G-BA benefit assessment of new orphan drugs in Germany: the first five years

KEYWORDS:

• Benefit assessment
• Germany
• health technology assessment
• orphan drugs

The January 2011 introduction of benefit assessment through the Act on the Reform of the Market for Medicinal Products in Germany, better known as AMNOG (Arzneimittelmarktneuordnungsgesetz), created a new way to assess the value of patented medicines at the time of launch for use as a basis to determine their ongoing reimbursement. This Act was basically intended to counteract increasing drug prices.[1] Implementation was the task of the Federal Joint Committee (Gemeinsamer Bundesausschuss (G-BA)), the decision-making body in the German statutory health insurance system (Gesetzliche Krankenversicherung (GKV)).

From the outset, orphan drugs were not excluded from AMNOG assessment, but a special legal framework was created for them. Indeed, considering the incentives offered after orphan designation in the European Union,[2] the German legislator guaranteed orphan drugs a positive additional benefit, as long as the value of sales at GKV expense stays below €50 million per 12 months.

The steps to benefit assessment over a fixed 6-month period are: (1) submission of a dossier by the applicant company at the time of introduction of a new active substance on to the German market; (2) dossier assessment, usually by the Institute for Quality and Efficiency in Healthcare (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG)), resulting in a proposal on the extent and probability of additional benefit over an appropriate comparator previously determined by the G-BA; (3) a hearing after publication of the assessment on the G-BA website; and (4) a resolution by the G-BA on the basis of the assessment and the hearing.

Price negotiations between the manufacturer and the National Association of Statutory Health Insurance Funds (GKV-Spitzenverband (GKV-SV)) follow from the G-BA resolution and take place over the next 6 months. Within 4 weeks of the resolution, a company can decide not to initiate negotiations and to leave the market (‘opt-out’). If no agreement can be reached, an arbitration board takes the final decision within 3 months. In certain cases, a company may even decide to take its new product off the German market after the arbitration board’s decision.

The steps of the AMNOG procedure apply to orphan drugs too. However, the legal framework led to important modifications. An additional benefit for orphan drugs was considered to be already proven through the grant of market authorization. Categorization of probability of the additional benefit in the form of ‘proof, indication or hint’, which applies to non-orphan drugs, is therefore omitted. The G-BA only determines the extent of additional benefit, which it can rate as ‘minor’, ‘considerable’, ‘major’, or ‘non-quantifiable’. The categories ‘no additional benefit’ or ‘less benefit’ are not applicable.

Pirfenidone was the first orphan product to undergo early benefit assessment. The G-BA commissioned IQWiG to assess the additional benefit over the appropriate comparator, best supportive care (BSC). However, IQWiG’s assessment, published on 15 December 2011, failed to demonstrate any additional benefit.[3] This result was seen as not in line with the legal requirements. The written statements on pirfenidone and especially the oral hearing on 24 January 2012 led to an adjustment of the procedure. On the basis of its market authorization and supporting studies, pirfenidone’s extent of additional benefit was classified as non-quantifiable (G-BA resolution from 15 March 2012 [4]). This first resolution for an orphan drug was only the third early benefit assessment overall under AMNOG, following resolutions for ticagrelor (Brilique^®) from 15 December 2011 [5] and boceprevir (Victrelis^®) from 1 March 2012.[6]

On the exact same day the resolution for pirfenidone took effect, an assessment on the second orphan drug by IQWiG, tafamidis meglumine, was published on the G-BA website.[7] IQWiG had once again been commissioned to assess the drug’s additional benefit over an appropriate comparator. The results showed additional benefit could be derived from the patient-relevant outcomes in the randomized controlled trial. Referring to the resolution for pirfenidone, the G-BA stated that the commissioned IQWiG assessment would not be used for the assessment of the additional benefit for tafamidis meglumine.[8] Assessment based on the studies for market authorization finally resulted in a minor additional benefit being shown.[9]

After two unconsidered IQWiG assessments, the G-BA adapted its procedure. Therefore, for the assessment of the third new orphan drug, pasireotide, the G-BA did not commission IQWiG for the benefit assessment but its own methodological department working in close collaboration with its pharmaceuticals department instead. The basis for the assessment was the dossier, the market authorization studies and associated documents, especially the European Public Assessment Report. IQWiG was, however, commissioned for an assessment of the number of eligible patients and the costs of treatment, which are part of the resolution too. As a result, two specific assessments were published on the G-BA website on 17 September 2012.[10,11] This was the first G-BA benefit assessment and a main pillar for G-BA resolutions from 6 December 2012.[12] This adjustment proved itself and is still implemented.

Since the introduction of AMNOG and as of 1 January 2016, 28 orphan drug procedures have been completed by the G-BA. In 13 cases the additional benefit was minor, in 12 non-quantifiable, and in 3 considerable (see Table 1).

Table 1. G-BA extent of additional benefit for orphan and non-orphan drugs in the period 2011–2015.

	Orphan drugs	Non-orphandrugs
Additional benefit	28 (100%)	54 (46.2%)
Major	0	2 (1.7%)
Considerable	3 (10.7%)	27 (23.1%)
Minor	13 (46.4%)	21 (17.9%)
Non-quantifiable	12 (42.9%)	4 (3.4%)
Additional benefit not proved	0	63 (53.8%)
No additional benefit	Not applicable^a	59 (50.4%)
Reference price group	0	4 (3.4%)
Less benefit than appropriate comparator	Not applicable^a	0
Total assessments	28	117

^a For orphan drugs below €50 million.

The main therapeutic area was oncology covering almost half of the active ingredients, followed by inherited metabolic disorders (see Table 2). The legal link of orphan drug designation to the market authorization with the implications of faster access for patients leads to the fact that 43% of the assessments result in a non-quantifiable additional benefit. This means that pending further scientific data, a classification in one of the other categories is not possible. In some cases, the G-BA puts a time limit on its resolutions to be able to conduct a further assessment after a period of post-marketing experience.

Table 2. Chronologic list of AMNOG benefit assessment procedures for orphan drugs in the period 2011–2015.

Active ingredient	Brand name	Therapeutic indication(s)	Resolution date	Additional benefit	Estimated GKV patients
Pirfenidone	Esbriet^®	Idiopathic pulmonary fibrosis	15 March 2012	Non-quantifiable	6000
Tafamidis meglumine	Vyndaqel^®	Familial amyloid polyneuropathy	7 June 2012	Minor	40–104
Pasireotide	Signifor^®	Cushing’s disease	6 December 2012	Minor	160–360
Ivacaftor	Kalydeco™	Cystic fibrosis	7 February 2013	Considerable	170
Ruxolitinib	Jakavi^®	Myeloproliferative disorders	7 March 2013	Minor	1600
Decitabine	Dacogen^®	Myeloid leukemia	2 May 2013	Minor	300–780
Brentuximab vedotin	Adcetris^®	Hodgkin and non-Hodgkin lymphoma	16 May 2013	Non-quantifiable	60–260; 15–160
Bosutinib^a	Bosulif^®	Myeloid leukemia	17 October 2013	Non-quantifiable	380–500
Ponatinib^a	Iclusig^®	Myeloid and acute lymphoid leukemia	23 January 2014	Non-quantifiable	500–940; 25–195
Pomalidomide	Imnovid^®	Multiple myeloma	20 February 2014	Considerable	1900
Macitentan	Opsumit^®	Pulmonary hypertension	17 July 2014	Minor	580–7850
Riociguat	Adempas^®	Pulmonary hypertension	16 October 2014	Minor	580–7850; 920–5460
Cholic acid	Orphacol^®	Inborn errors in primary bile acid synthesis	6 November 2014	Non-quantifiable	10–25
Ruxolitinib (>€50 million)^b	Jakavi^®	Myeloproliferative disorders	6 November 2014	Considerable	1600–5000
Elosulfase alfa	Vimizim^®	Mucopolysaccharidosis IVA	20 November 2014	Minor	15–95
Siltuximab	Sylvant^®	Giant lymph node hyperplasia	4 December 2014	Non-quantifiable	130–1460
Cabozantinib^a	Cometriq^®	Thyroid cancer	22 January 2015	Minor	60–500
Obinutuzumab	Gazyvaro™	Chronic lymphocytic leukemia	5 February 2015	Non-quantifiable	818–1477
Teduglutide	Revestive^®	Malabsorption syndromes	19 February 2015	Minor	1100–2400
Ivacaftor (new indication)	Kalydeco™	Cystic fibrosis	19 February 2015	Minor	10–11
Ibrutinib	Imbruvica^®	Mantle-cell lymphoma; chronic lymphocytic leukemia	16 April 2015	Non-quantifiable	700–950; 2200–7800
Alipogene tiparvovec^a	Glybera^®	Lipoprotein lipase deficiency	21 May 2015	Non-quantifiable	17–35
Ataluren^a	Translarna™	Duchenne muscular dystrophy	21 May 2015	Minor	82–110
Pasireotide (new indication)	Signifor^®	Acromegaly	18 June 2015	Minor	265–1133
Ramucirumab	Cyramza^®	Stomach cancer	16 July 2015	Minor	5900–7900
Nintedanib	Ofev^®	Idiopathic pulmonary fibrosis	3 September 2015	Minor	2080–19,700
Eliglustat	Cerdelga^®	Gaucher’s disease	1 October 2015	Non-quantifiable	150–500
Olaparib^a	Lynparza™	Ovarial cancer	27 November 2015	Non-quantifiable	818–1477
Lenvatinib	Lenvima^®	Thyroid cancer	17 December 2015	Non-quantifiable	600–815

^a Time-limited resolution.

^b This resolution replaced the first one.

Before the G-BA resolution, no clear classification of the additional benefit into categories is made in the G-BA’s assessment. In fact, the absence of a clear initial statement may provide an opportunity to highlight instead the importance of the written and oral hearing procedures and the involvement of stakeholders—including patient representatives within the G-BA—in determining the additional benefit.

A consequence of the legal wording is that the additional benefit for orphan drugs has been proven by market authorization regardless of the level of forecast sales. However, if actual sales over the previous 12 months exceed €50 million the G-BA will conduct a re-assessment with an appropriate comparator and the involvement of IQWiG.

The initial assessment is based on the studies for market authorization and not on a comparison over an appropriate comparator therapy. This means in practical terms that a couple of sections in the dossier need not be completed. At the same time however, it constitutes a challenge for the negotiating partners. No appropriate comparator means there is no obvious basis for a price comparison for use either by the manufacturer or by GKV-SV. However, the number of successful price negotiations (18) and the absence of market exits show that the G-BA produces solid value assessments on which to conclude negotiations.[13]

One temporary opt-out was registered for bosutinib. However, price negotiations continued between the pharmaceutical company and GKV-SV and have even been completed. Another important challenge in the procedure was the assessment of ruxolitinib after sales reached the €50 million threshold. Consequently, a full dossier was required, including data analyses over the appropriate comparator, as the same procedure for non-orphan drugs is applied. IQWiG was commissioned for a dossier assessment and a comparison of ruxolitinib over the appropriate comparator. This challenge was successfully overcome with the resolution from 6 November 2014 [14] and a re-assessment of another orphan drug after sales exceeded €50 million is ongoing.[15]

After the G-BA assessment of pasireotide, the AMNOG procedure for orphan drugs became established. It is now, after several assessments on orphan drugs, acknowledged that it is working.

Expert opinion

The successful procedure with orphan drugs may be a model for other planned important legal changes in the benefit assessment procedure under AMNOG. Indeed, for medicines with pediatric-use marketing authorizations, a granted additional benefit might be considered as a practicable solution in the future. The expected growth in number of new orphan drugs will lead to an increasing importance to their assessment. New advanced therapies like the pioneering gene therapy alipogene tiparvovec are obviously still a challenge. Balancing legal and evidence requirements taking into account possible modifications at the European Medicines Agency will demand re-adjustments, especially recognizing the privileged position rare diseases occupy among all indications.

Declaration of interest

M Bouslouk is an employee of the G-BA and has no other affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Acknowledgement

The author thanks Donald Macarthur for his suggestions to improve the clarity of the text, and Peter R Marx for his suggestions to improve the tables.