Early benefit assessment dossiers
Germany's early benefit assessment dossier presents a new drug's added benefit over the comparator specified by the Federal Joint Committee. Its modules contain the clinical evidence, patient population, treatment costs and supporting documents used in the assessment and subsequent reimbursement decision.
Legal framework and responsibilities
The Act on the Reform of the Market for Medicinal Products (AMNOG) took effect on 1 January 2011, seeking to counter high patented-drug prices and rising pharmaceutical expenditure. Its main rationale was to support pricing decisions and slow drug-price growth.
Under the framework described in 2013 and 2021, Paragraph 35a of Social Code Book V required a company launching a new drug or a newly approved indication to submit evidence of added patient benefit against an appropriate comparator therapy (ACT), specified by the Federal Joint Committee (G-BA). The G-BA managed the procedure and made the final added-benefit decision, usually commissioning the Institute for Quality and Efficiency in Health Care (IQWiG) to assess the dossier. Orphan-drug assessments were an exception, mainly the G-BA's responsibility under specific regulations in 2013 and conducted directly by it in 2021.
In 2021, the German reimbursement dossier usually required no economic evaluation, making the argument for the degree of additional benefit depend on clinical efficacy rather than an economic model. In 2013, medical writers employed by companies or agencies, or commissioned as freelancers, were heavily involved in preparing the German-language dossier; English-language writers could prepare text for translation.
Consultation and assessment timetable
In 2013, G-BA consultation on documents, studies and the ACT required payment and could occur before phase 3 studies began. The 2021 advice-meeting application asked which comparator was appropriate, whether trial design and patient-relevant endpoints were acceptable, and whether subgroups were correctly chosen from available data, with company arguments for and against each point. Preparing it required team agreement on questions, research and writing, including recent national guidelines, European or international guidelines where national ones were unavailable, and previous assessments in the same or similar indications.
The 2021 timetable required submission on the day of market entry, or within three months for a newly approved indication. The G-BA checked formal compliance before commissioning IQWiG; external experts and patient representatives answered questionnaires before assessment, and experts advised on specific issues during it. IQWiG's assessment of the probability and extent of added benefit was published on both bodies' websites within three months after market entry; the 2021 account also described publication three months after commissioning.
The company and specified scientific and commercial parties could then comment in a written hearing, followed by an oral hearing. In 2021, only three weeks separated publication from written statements, so advance preparation of possible responses was advisable. Writers often researched and formulated responses for the oral hearing, preparing for different possible scenarios.
The G-BA resolution followed three months after assessment publication under the 2013 timetable, or within six months of market entry in 2021. It considered the assessment, written statements and oral hearing and specified added-benefit extent, eligible patient groups, quality-assured administration requirements and treatment cost. The resolution formed the basis for price negotiations between the statutory health-insurance umbrella organisation and the company.
Published requirements and reference material
Close adherence to published guidance helps dossiers meet formal and content requirements. In 2013, Chapter 5 of the G-BA Rules of Procedure specified the following.
- Scope.
- Processes: G-BA consultation; dossier submission, assessment and publication; commenting; and publication of the G-BA resolution.
- Definitions: drugs with new active ingredients, ACT, benefit and added benefit, and extent of added benefit.
- Requirements for deriving proof: preferably randomised trials directly comparing the drug with the ACT; preferably patient-relevant mortality, morbidity and quality-of-life outcomes; and assessment and consideration of study quality.
- Dossier-content requirements.
- Special situations, including orphan drugs.
The 2021 assessment likewise preferred randomised trials and patient-relevant outcomes, including mortality, morbidity with adverse events, and health-related quality of life. Public reference material available in 2013 included the following.
| Information | G-BA website | IQWiG website |
|---|---|---|
| General information | Summary and questions and answers, German and English | Summary, German and English |
| Methods and requirements | Rules of Procedure and dossier template, German | General Methods version 4.0 and methods for classifying added-benefit extent, German and English |
| Dossier for each drug | Modules 1–4, German | — |
| Assessment results | Full assessment, German | Full assessment, German; extract with executive summary, methods, results and conclusions, English; health information, German and English |
| Commenting | Submitted comments, G-BA responses and hearing minutes, German | — |
| Resolution | Resolution, German and English; reasons for the decision, German | — |
Dossier modules
The five-module dossier used mandatory German-language G-BA templates in 2021. These templates specified content and methods as well as format; failing to follow them increased the risk of an inadequate dossier and a conclusion that no added benefit was proven. A completed formal-completeness checklist also had to be submitted.
Modules 1–4 included information on the drug, standard care, patient numbers and costs, and a systematic review with the company's classification of added-benefit extent. In 2013, evidence generally comprised all relevant published and unpublished direct-comparison trials; indirect comparisons could be used where direct comparisons were unavailable, but treatment administration had to accord with both drugs' approval status. The module contents described in 2021 were as follows.
- Summary. Summarise Modules 2–4 within word limits, comparable to NICE document A.
- General information. Give mode of action and approved indications, usually obtained from the summary of product characteristics and regulatory documents.
- Comparator, population and costs. Name and justify the ACT. Derive the target population, especially patients expected to gain additional benefit, for later price negotiations. Overall patient numbers can come from destatis.de and more specific numbers from registries or publications. Give therapy and comparator costs from the paid Lauer-Taxe database.
- Results and added benefit. Present and interpret all measured endpoints from the described trials, preferably randomised trials, using clinical study reports and published literature on the drug and ACT. Include the company's final assessment of added benefit and its probability.
- References. Include all references cited in Modules 1–4.
The 2013 cost information covered drug costs only. Module 5 was described more broadly in 2013 as the full evidence base, including full reports of all manufacturer-sponsored trials. A separate 2021 description listed the following supporting material.
- Clinical study reports, including protocols but excluding individual patient data.
- Clinical sections of the Common Technical Document.
- European Medicines Agency reports, including European public assessment reports.
- Systematic-search documentation.
- Full-text publications.
Added-benefit conclusions
IQWiG's general methods were published in its methods paper; the specific extent-classification method was published as an appendix to its first new-drug dossier assessment, for ticagrelor. In 2021, IQWiG systematically reviewed the approved indication and population, specified standard care and patient-relevant outcome analyses, comparing the new drug's benefits and harms with standard care. Patient-relevant outcomes describe how a patient feels, functions or survives.
The 2013 grading distinguished probability from extent of added benefit or harm.
- Probability: proof, indication, hint, or no conclusion possible because data are insufficient or absent, depending on study numbers, bias risk, direction and statistical significance of effects.
- Extent where benefit is shown: major, considerable or minor; additional categories are non-quantifiable extent, no added benefit or less benefit.
- Overall conclusion: qualitative aggregation of results across outcomes.
In 2021, certainty was graded from hint through indication to proof according to data quantity and quality; extent was minor, considerable, major or not quantifiable, depending on outcome type and effect sizes.
A 2020 apalutamide assessment illustrates the combination of certainty and extent. For castration-resistant prostate cancer at high risk of metastasis, G-BA specified watchful waiting, with conventional androgen deprivation maintained in both groups. The company identified one relevant randomised trial and IQWiG confirmed it, assessing survival, symptom progression, health status, quality of life and adverse events. Apalutamide had favourable effects particularly on overall survival, serious or severe symptoms and some adverse events, while standard care was favourable for other adverse events. The survival benefit meant unfavourable effects did not offset favourable ones, producing an indication of considerable added benefit.
Publication and subsequent use
Publication of Modules 1–4, full assessments and resolutions was legally required in 2013, with additional material such as patient health information. In 2021, Modules 1–4 appeared in German on the G-BA website; the full assessment appeared in German on both bodies' websites, with an English and German extract. The assessment's comment section explained deviations from company data presentation, analyses and conclusions. Module 5 was not published whole, although IQWiG could publish its data as required and some documents were available elsewhere. The final decision appeared with its underlying reasons, the Tragende Gründe, and stakeholder comments, containing clinical data from the dossier and included studies' reports.
The published material had several uses in 2021.
- Payers. Reimbursement prices were negotiated using added benefit; only the final price, not negotiation records, was public. Statutory-insurance prices also applied to private insurers.
- Physicians. Public conclusions and data supported prescribing; an electronic system launched in 2020 transferred structured G-BA files into prescribing software to make evidence accessible, without giving legal directives.
- Guideline developers. Assessments added trial methods, bias, limitations, results and subgroup analyses beyond journal publications, using full clinical reports without some restrictions affecting the European Medicines Agency's clinical-data database.
- Patients. Easily understandable assessment findings appeared at gesundheitsinformation.de and its English version informedhealth.org, supporting shared decisions and IQWiG's legal public-information remit.
IQWiG's account of its early-benefit-assessment work in 2021 described comprehensive public information in scientific and accessible formats, often including previously unpublished data, supporting pricing, guidelines and shared decisions.
Early experience
By 2013, about 30 assessments had been completed; an analysis of the first 21 non-orphan-drug dossiers found 13 adequate for evaluation, with some inadequate dossiers showing evidence gaps or departures from the specified comparator. The assessors considered these findings evidence that early benefit assessment was feasible. Assessment of pre-AMNOG drugs was also introduced by 2013, beginning with gliptins for type 2 diabetes, covering older and newly approved drugs together; further groups had been called for assessment.