>> The zVT is determined by the G-BA according to standards that result from its rules of procedure (VerfO). The basis for this is again Section 35a SGB V in conjunction with Section 6 AM-NutzenV. Accordingly, the zVT must be determined regularly according to standards resulting from the international standards of evidence-based medicine. It must be an appropriate therapy in the area of application according to the generally recognized state of medical knowledge, preferably a therapy for which endpoint studies are available and which has proven itself in practical application, unless there are guidelines according to § 92 Para. 1 of SGB V or the cost-effectiveness requirement to speak up against. If several alternatives for the comparator therapy are equally useful, the additional benefit compared to each of these therapies can be proven. The same appropriate comparator therapy must be used for drugs in a class of active ingredients in order to ensure a uniform assessment.
According to the G-BA's Rules, the following criteria in particular must be taken into account when determining the appropriate comparative therapy:
1. If a drug application is considered as a comparator therapy, the drug must generally have approval for the area of application.
2. If non-medicinal treatment is considered as a comparator therapy, this must be able to be provided within the framework of statutory health insurance.
3. Drug applications or non-drug treatments whose patient-relevant benefits have already been determined by the Federal Joint Committee should preferably be used as comparator therapy.
4. According to the generally accepted state of medical knowledge, the comparison therapy should be part of the appropriate therapy in the area of application.

With the publication of the benefit assessment, i.e. three months after the start of a procedure, the G-BA publishes some “information on appropriate comparative therapy”. This includes the list of approved drugs, the description of the research strategy and the results of the research as a tabular representation of the content of the relevant publications. The actual basis for the decision (the main reasons) for the above-mentioned criteria when determining the ZVT are only subsequently published with the decision, i.e. six months after the start of the procedure.

The pharmaceutical company concerned can obtain advice from the G-BA on the zVT to be determined. The pharmaceutical entrepreneur receives a transcript of the consultation. However, according to Chapter 5 § 7 VerfO, the information provided by the G-BA as part of a consultation is not binding. This means that the G-BA can change the reported zVT at a later date.
The G-BA charges fees for the advice, which are to be paid by the pharmaceutical company. According to the current fee schedule, such consultations generally fall into category III and cost 16,000 euros each.
According to the VerfO, the consultations should be carried out within eight weeks of submitting the documents. According to industry experience, this deadline is not always met. At the same time, submitting the documents is not possible at any time, but is linked to a consultation appointment that must be booked in advance. In the recent past, such consultation appointments were only available 5 to 9 months in advance. Effectively, consultations on the ZVT were therefore only possible in 7 to 11 months, as can be seen from the presentation of the available appointments on the website of the G-BA during 2022 (G-BA 2022b). In exceptional cases, however, there was the possibility of an earlier date for submitting the documents.
Advice on determining a zVT can basically be differentiated according to two purposes:
• for planning pivotal clinical studies
or
• before submitting a dossier for benefit assessment.

Advice on zVT before the start of pivotal approval studies can take place with the participation of the Federal Institute for Drugs and Medical Devices (BfArM) or the Paul Ehrlich Institute (PEI). According to Section 35a Para. 7 SGB V, the scientific and medical specialist societies and the Drug Commission of the German Medical Association (AkdÄ) should be involved in writing, particularly in consultations on zVT.

The specified ZVT can be roughly summarized in five categories:
(1) A therapy with the specification of a single therapy option.
(2) Multiple alternative therapies that serve as equally useful options in the sense of an or-link and can be examined in a single-comparator study.
(3) A patient-specific therapy according to the doctor's decision/choice with several therapy options. In the implementation here are compared to the above. Categories generally require multi-comparator studies with documentation of the individual therapy decision, although in certain cases single-comparator studies (e.g. formation through the formation of patient groups) can also be taken into account.
(4) A therapy according to the doctor's decision/choice. This option is specified in cases where there are relevant discrepancies between approved medicinal products and medicinal products relevant to healthcare or recommended in guidelines. In comparison to the categories mentioned above, therapy according to the doctor's instructions also includes off-label therapies that cannot be regularly prescribed. Specifications for both single-comparator and multiple-comparator studies are possible here.
(5) Best Supportive Care (BSC), when there are no relevant therapeutic alternatives and a patient-specific approach in the sense of optimized, supportive treatment is therefore appropriate.

Content justification
The zVT set by the G-BA is not binding and can be changed at a later date. The need for an adjustment can result, on the one hand, from a change in the area of application of a drug during the study or approval process. On the other hand, the necessity of the change can result from a corresponding further development of the state of medical knowledge and the relevance of care in practice. This can be reflected, for example, in the changed recommendations of the clinical guidelines of the medical societies. At the same time, these findings can also become clear in the course of the procedure in the context of the written and oral commenting procedure. Another factor for the change can result from the G-BA decisions themselves, if evaluated drugs with or without proven additional benefit are identified as new comparative therapies (or as part of them). However, with regard to the justification for the content, there is no clearly defined system or certainly no algorithm; rather, it is a balancing decision by the G-BA as to whether and for what reasons it initiates a change to the zVT.
A change in zVT can occur at any time, e.g. B. just a few months after a G-BA consultation or during a study that is already ongoing with the comparator advised. In some cases, several adjustments can be made by the G-BA during this time (G-BA 2018). A change is also possible immediately (i.e. a few weeks as in the procedure for the active substance ertugliflozin) before the dossier is submitted (G-BA 2022). Likewise, the G-BA can only make an adjustment after dossier submission in an ongoing procedure in its decision, as was recently the case with the active ingredient mepolizumab (G-BA 2022a). In addition, changes to the zVT for an area of application are also possible as a result of a decision, which are then relevant for subsequent procedures. This can e.g. This can also happen, for example, if an AMNOG drug itself becomes a ZVT, such as the active ingredient dupilumab in the therapeutic area of atopic dermatitis (G-BA 2021).

As already mentioned above, the change to the zVT is a balancing decision by the G-BA for which there is no clearly defined system. A justification for the change that may have been made is only published in the supporting reasons for the subsequent benefit assessment decision (as is also the case when the zVT itself is determined). However, such a publicly available declaration on changing the zVT in an area of application only takes place in the case of changes in procedures that are already in progress. These explicit designations in the underlying reasons can therefore be clearly identified. A change to the zVT in proceedings that are already ongoing has taken place in around one in five proceedings in the last two years (completed proceedings with proceedings beginning since December 1, 2019). Changes that occur before the dossier is submitted are not listed as such in the basic reasons of the G-BA and are not justified, but in some cases they can be found in the manufacturer dossiers (G-BA 2018). It is therefore not possible to quantify the frequency of such changes. Overall, however, the proportion of procedures with a previous adjustment of the zVT is likely to be significantly higher.

In recent years, pharmaceutical companies have had various options for obtaining information regarding adjustments to a ZVT. On the one hand, after G-BA consultation was completed, the companies were informed at a later date by the G-BA itself of any changes to the zVT. On the other hand, information could be changed by submitting a new request for advice to the G-BA on the part of the manufacturer. In addition, information on current comparative therapies could be taken from the decision-making practice of the G-BA, provided that conclusions about others could be drawn from the wording of the areas of application of such drugs.
In 2022, however, the G-BA stopped communicating the changes, which it had been doing for years. After the conclusion of an advisory process, no further information has been sent to the pharmaceutical companies (G-BA 2022b). It is now solely the responsibility of the pharmaceutical company concerned to check whether the appropriate comparator therapy is up to date at the latest when preparing a dossier for the benefit assessment. The G-BA points out the possibility of further consultation.

The extent of the impact of a zVT change on the respective AMNOG procedure depends on the scope and the details. An objective assessment of the consequences is only possible to a limited extent. Nevertheless, some scenarios can be roughly depicted from previous practice. For example, the addition of a further option to a zVT consisting of several alternative therapies (or combination) may initially have no direct impact on the result of the benefit assessment. However, such a change always has consequences for the framework of the subsequent negotiations according to § 130b SGB V, especially if the basket of comparative therapies to generic or patent-protected drugs is significantly changed.
Other zVT changes, on the other hand, have a direct impact on the benefit assessment and can make the difference between proven and non-proven additional benefits. A change can result in a study only being classified as suitable for the benefit assessment after the commenting procedure, since the comparator used in it is recognized as a suitable implementation of the zVT. For example, in the proceedings on the active substance tucatinib with a change in the comparator therapy to therapy according to medical prescriptions and consequently a consideration of the comparison with trastuzumab plus capecitabine (G-BA 2021b).
On the other hand, it also happens that a study with a direct comparison is classified by the G-BA as no longer usable, since the study comparator is no longer considered a ZVT in the ongoing procedure. Since the advice of the G-BA is not binding, the zVT can also be changed if the comparator of a study was explicitly recommended by the G-BA or the respective study was used specifically for the AMNOG benefit assessment (as in the case of the procedure for the active substance Risankizumab) was carried out in accordance with G-BA guidelines (G-BA 2019). Changes to the zVT can also mean that an additional benefit initially determined by IQWiG in the procedure is no longer recognized in the subsequent G-BA decision, since the zVT is changed during the ongoing procedure. These effects were found, for example, in the proceedings regarding the active ingredients nivolumab or mepolizumab (G-BA 2017, 2022a).

If there is a change in the zVT, the question arises as to how a pharmaceutical company can react to it. This always depends on the specific data situation and the point in time. Certain early changes, such as B. supplementing a zVT with another alternative option that has no impact on the suitability of the study to be submitted only requires an update of the evidence research and cost information.
When changes occur in ongoing proceedings, several constellations arise in decision-making practice. In some cases, an adjustment to the zVT means that a study is only classified as suitable after the commenting process. In such cases, the study that has already been submitted can be subsequently evaluated in an addendum to be drawn up by IQWiG and taken into account in the decision. In such cases, the G-BA does not consider it necessary to carry out the benefit assessment procedure again (G-BA 2021b).
In other cases, the G-BA changes the zVT, but does not draw any direct consequences for the proof of additional benefit. For example, if, according to the G-BA, the data presented are not suitable to prove an additional benefit, regardless of the question of the adequate implementation of the zVT, which is why a change in the zVT does not make it necessary to carry out the benefit assessment procedure again (G-BA 2021a).
In the case of some changes, however, the G-BA usually limits the procedures to six months. According to the G-BA, the pharmaceutical company is given the opportunity to submit a new dossier taking into account the current zVT (G-BA 2021c). However, this time limit can be lifted later by the G-BA if the pharmaceutical company (as in the case of the procedure for the active substance ozanimod) expressly waives the possibility of resubmitting a dossier taking into account the newly determined zVT, since there are no direct comparative data and an optional There are methodological reasons that preclude an indirect comparison (G-BA 2021c).
A very rare and new practice of the G-BA is the provisional suspension of the decision-making process for six months due to the zVT change, as in the case of the procedure for the active ingredient ponesimod (G-BA 2021d). The G-BA justifies this by saying that the manufacturer has already submitted a direct comparative study of the new zVT, but the study comparator was not yet part of the zVT at the time IQWiG was commissioned. Until the submission of the new benefit assessment, a decision by the G-BA is therefore not possible because all the prerequisites for the factual decision have not been met. The applicable deadlines are therefore interrupted by the changes that have occurred in the prerequisites for the factual decision in order to carry out a benefit assessment and a commenting procedure again.
Changes that no longer allow adjustments to the dossier due to the short-term nature (such as in the current procedure for the active ingredient ertugliflozin), to the extent that these are even possible, prove to be problematic (G-BA 2022). In the event of serious changes to the zVT, adequate adjustments can no longer be made, despite early information before dossier submission, for example if a registration study taking into account early G-BA advice is already being carried out (G-BA 2018).

It must be recognized that a ZVT should correspond to the generally recognized state of medical knowledge and the care process. It is also understandable that these requirements can change over time. In some areas of application, such as in oncology, this change is taking place very quickly due to innovative treatment options (Italia 2019). The zVT must also take this change into account in a G-BA resolution. At the same time, other factors must also be taken into account in the determination, without which the overall structure of drug research and subsequent HTA regulation cannot function optimally. On the one hand, this is the consistency of the benefit assessment to ensure a uniform assessment. According to the legal requirements, a change in the zVT is therefore also a consideration between a change in the state of medical knowledge (which very “rarely changes almost overnight” (LSG Berlin-Brandenburg 2013)) and the consistency in the assessment of an area of application or a class of active ingredients. On the other hand, this provides planning security for pharmaceutical companies. This proves to be the central problem of the ZVT change, especially if a study is subsequently classified as no longer usable according to G-BA specifications. The investments made in a suitable study situation based on trust in the G-BA advice are therefore not adequately rewarded either in the assessment or in the reimbursement situation. This situation creates considerable uncertainty for manufacturers and can have a negative impact on innovation.

When considering the adaptation of a zVT and when making decisions, the manufacturer's study situation should be better taken into account via additional legal requirements in SGB V if this was generated on the basis of G-BA advice. As a result, the previously advised comparative therapy, for which a clinical study was generated, should also be included in the basket of comparative therapies if the G-BA considers subsequent changes to the comparative therapy to be unavoidable. This approach can serve as a bridging regulation for the manufacturer's study situation in situations in which the state of medical knowledge gradually changes. This would lead to greater acceptance of the clinical studies generated, improve planning security for manufacturers and avoid negative effects on supply.

What should be critically mentioned is the G-BA's recently discontinued practice of proactively informing the pharmaceutical companies it had previously advised about changes in the wording of the zVT. In combination with the lack of binding nature of the advice, this means that the advisory service has no reliability whatsoever and could no longer correspond to a newly defined position of the G-BA on zVT in a very short time. This not only fundamentally questions the meaningfulness of advice. This is because advice is of particular importance (also due to the far-reaching exclusion of legal remedies).
Therefore, due to the principle of fair procedure, the G-BA would be required to inform pharmaceutical companies as early and comprehensively as possible of any changes to its advice and thus changes to its decision-making basis (LSG Berlin-Brandenburg 2013). It would also be expected that a lack of information about the consultations would lead to a significant increase in additional follow-up consultations. The pharmaceutical companies are now forced to seek advice at shorter intervals on the G-BA's current view regarding potential zVT changes. The already insufficient capacities in the G-BA's advisory time windows are thereby blocked even more unnecessarily. Proactive communication by the G-BA in the event of changes is therefore absolutely necessary in order to guarantee the principle of fair procedures, reliability and advisory capacities.
At the same time, a transparent presentation of all changes to the previously discussed zVT is necessary. Currently, such adjustments are only clearly shown if they are made during the ongoing process. As a result, it is rarely possible to understand which zVT originally advised, when, how often and, above all, for what reasons it was subsequently changed.

The G-BA only publishes the zVT it has specified and the document on "Information on the appropriate comparative therapy" together with the benefit assessment. It is not clear why these existing decision-making principles are not announced at the beginning of the procedure. There is no factual justification for this. As also already mentioned, the document "Information on the appropriate comparative therapy" contains comprehensible and therefore welcome information on the research strategy and the results of this research. However, the considerations made to determine the zVT remain non-transparent for the duration of the benefit assessment and the legally prescribed commenting procedure. The necessary supporting reasons for this will only be published with the decision. Overall, this delay in the transparency of the rules of the game is not appropriate. The established zVT, the document for the zVT research as well as the main reasons for determining the zVT (and, if applicable, the previously discussed versions) should therefore be published together by the G-BA at the start of the procedure.

Determining the appropriate comparator therapy is a central component of the AMNOG benefit assessment and is crucial for assessing the additional benefit of a new drug. After a consultation, however, subsequent changes to the zVT are made in many cases, which can have massive consequences for the assessment. To ensure planning security, the advised ZVT, for which a clinical study was generated, should also be taken into account. At the same time, the transparency of the changes is not sufficient. Therefore, proactive communication from the G-BA should be necessary in the event of changes in order to ensure the principle of fair procedure, reliability and advisory capacities. Better transparency is also required when it comes to changes to the ZVT before the start of the procedure and during the determination itself. <<
from:
Dr. PH Andrej Rasch, Senior Manager Benefit Assessment and HTA Coordination at the Association of Research-Based Drug Manufacturers

Italia N et al. (2019): Fast changing appropriate comparators in German AMNOG benefit assessments in multiple myeloma, In: Value in Health, Vol. 22, Suppl. 3, S502
G-BA (2017): Benefit assessment procedure for the active ingredient nivolumab (new area of application: melanoma, combination with ipilimumab). In: https://www.g-ba.de/information/nutzenvaluation/240/ (accessed on June 13, 2022)
G-BA (2018): Benefit assessment procedure for the active ingredient fluticasone furoate/umeclidinium/vilanterol (COPD). In: https://www.g-ba.de/vergleichverfahren/nutzenvaluation/352/ (accessed on June 13, 2022)
G-BA (2019): Benefit assessment procedure for the active ingredient risankizumab (plaque psoriasis). In: https://www.g-ba.de/vergleichverfahren/nutzenvaluation/465/ (accessed on June 15, 2022)
G-BA (2021): Benefit assessment procedure for the active ingredient baricitinib (new area of application: atopic dermatitis). In: https://www.g-ba.de/vergleichverfahren/nutzenvaluation/608/ (accessed on June 15, 2022)
G-BA (2021a): Benefit assessment procedure for the active ingredient dostarlimab (endometrial cancer, after previous platinum-based therapy). In: https://www.g-ba.de/vergleichverfahren/nutzenvaluation/708/ (accessed on June 15, 2022)
G-BA (2021b): Benefit assessment procedure for the active ingredient tucatinib (breast cancer, HER2+, at least 2 previous therapies, combination with trastuzumab and capecitabine). In: https://www.g-ba.de/vergleichverfahren/nutzenvaluation/663/ (accessed on June 15, 2022)
G-BA (2021c): Benefit assessment procedure for the active ingredient ozanimod (relapsing-remitting multiple sclerosis). In: https://www.g-ba.de/vergleichverfahren/nutzenvaluation/566/ (accessed on June 15, 2022)
G-BA (2021d): Benefit assessment procedure for the active ingredient ponesimod (relapsing-remitting multiple sclerosis). In: https://www.g-ba.de/vergleichverfahren/nutzenvaluation/706/ (accessed on June 15, 2022)
G-BA (2022): Benefit assessment procedure for the active ingredient ertugliflozin (diabetes mellitus type 2). In: https://www.g-ba.de/vergleichverfahren/nutzenvaluation/759/ (accessed on June 13, 2022)
G-BA (2022a): Benefit assessment procedure for the drug mepolizumab (new indication: chronic rhinosinusitis with nasal polyps). In: https://www.g-ba.de/valuation-procedures/benefit-assessment/764/ (accessed on June 13, 2022)
G-BA (2022b): Answers to frequently asked questions about the benefit assessment process. In: https://www.g-ba.de/themen/arzneimittel/arzneimittel-politik-anlagen/nutzenvergleich-35a/faqs/ (accessed on June 10, 2022)
LSG Berlin-Brandenburg (2013): Decision of February 28, 2013, file number L 7 KA 106/12 KL ER. In: https://gesetze.berlin.de/bsbe/document/JURE130004466