>> Müller, who sees his role at the BMG as being responsible for "ensuring that medicines are available in Germany and that new ones are developed," but also for setting the legal framework in such a way that there are incentives for innovative medicines to be "available in high quality and ultimately affordable in healthcare." While at his previous employer, as head of the Pharmaceuticals Department of the Federal Joint Committee (G-BA), his responsibilities included preparing the early benefit assessment procedures, he can now, with the experience he gained there, work directly on the laws he previously had to implement in his new position as head of the Pharmaceuticals/Medical Devices Department at the Federal Ministry of Health (BMG).
Almost exactly halfway through the current legislative period, Müller gave an overview of upcoming legislative changes affecting the pharmaceutical sector at the MSD symposium at the DGHO Spring Conference 2019. He left out the Appointment Service and Supply Act (TSVG), which had already been passed by the Bundestag and which addresses pharmaceutical issues—except for a new regulation on vaccine supply. Instead, the BMG department head focused on the upcoming GSAV, which requires approval from the Bundesrat and is scheduled to enter into force by mid-year.
Guidelines for biosimilars
This law, triggered by recent pharmaceutical scandals, regulates far more than just safety issues, such as expanded federal powers regarding drug recalls and controls on manufacturers in third countries, or tightening the framework for the manufacture and dispensing of cancer drugs by pharmacies. The current draft law also contains a tight timetable for the introduction of electronic prescriptions—requiring self-governing bodies to create the necessary regulations for the use of e-prescriptions within seven months of the law's entry into force.
Furthermore, patient access to biotechnologically produced medicines whose patents have expired is to be improved in the future. "With regard to biosimilars, there is a new regulation under which we will give the Federal Committee the instrument over the next three years to oblige doctors to use biosimilars through certain guideline specifications," explained Müller. This means that although the doctor alone still decides whether a patient receives a biosimilar, if he or she does so, this must be done within the framework of the guideline yet to be issued by the G-BA. Müller: "We have already stipulated in the law that this exchange will take place at the pharmacy level three years after the law comes into force." Based on the quality of the biosimilars and the experience gained with them so far, the BMG assumes that this is possible, in Müller's opinion, "without endangering patient and drug safety." With this step, the BMG hopes to increase competition in this still very expensive area; Müller is well aware that “the market must be given the opportunity to develop in this way” so that price competition can emerge.
Application-related data
A second major new regulation within the GSAV concerns the handling of marketing authorisation data. For the assessment of the benefit of medicinal products for the treatment of orphan diseases, for conditional marketing authorisations and for marketing authorisations under exceptional circumstances, the
In future, the G-BA will have the authority to require the pharmaceutical company to carry out accompanying data collection.
Müller even described this passage as a "focus of the further development of the AMNOG." According to Müller, the background to this is that the EMA, in particular, is granting approvals for new products for which high patient demand and major therapeutic advances for patients are expected, allowing them to reach patients much more quickly than before; this is particularly evident in oncology. The problem, according to the BMG department head, is that this would result in changes to the study process from phases 1 to 3. Müller: "We have seen that products are often approved after the phase 2 study with the argument that there is high patient demand." This leads to a lack of consistency in the benefit assessment, since the G-BA generally expects comparative phase 3 studies with a high level of evidence for its benefit assessment, but these data are often not even available due to the early approval.
The Federal Ministry of Health (BMG) intends to counteract these "conflicting requirements" – on the one hand, accelerated approvals based on therapeutic need, and on the other, the requirement for a benefit assessment by the Federal Joint Committee (G-BA), in which no additional benefit can be declared without sufficient data. Here, too, the Federal Joint Committee (G-BA) is to be given an additional tool that allows it to "maintain a product in the supply chain with a preliminary assessment in certain situations."
This is intended to prevent price negotiations between pharmaceutical companies and the GKV umbrella association from almost inevitably ending with innovative products being withdrawn from the market because, according to Müller, “price negotiations cannot be conducted on the right basis” on the basis of “no additional benefit”.
Therefore, a temporary price agreement based on the available data should be reached until improved evidence allows for a follow-up evaluation. This evidence will be generated through the new "use-accompanying data collection" introduced into the upcoming law; with the stated goal of closing the evidence gap that exists in some AMNOG procedures – both in accelerated procedures and for orphan drugs.
Incidentally, in the future, inpatient sales will also be included in the 50 million Euro sales threshold for orphan drugs, which, according to Müller, will result in these drugs reaching this threshold more quickly. The company also has the new option of going directly to full assessment from the start, which he describes as an "incremental development of the AMNOG."
The EMA has long had additional registration requirements for accelerated approvals, with the European regulatory authority defining the additional data it wants to see. "What we're seeing, however, is that this data isn't consistently collected in large quantities," Müller explained.
Therefore, "use-related data collection" should become mandatory. In order to "get everyone on board," according to Müller, healthcare providers will be required to participate in these data collections if they intend to use the new active ingredient in question. Conversely, as the BMG department head explained, this means that a healthcare provider who considers such data collection (which, however, is to be paid for by the company within a study or registry environment) too costly will no longer be able to prescribe the product in question in the future.
However, the legislature left completely open the form and level of evidence for these data collections. Müller stated, "These can be registries and any type of study." However, no RCTs!
The reason for this is already provided by the term "accompanying data," which, according to Müller, "should make it clear that patients are being provided with the new active ingredient during this phase." However, since in RCTs, in which patients are randomized, half do not receive the new drug, "we as legislators cannot imagine this option." Now, it is everyone's challenge to create ways to guarantee the level of evidence required for a follow-up evaluation in the future.
On the one hand, these could be study types other than RCTs. Figure 1 describes one of many possible solutions for implementing the new law. This proposal by Prof. Dr. med. Franz Porzsolt, founder of the Institute of Clinical Economics (ICE) eV, already published in MVF 03/18, states that every institution wishing to implement a new innovation must commit to including all patients cared for at that institution, regardless of the therapy administered, in the project during the recruitment phase (which only takes a few months), in order to reflect the reality of care as realistically as possible. Patients not treated with the innovative drug must then be stratified into study arm B and/or the control group. This step could create a study design comparable in evidence level to the RCT study type.
Another possible solution, however, is registries, which Prof. Dr. Jürgen Windeler, Head of the Institute for Quality and Efficiency in Health Care, believes are "not suitable for benefit assessments" (MVF 01/18). When asked by MVF whether the IQWiG now needed to rewrite its rules of procedure, Müller evaded the question, but said that the legislature could not resolve the question of what a registry suitable for benefit assessment should look like. Furthermore, "the G-BA's green light is needed first to ensure that these data are also suitable for making statements in a follow-up assessment." For this reason, Müller described the upcoming legislative amendment as a "trial balloon." If the G-BA concludes that the data cannot be used, "we will have to rethink things."
To avoid this, professional societies, health services researchers, and registry specialists must now work together with the Federal Joint Committee (G-BA) and the Institute for Quality and Health (IQWiG) to define how the highest possible level of evidence can be maintained within the "procedure-accompanying data collection." "This is a major challenge for everyone involved," Müller knows from his many years of experience. It is clear to him that professional societies must play an important role, also because they are "more mature for such registries." Ideally, in order to make comparative statements, one needs not a product register, but an indication register. Maintaining this indication register requires an authority that professional societies could assume.
The incentive for this is certainly there, because according to the draft law, appropriate discounts on the originally agreed reimbursement amount can be agreed if the pharmaceutical company fails to comply with this conditional requirement or if no quantifiable additional benefit is evident in the data collected. Conditional because the G-BA can, but is not required to, use the new instrument. However, according to Müller, the following applies to policymakers: "Patients must not be the ones to suffer, without, however, compromising the standards we have in Germany regarding products and evidence." In this balancing act, Müller assumes that "there are situations in which we must persuade the G-BA to also use registers for the additional benefit assessment."
Professional societies involved in defining therapy standards
An important, if not the central, factor in the benefit assessment is the definition of the appropriate comparator therapy. Previously, in the so-called Scientific Advice procedure (around 200 have already been conducted), the pharmaceutical company bringing the product to market could submit its idea of an appropriate standard of care, but the Federal Joint Committee (G-BA) retained sole authority to define the treatment. The Federal Joint Committee (G-BA) will retain this authority, but according to the draft law, it will in future be required to involve the professional societies involved in the relevant indication in writing. This requires timely notification to the AWMF that a standard of care is to be defined by the G-BA and used in a study design. Müller: "Since we believe the professional societies are predestined and competent for this through their guideline and clinical work, we have included them in a written participation procedure."
"A professional society that wants to support knowledge-generating care cannot ignore this," responded symposium moderator and DGHO chairman Prof. Dr. med. Carsten Bokemeyer (UKE). In his view, not using care data for high-priced medications and rare indications represents "a loss that society cannot afford." Likewise, many professional societies, including the DGHO, wish to participate in defining treatment standards within the early benefit assessment. However, he cautioned that the question remains "whether we will be able to predict years in advance what the standard treatment will be years later," but he remains optimistic.
by: MVF editor-in-chief Peter Stegmaier
Citation note:
