AMNOG since 2011

How beneficial are drugs entering the market in Germany? IQWiG has been dealing with this question since 2011. The legislator created the basis for this with the Act on the Reform of the Market for Medicinal Products (AMNOG).

Probability and extent of added benefit

The early benefit assessment, the core of AMNOG, brought new challenges for IQWiG from 2011 onwards. The AMNOG reports (“dossier assessments”) must be provided within 3 months; the deadlines are thus much tighter than for assessments following § 139b Social Code Book V. In this context the Institute must not only determine the probability, but also the extent of added benefit. In 2010 and 2011, IQWiG therefore developed appropriate scientific methods, newly organized procedures, and trained additional staff.

Content of early benefit assessment

Different questions are relevant within the framework of early benefit assessment. Which specific advantages and disadvantages does the new drug have for patients? Is it really better than the treatments already on the market? Which added benefit is proven for which patient group and to what extent? What is the relevance of the data presented? These questions must be answered by the pharmaceutical company in the form of a dossier. This applies to every newly approved drug from 1 January 2011. New indications of drugs approved from 2011 are also assessed.

As with the conventional benefit assessments, the dossier assessments also focus on conclusions and evidence with regard to patient-relevant outcomes: mortality, symptoms, adverse effects, late complications, and quality of life.

AMNOG procedure

The G-BA is responsible for the overall procedure of early benefit assessment and the pharmaceutical companies submit their dossiers to the G-BA. The G-BA usually commissions IQWiG with the scientific report. After publication of the report, the G-BA conducts a commenting procedure. This can provide supplementary information and can consequently also lead to a modified result of the assessment. The assessment procedure is only complete with a formal decision by the G-BA on the added benefit and on the extent of added benefit.

The further procedure depends on this decision and can, in simple terms, take two directions. If no added benefit can be determined, a reference price is allocated to the new drug (or a price that is not allowed to be higher than that of the comparator therapy). The latter is the case if no suitable reference price group exists. If an added benefit has been determined, then price negotiations are conducted between the Umbrella Organization of Statutory Health Insurance (“GKV-Spitzenverband”) and the pharmaceutical company.

Assessment categories

In a dossier assessment IQWiG evaluates the dossiers submitted with regard to their completeness of content, reliability, and the relevance of the information provided by the pharmaceutical companies. To provide evidence of added benefit, the companies must present all study results, study reports, and study protocols of studies on drugs  used in the therapeutic indication. IQWiG assesses the certainty of results on the basis of these data. Depending on the evidence available, in descending order IQWiG distinguishes between “proof” , “indication” or “hint” of added benefit. According to the legal requirements, the extent of added benefit is categorized with descending weighting as “major”, “considerable”, and “minor”. In addition, 3 further categories are available “non-quantifiable”, “no added benefit”, and “lesser benefit”.

60 assessments

Up to mid-February 2014, IQWiG sent a total of 60 assessments to the G-BA (excluding assessments of orphan drugs). In 28 dossiers IQWiG determined an added benefit in at least one group of patients (in 5 cases “proof”, in 14 an “indication”, and in 9 a “hint” of added benefit).

Novelty in 2013: “major benefit” for the first time

In the third year of early benefit assessments IQWiG determined the highest category of benefit for the first time, and in several cases. Up to February 2014 IQWiG determined a “major added benefit” for 6 drugs in at least one group of patients. However, the G-BA did not share IQWiG’s opinion, but downgraded the extent of added benefit from “major” to “considerable” for the drugs enzalutamide, ocriplasmin, and pertuzumab, and from “major” to “minor” in the case of sitagliptin. This downgrading was also due to additional information from the commenting procedures at the G-BA, which are routinely conducted after completion of the dossier assessments.

Exceptional regulation for orphan drugs

In the case of drugs for rare diseases (orphan drugs), the approval of the drug is at the same time deemed to be proof of added benefit. Therefore, for orphan drugs, IQWiG’s commission is limited to an assessment of information provided by the pharmaceutical companies on the number of affected patients and the cost of treatment. If the cost of treatment exceeds a yearly turnover limit of 50 million euros in statutory health insurance, then the orphan drug is subject to the regular procedure of early benefit assessment. As the first orphan drug, ruxolitinib exceeded the threshold of 50 million euros in 2013. The G-BA therefore called upon the pharmaceutical company to submit a dossier presenting evidence on the added benefit of ruxolitinib versus the appropriate comparator therapy. The dossier was forwarded to IQWiG for assessment. IQWiG determined an added benefit of ruxolitinib, as it alleviates symptoms better than the appropriate comparator therapy and offers survival benefits.

Concerns of pharmaceutical companies rebutted

The concerns of pharmaceutical companies, which claimed that the legislator specified “unfulfillable requirements for the time of market entry” with regard to the evidence to be provided, turned out to be unfounded. In October 2012, one year after publication of the first early benefit assessment, IQWiG staff members published an analysis of the dossier assessments completed up to the end of June 2012. They determined that 13 of the first 21 dossiers contained high-quality data on patient-relevant outcomes; these data allowed the assessment of added benefit in at least one group of patients.

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Glossary entries