inlyta (axitinib) was approved in kidney cancer for patients pre-treated with either another targeted therapy, Sutent (sunitinib), or with older drugs called cytokines. In its phase 3 trial it was compared with a single rival targeted therapy, Nexavar (sorafenib). Consistent with EMA market authorisations for other kidney cancer treatments, the G-BA ruled that the population should be segmented on the basis of earlier therapy, and that for sunitinib-treated patients the comparator was a different targeted therapy, Afinitor (everolimus), rather than Nexavar - although for cytokine-pretreated patients the trial comparator could be used.
The G-BA still exercises its right to decide on segmentations and subgroup comparators in some cases.

This meant that due to lack of data, there was no benefit found for any patients eligible for treatment with Sutent. A benefit was found for Inlyta compared with Nexavar in the cytokine treatment group, on the basis of increased tolerability. Despite the fact that most patients can receive Sutent and that the cytokine-pretreated group was estimated at only 1 per cent of the label patient population in Germany, this finding of benefit in one category for these patients was enough to send Inlyta to negotiations for pricing. However, it seems likely that the lack of proven benefit in the wider population may have impacted price negotiations or clinical practice.

How to prepare
Germany is one of the largest pharmaceutical markets in Europe and drug prices there are used as reference prices in other markets. Gaining access to this market at an acceptable price therefore has wider repercussions, and manufacturers need to consider how their phase 3 trials will be looked at by the G-BA in Germany. 

Manufacturers can work to address segmentation early by amassing evidence to identify population segments: engaging with key opinion leaders in the German market to get a sense of where the ‘fault-lines’ lie within a patient population - where the G-BA is likely to segment the population based on earlier treatments or suitability for chemotherapy, for example. Current practice can also be revealed by observational studies, secondary research in literature or sales databases, or market research. This may reveal how oncologists in Germany decide on current treatment based on patient characteristics. 

In response to this information, manufacturers will need to choose how to proceed. In designing a global trial programme, manufacturers must balance requirements and practices of many different markets. Often, oncology drug manufacturers choose to conduct a single trial, which means that the chosen comparator may not match with German clinical practice across the whole trial population - but manufacturers can explore other options to better address the likely requirements of the G-BA. They could, for instance, target a more narrow marketing authorisation in a clearly defined patient sub-segment with a single comparator - an option which would, of course, narrow the authorisation in other markets as well. They could choose to run more than one trial with different comparators in different patient segments or geographies.Manufacturers can also pre-specify subgroup analyses for key patient segments, perhaps based on pre-treatment or patient characteristics, to ensure statistical powering not just for the primary trial endpoint but for key secondary endpoints.

Manufacturers can inform their trial planning by consulting with the G-BA at an early stage of product development in order to get a sense for whether the trial design is appropriate for the segmentation and comparator selections of the G-BA. Although the AMNOG regulations have been tweaked since the early decisions, so that there is greater openness to the manufacturer’s chosen trial comparator if it is one of a range of clinical alternatives, the G-BA is still exercising its right to decide on segmentations and subgroup comparators in some cases.

With the advent of the AMNOG assessment, manufacturers face new challenges in gaining an acceptable price for novel oncology drugs in Germany. A key step is a positive assessment by the G-BA of a drug’s added benefit relative to comparators, in at least one segment of the label patient population. Manufacturers should prepare for segmentation of the target patient population and the clinical trial population, by identifying likely subgroups and comparators and deciding whether to amass evidence of added benefit in each group.

Written by Christine Henry, oncology market access – EU consultant, Kantar Health

7th May 2014



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