How tough is AMNOG—and is it about to get tougher?

Germany’s Gemeinsamer Bundesauschuss (GBA; Federal Joint Committee) has earned a reputation for toughness in its AMNOG early benefit assessment process. An analysis of data compiled by the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF; Working Group of Scientific Medical Specialist Societies) shows just how exacting the GBA has been.

From 2011 through 2018, the GBA performed 344 assessments of 684 sub-groups/sub-populations (including reassessments.) In most cases, the committee found no evidence of additional benefit over designated comparators. Figure 1 shows that, for all drugs approved since 2011, the judgement was that there was no evidence of additional benefit for 61% of sub-groups/sub-populations. The figure was even higher—70.7%—for non-orphan drugs.

Orphan drugs are generally treated differently from other new medicines under the AMNOG process: provided that their annual sales are less than €50 million, they are automatically deemed to have additional benefit. However, the GBA does have to determine their level of additional benefit. Orphan drugs are significantly more likely than non-orphan medicines to be judged to have minor additional benefit, but they do not have a substantial advantage in terms of qualifying for the highest levels of additional benefit—“considerable” or “major.” Yet, the majority of orphan drugs are judged to offer a non-quantifiable level of additional benefit—the lowest level possible under the concessionary AMNOG process for drugs with annual sales of less than €50 million. Note, too, that orphan drugs have to undergo a reassessment based on the standard evaluation procedure if their annual sales increase to more than €50 million, which may lead to a judgement of a lower level of additional benefit. Indeed, in reassessing some medicines, the GBA found no evidence of additional benefit for 9.3% of orphan drug sub-groups/sub-populations.

Overall, the GBA has found concrete evidence of additional benefit (minor, considerable or major) in just 26.3% of sub-groups/sub-populations. Orphan drugs have fared rather better, being judged to offer minor, considerable or major benefit in 36.1% of sub-groups/sub-populations.

In evaluating these figures, it is important to understand that judgements of no evidence of additional benefit are generally based on technical grounds. An analysis by the Bundesverband der Pharmazeutischen Industrie (BPI; Federal Association of the Pharmaceutical Industry) found that, in 79.4% of cases, a judgement of no evidence of additional benefit was based on perceived deficiencies in the manufacturer’s dossier (Figure 2). In a further 3.7% of cases, manufacturers elected not to submit a dossier at all. In only 16.9% of cases was a judgement of no evidence of additional benefit based on what the GBA deemed to be a complete dossier in which the evidence failed to demonstrate superiority over the comparator.

Outlook and implications for the pharmaceutical industry

More than eight years after the introduction of the AMNOG process, it is disturbing for the pharmaceutical industry that so many drugs are still foundering on technical grounds. Early consultation with the GBA—and possibly with the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM; Federal Institute for Drugs and Medical Devices) and/or the Paul-Ehrlich-Institut (Federal Institute for Vaccines and Biomedicines), too—should help manufacturers to prepare well in advance for the benefit assessment process. In particular, companies need to seek detailed guidance regarding the choice of comparator and endpoints for clinical trials. However, it is not always easy to align clinical trials conducted primarily for global regulatory purposes with the specific requirements of the GBA, which is, after all, just one of a multitude of HTA bodies around the world, each of which makes its own demands. Moreover, the GBA’s guidance is subject to change by the time a drug eventually undergoes post-marketing benefit assessment.

Impending legislation—the Gesetz für mehr Sicherheit in der Arzneimittelversorgung (GSAV; Act for Increased Safety in the Pharmaceutical Supply System)—is expected to bring some changes to the AMNOG process. Scientific and medical societies and the Arzneimittelkommission der deutschen ?rzteschaft (Akd?; Drug Commission of the German Medical Association) will have the opportunity to make written submissions in relation to questions regarding appropriate comparator therapies. This change should help to ensure that chosen comparators reflect prevailing standards of care, a positive development for the pharmaceutical industry.

On the other hand, the GSAV will also empower the GBA to mandate the collection of indication-specific data to enhance the assessment of certain medicines—notably, orphan drugs. In certain circumstances, the GBA will be able to require prescribing physicians and hospitals to participate in the data collection process. Manufacturers will have to cover the costs of this activity. Prescribing of orphan drugs might be restricted to physicians or hospitals that participate in the data collection programme. The GBA will determine the parameters of the data collection and review each year whether the data gathered warrant a new benefit assessment. Prices could be reduced if manufacturers do not comply with the data collection requirement, or if a drug is found to have a non-quantifiable level of additional benefit.

In addition, the new law will revise the methodology for calculating the €50 million annual sales threshold for orphan drugs: instead of being based exclusively on prescriptions written by outpatient physicians for patients in the statutory health insurance system, it will also include inpatient prescriptions and prescriptions issued to privately insured patients. Manufacturers will have an obligation to provide the GBA with sales data for their orphan drugs. This change will mean that more orphan drugs exceed the sales threshold, triggering mandatory reassessments that could lead to net price reductions as a consequence of their level of additional benefit being downgraded from unquantifiable to not proven.