In April 2017, AIFA (Agenzia Italiana del Farmaco, Italian Medicines Agency) released a new algorithm to assess and evaluate the level of innovativeness of new drugs aimed to get reimbursement by the SSN (Sistema Sanitario Nazionale, National Health System) through the EUR 1 billion fund made available by the Italian MoH (Ministero della Salute, Ministry of Health) for innovative therapies. As manufacturers prepare to pursue access through this new system, several aspects of the advantages and challenges related to the new system are becoming increasingly apparent. On paper, the algorithm provides a multi-dimensional approach: innovativeness will be judged by AIFA’s CTS (Commissione Tecnico-Scientifica, Technical and Scientific Committee) on the grounds of three evaluation criteria: unmet therapeutic needs, added therapeutic value, and quality of the evidence from the clinical trials. However, manufacturers will be wise to look beyond what is dictated by ITA authorities, and focus their attention on how to maximise their opportunities based on the new market realities.
The evaluation process has been defined by AIFA, and will guide a new product into one of three designations: INNOVATIVE (Riconoscimento dell’Innovativita’), NOT INNOVATIVE (Mancato Risconoscimento della Innovativita’) and CONDITIONALLY INNOVATIVE (Riconoscimento dell’Innovativita’ Condizionata). Those therapies earning an ‘INNOVATIVE’ status special innovative drugs fund, as well as becoming exempt from pay-back requirements common in ITA, and immediate inclusion in regional formularies. On the other hand, those therapies earning a ‘CONDITIONALLY INNOVATIVE’ designation would ‘only’ benefit from immediate regional formulary inclusion. Those therapies which are designated as ‘NOT INNOVATIVE’ will not benefit from any of the above mentioned allowances.
During the past few years, lack of structure, unclear methods of assessment, and dubious transparency were recurrent criticisms that characterised CTS assessments. ITA authorities thus took on development of the new system in an effort to minimise these challenges. As a result, it took over five years to fully design and launch this new system, as its structure went through several iterations of refinement before being fully accepted by all parties, including the MoH.
Despite decreasing the number of technicalities and thus increasing the level of discretion, the new system brings a set of challenges from a clinical value and study-design standpoint. Due to these challenges, uncertain implications loom for the manufacturer in terms of price and reimbursement potential.
The new AIFA algorithm will judge the level of innovativeness based on three dimensions…
As described in FIGURE 1, the three main dimensions utilised by the CTS for assessing the innovativeness of a new product will be:
- UNMET THERAPEUTIC NEED
- ADDED THERAPEUTIC VALUE
- QUALITY OF EVIDENCE
FIGURE 1. The New AIFA Innovation Algorithm: Dimensions, Ratings, and Criteria
While all three dimensions will bring unique challenges to the manufacturers of innovative therapies, the ‘ADDED THERAPEUTIC VALUE’ dimension creates some unique complications. AIFA made clear in their guidance that outcomes must be recognised as clinically relevant and validated for the pathology in question. This consideration is even more relevant within the oncology space, where the gold standard is overall survival (OS). While continuing to value non-traditional measures (e.g., MRD+ in some tumour types), it is also likely that AIFA will place greater attention as to how this will link to an actual improvement in OS and PFS. In other words, previously acceptable endpoints may no longer be viewed as positively in ITA.
…the evaluation will result in the product being awarded with the status of INNOVATIVE, NOT INNOVATIVE, or CONDITIONALY INNOVATIVE.
From FIGURE 1, there are three potential designations: INNOVATIVE (Riconoscimento dell’Innovativita’), NOT INNOVATIVE (Mancato Risconoscimento della Innovativita’) and CONDITIONALLY INNOVATIVE (Riconoscimento dell’Innovativita’ Condizionata).
The INNOVATIVE status comes with a series of rewards to boost patient access and availability of the product within the ITA market for a period of 36 months:
- access to the innovative drugs’ fund
- Immediate access to regional formularies, which will also translate in decreased hurdles posed by the regional HTA authorities, forcing prompt access to INNOVATIVE products at the sub-national level, with no / minor delays and diminished access inequalities throughout the market
- Exemption from payback mechanisms, which, in case any alternative contracting agreement is stipulated between parties, will eliminate the option of the manufacturer paying back to AIFA the costs of the therapy for non-responding patients
While the overall evaluation process is intended to give a clear framework when assessing a product’s innovativeness, some points are important to note:
- For products which achieve a ‘NOT INNOVATIVE’ designation, the manufacturer is allowed to re-submit their application and request a new evaluation by the CTS if and when new evidence becomes available
- While the benefits will last 36 months for the first-in-class ‘INNOVATIVE’ drugs, any subsequently launched INNOVATIVE product will benefit for the time remaining from the initial first-in-class evaluation
- As an example, if PRODUCT X is awarded an ‘INNOVATIVE’ designation, its benefit will last 36 months as per legislation; however, if a PRODUCT Y (follower within the same patient population and MoA) is also awarded as INNOVATIVE five months after PRODUCT X, it will benefit from this status for only 31 months. In other words, the second-in-class therapy with an ‘INNOVATIVE’ designation cannot extend the period of benefits – it can only attach itself to the remaining period of benefit created by the first-in-class product
It is important to note that this particular detail is still relatively unclear based on the current policy’s language and may evolve as the system takes hold.
- As highlighted in FIGURE 1, orphan drugs can achieve INNOVATIVE status even with moderate to low quality of evidence. Indeed, it appears that authorities will acknowledge the challenges of conducting studies within these smaller patient populations, and therefore place greater value in these situations to a high unmet clinical need, as well as added therapeutic benefit.
FIGURE 2. AIFA CTS Innovation Algorithm Process
As depicted in FIGURE 2, the CTS will disclose their own decision at the conclusion of their assessment. However, the onus of introspection is presented to manufacturers, who will be required to propose what amounts to a self-evaluation of their evidence, therapeutic need, and potential value – including detailed rationale – within the official submission form.
Innovation status has clear benefits to the manufacturer and the new algorithm is a step forward in the evaluation of drug innovation…
The new process allows for a more discretionary approach to the evaluation of the product, decreasing the level of technicalities in favour of a more straight-forward process, while enhancing the level of evidence-based dialogue between the manufacturer and AIFA.
For instance, a previously sub-optimal evaluation result can now improve their standing through a clearer process and expectations for additional evidence.
More importantly, the new AIFA algorithm promises to differentiate the level of clinical benefit for each product, while avoiding any possible overlaps between clinical and purely economic considerations.
…however, a number of challenges need to be taken into account from a pricing and access perspective.
FIGURE 3. AIFA CTS Innovation Algorithm Developments and Implications
What actions can be undertaken by the manufacturer, in order to fully leverage the benefits of the new AIFA algorithm?
Considering the increasingly challenging market access environment in ITA given budgetary pressures, and to fully address the above-mentioned challenges that come with the introduction of the new AIFA algorithm, the manufacturer should consider these key actions during the submission process and CTS evaluation:
- PREPARE FOR ASSESSMENT SUBJECTIVITY THROUGH ONGOING PAYER COLLABORATTION AND COMMUNICATION
- Manufacturers should develop their clinical value dossier for submission in ITA based on the CTS perspective on preferred clinical evidence dimensions
- To accomplish this, manufacturers should take advantage of AIFA’s Early Scientific Advice service in order to align around expectations for their product
- Manufacturers should promote more frequent and productive communication with AIFA to ensure alignment on key milestones and achieve common goals from the earliest stages of the process
- ANTICIPATE HIGHER QUALITY CLINICAL EVIDENCE REQUIREMENTS AND SEEK BUY-IN FOR NOVEL ENDPOINTS
- Manufacturers should focus on designing trials to yield what AIFA considers ‘high quality evidence’, seeking to reflect AIFA’s expectations through early communication with the authority
- Manufacturer should initiate payer education initiatives (i.e. conferences, symposia, sponsored events) in order to gain buy-in from the CTS with regard to lesser known endpoints for evaluation (i.e., those beyond the traditional OS, PFS in oncology)
- DEVELOP FINANCIAL BASED CONTRACTS TO SUPPORT ‘INNOVATIVE’ PRODUCT ACCESS
- While ‘payback mechanisms’ involving outcomes-based agreements are expected to decline as a result of the new policy, manufacturers should develop a stronger focus on purely financial based solutions (i.e. price / volume, patient and cycle cap) given the historical focus on such arrangements in an effort to secure access throughout the country’s many regions
- PREPARE FOR ASSESSMENT SUBJECTIVITY THROUGH ONGOING PAYER COLLABORATTION AND COMMUNICATION