Market access

Specification of fictitious additional benefit when entering the unconfirmed orphan drug market

In order to promote the development of drugs for rare diseases (orphan drugs) despite market risks, they are exempted in Germany from the regular benefit assessment procedure introduced in 2011 with the Medicines Market Reform Act (AMNOG ). Instead, an additional benefit is assumed to be proven for orphan drugs at the time of European approval and subsequent market access (§35a German Social Code [SGB] V) – regardless of the actual evidence available.

The Federal Joint Committee (G-BA) can only quantify the incremental benefit of a new drug based on evidence submitted by the drug’s manufacturer. If no classification in the “minor”, “important” or “major” categories is possible, he must attest to an “unquantifiable” additional benefit of the drug, which has been qualified as a “fictitious” additional benefit. A regular benefit assessment by the Institute for Quality and Efficiency in Healthcare (IQWiG) and the G-BA is only carried out when the drug exceeds an annual revenue threshold of €50 million.

For all orphan drugs that have undergone a regular benefit assessment procedure since 2011 due to exceeding the above threshold, IQWiG has now analyzed whether the initially specified fictitious additional benefit still holds, and therefore whether prior preferential treatment of these drugs in the assessment of benefits was warranted.

Result: The specification of a fictitious benefit on access to the orphan drug market was not confirmed in more than half of the cases. The deciding factor was usually that the standard of care (referred to as “appropriate comparator treatment”) was not used as a control until the time of regular evaluation of benefit, i.e., it could not be assessed only at this stage whether there was a real additional benefit.

This has implications for the quality of patient care. In these cases, new drugs are prescribed preferentially, without a database. Patients may then have great hope in a new drug for which it only becomes clear years later that there is no evidence of superiority over existing treatment options..”

Thomas Kaiser, Head of Department of Drug Evaluation, Institute for Healthcare Quality and Effectiveness

Kaiser also explains: “Furthermore, the fictitious additional general benefit makes it difficult to distinguish between orphan drugs with and without real progress for the care of patients. A key objective of AMNOG, namely to separate the wheat from the chaff, is therefore not achieved. for orphan drugs.

No benefit added in the regular benefit assessment in 54% of cases

For its current analysis, IQWiG has identified 41 orphan drug reviews for which a special orphan drug review (“limited review”) and subsequent regular benefit review have been conducted since 2011. These 41 reviews refer to 20 different orphan drugs , as some have been approved for more than one therapeutic indication.

The analysis shows that in 22 of the 41 evaluations (54%), no additional (“unproven”) benefit could be determined in the regular benefit evaluation.

In contrast, in the assessments limited to market access, in accordance with legal requirements, a fictitious additional benefit was specified in all 41 assessments: in more than half of the cases (21 assessments, 51%), the additional benefit was “unquantifiable”.

Moreover, further analyzes by IQWiG show that the classification of incremental benefits is usually corrected only after a few years: For the 22 research questions without evidence of incremental benefit, the period between the assessment of limited and regular benefits averaged 3 good years (range: 1 to 9 years). In some cases, however, the additional benefit qualification is not corrected at all: this is the case if the income threshold of 50 million euros is not exceeded for the orphan drug and a regular evaluation profit is therefore not made.

Ending the flawed approach to orphan drug evaluations

IQWiG Director Jürgen Windeler notes: “Our analysis proves a flawed approach to orphan drug evaluations. additional benefit specified at the origin is not confirmed, and orphan drugs representing real added value can no longer be identified as such from the outset, action is needed Ten years after the establishment of AMNOG, it is therefore time to abolish the fictitious added benefit privilege for orphan drugs! with the appropriate comparator treatment in a regular early benefit assessment conducted by IQWiG and the G-BA at market entry.”

The flawed approach to the evaluation of orphan drugs affects not only patient care, but also drug expenditure by health insurance funds. Indeed, according to the “Drug Compass 2021” published by the Scientific Institute of Germany’s largest statutory health insurance fund, the AOK, orphan drugs for very specific types of cancer are the main cost drivers of the SHI system. High prices may be justified for orphan drugs representing real progress for patient care, but not for those without more benefit. Windeler points out: “For several reasons, a careful distinction is therefore judicious and belated.

Report production procedure

This report was prepared in the form of a working document within the general commission entrusted to the IQWiG by the G-BA in December 2004 in order to reinforce the scientific independence of the Institute. The general commission allows IQWiG to select scientific projects independently. Unlike other types of reports, there is no deadline for publishing working papers. The working document “Evidence on orphan drugs” was sent to the G-BA on December 23, 2021.