Are you ready for the Danish Medicines Council 2.0? – The appraisal process and the clinical application
In this second article, we touch upon the most significant changes made to the application process and to the clinical application and theorize on its importance in the future appraisal process. The implementation of a “QALY model” in the Danish Medicines Council (DMC) will have a significant impact on the assessment process, so make sure to check our initial post on the QALY (link).
Major shift in timelines and responsibility.
The new DMC process is a complete revision of the current process, and if successfully implemented could allow for more flexible and rapid assessments. This will however to a great extend depend on the companies, which will need to take on more responsibility than previously. Below, highlights of the new application process are presented and subsequently discussed.
Highlights of the new application process:
- In the new process the clinical and the health economic application are inherently linked, and will need to be completely aligned.
- The clinical application will shift from forming the basis of the clinical benefit category to serving as a presentation of the evidence informing the health economic model.
- The importance and focus on the health economic model increases, as it is no longer used only to assess added cost, but also to assess cost-effectiveness. The two primary outcomes for decision making (i.e. costs and QALYs) are estimated in the health economic model – not the clinical application.
- There will be no protocol or scoping of the application by the DMC.
- There are no binding alignment mechanisms to ensure agreement between the company and the DMC.
- No alignment mechanisms within the DMC between the clinical expert committee and secretariat and the council
- The draft assessment report and the recommendation is delivered together in a single DMC meeting for adoption.
As a consequence:
- The companies now carry the burden of evidence in scoping the application
- There is a need to start the preparation of the application earlier
- There is a need for more elaborate upfront discussions with the DMC and potential KOL engagement
- There is a higher risk of disagreements with the council at the final decision meeting, as the scoping of the application and the evaluation and assumptions made in the draft assessment report will not be presented to the Council prior to the final decision meeting.
- This could increase risk of reassessment as the preferred base case presented to the council has not been aligned with the Council
- Initial dialogue can start with a request for assessment after the list of question from the primary evaluation at EMA are received by the company (EMA day 120)
- In addition, by bypassing the protocol step, it means the company can start preparing the application and submit earlier
- This change can potentially allow for a reduced go to market time (from EMA approval until recommendation from the DMC)
In the current process the DMC provides a protocol for the applicant to be used to address the decision problem in the final application. The protocol is not a part of the new process, and surprisingly in the draft process guideline, it has not been replaced by a more simplistic scoping document as NICE has adopted.
What are the implications?
It sends a clear signal from the DMC, that the burden of evidence has shifted to the companies, who are now responsible for documenting the clinical decision problem in a Danish context. It also signals the end of a very frontloaded process, in which the DMC effectively determined both the scope of the assessment and by setting certain minimal clinical important differences heavily predetermined the categorization of the added clinical value and therefore the willingness to pay.
The protocol step has previously caused downstream delays in the evaluation process, because the companies have to await a protocol, before they can start their application, this may then lead to delays in developing the application as the protocol dictated specific analyses or comparisons, that the company may or may not have been able to conduct. The lack of a protocol will certainly come with hurdles, but also with significant opportunities, which we will discuss further below.
Request for assessment and dialogue meeting (day 120 EMA)
At present the initial dialog meeting is possible after EMA day 150 (after CHMP assessment report). Going forward you will be able to make a request for an assessment at day 120 (receiving the list of questions after the primary evaluation at CHMP), and then set up a meeting with the DMC when feasible. This is more significant than indicated, as there is at least a 3-6 months gap between day 120 and day 150, as in between these “reference days” is a clock-shop, where the company prepares and responds to CHMPs initial assessment and list of questions.
Because the protocol step has been removed in the new process, the purpose of the initial dialogue meeting has changed. The initial dialogue meeting will be a pivotal time to ask all questions which will be important for informing, scoping and developing your value demonstration strategy for your application. Central to this will be asking questions, that secures alignment between your application scope, and its applicability to the Danish setting. Therefore, you may need early KOL engagement to prepare for the meeting as well as a high degree of awareness of what evidence is available to prepare different value demonstration scenarios.
To address the need for alignment at an early stage, the clinical expert committee members can be invited to take part in the dialogue meeting. For the meeting to be successful the company need to consider in further detail the weakness(es) or gaps in the evidence, and what will be the best way forward, otherwise the company will end up applying blindly hoping for agreement later on but having little upfront reassurance. Importantly, the DMC will only be providing non-binding advice during the meeting, and any statements by the company will also be considered non-binding.
Our initial thoughts on this is, that the company should take time to assess when a meeting is feasible, taking both into account internal timelines and priorities, as well as the maturity of the value dossier. The company will need to have a firm grasp on the clinical evidence as well as the health economic modeling before entering the meeting room, otherwise they are missing an opportunity for alignment.
Final application (clinical application)
We will release a separate post on the health economic part of the application, however in the new process it is important to stress, that there are now no longer two separate applications. The clinical and health economic application is now fused into a single application, due to the adoption of the QALY-based approach to the assessment. The adoption of QALY-based approach will naturally lead to an increased focus on the health economic modeling, with the cost-effectiveness results as the primary focus for decision-making.
Technical considerations include, that the DMC to a much higher degree will need to be open to external data sources including unpublished data. We have seen the beginning of this shift, with the adoption of a DMC position paper on the use of unpublished/not peer reviewed data sources. In terms of providing the necessary input for the health economic model, the DMC will have to accept external data on utilities, as this is often a necessity for the modelling of QALYs.
Having a combined application signals a change from the current categorization process, which has the clinical application as a focal point for the entire evaluation, which narrowly focuses on the pivotal studies informing relative effectiveness.
We expect that the clinical component of the application will now be used more in accordance with NICE’s approach, meaning it is mostly used as a validation of the clinical studies eventually informing the effectiveness and inputs used in the health economic model. We do, however, still foresee a considerable attention to the clinical studies in terms of the applicability of the results to the Danish setting. This will be an important narrative to control in order to increase confidence in the output from the health economic model. Furthermore, as there is still an clinical expert committee and the Council largely consisting of doctors, we presume, that the DMC will still (directly or indirectly) to some extent be considering benefit, by examining the study results and whether they consider there is benefit independent of the health economic modelling of cost-effectiveness. So to conclude the new process adopts some components from the NICE approach, but remains some of the elements specific for the Danish HTA-process with intricate involvement of the clinical expert committee and the doctors of the Council.
The lack of a protocol will for certain increase the work needed from the company in order to document the scoping of the application and make sure it aligns with the Danish setting. We foresee this to be a challenging task, especially in therapeutic areas with little or no clinical guidelines and therefore little consensus on e.g. the standard treatment.
Having no constrains of a protocol means you have increased freedom to present your data and control the narrative and value demonstration of the medicine. It however comes at a cost of uncertainty – what will the clinical expert committee and the DMC put emphasis on and value, what are their requirements? Early preparation and open dialogue with the DMC are going to be more key than ever to secure a successful appraisal process.
The appraisal and recommendation
The largest uncertainty in the new process is the lack of alignment and consensus not only between the company and DMC, but in essence between the three parts of the DMC, the secretariat, the clinical expert committee and the council. When the final evaluation report is presented and the council are set to make a recommendation, it will be the first time the council are presented with the case.
All the checks and alignment mechanisms of the previous process has been effectively removed. In the current process, you have alignment both at protocol level, evaluation report and model assumptions before the final recommendation meeting. This opens for very difficult scenarios where the DMC, disagrees with either the scoping, the assessment made by the secretariat and the clinical expert committee and/or the assumptions made in the health economic model. This will effectively cause a reassessment and open for significant delays. We note that the DMC itself has highlighted this very issue in its most recent meeting notes, so perhaps this will be addressed in the final process.
This highlights the importance of close dialogue with the DMC and deliverance of a complete and well-argued application based on the best available evidence for the clinical questions most relevant for Danish clinical practice.