Drug development is a long and expensive process. Picture this, you have finally received EU/MHRA marketing authorization approval for the product that you have spent many years developing – it is finally time to get your product on the market, most-importantly to benefit the patients who desperately need it, but also to recoup the significant costs for its development. However, you are unable to gain reimbursement for your product from the payers, not due to lack of effectiveness, but because your product fails to meet HTA authorities’ clinical and economic data requirements. You now face a significant time delay in patients’ accessing your product and potentially a restricted market.
Unfortunately, this is not some imagined horror story – this is a very real risk that drug developers face. Pharmaceutical companies need to generate sufficient data to satisfy the benefit-risk analysis by the regulators and the clinical and economic assessment by the HTA bodies and must strike a balance between successfully addressing these requirements whilst managing budget and time constraints.
To attend to this issue, regulators and HTA authorities now offer joint scientific advice to companies to aid them in designing their clinical programs to maximize their possibilities for reimbursement.
Consultations with regulatory agencies (e.g., EMA, FDA, and other national regulatory agencies) are a common practice to obtain scientific advice that guides the clinical development of new therapies for their approval. However, apart from the regulatory approval, a crucial goal for success is making new therapies accessible to patients by the demonstration of its clinical and economic benefits compared to already available therapies. This effectiveness is evaluated and assessed by the HTA agencies based on the reimbursement dossier, which describes the economic and clinical benefits of the product.
Usually, the reimbursement dossier for the HTA authorities is prepared and submitted as a last stage of the drug development program, in parallel with the compilation of the eCTD dossier for the marketing authorization application (MAA). However, at this stage, most of the clinical trials, including the pivotal studies that will demonstrate efficacy and safety for the intended indication, have been finalized or are close to completion. The opportunity to add specific assessments to demonstrate clinical effectiveness is probably lost, and unluckily, this could have a negative impact for the forthcoming price and reimbursement evaluation. Companies therefore often stumble at the HTA stage because their clinical programs are not designed with the HTA requirements in mind.
How can pharmaceutical companies avoid these situations? Engaging with HTA authorities early in the development process can help steer companies in the right direction and provide insights as to the data HTA authorities will be expecting. By receiving earlier feedback from the HTA authorities and considering their inputs during the clinical development program, many of the existing issues could be avoided.
While decision on price and reimbursement of a new therapeutic is made subsequent to marketing approval, multiple HTA authorities offer tools for early consultation during drug development.
In the UK for instance, there is a possibility for a pharmaceutical company to seek and attend a NICE (UK HTA authority) MHRA (UK regulatory agency) scientific advice session. This advice ensures that your proposed development plans produce evidence that is relevant for a future NICE evaluation. It will help you add value by helping you understand how to generate robust evidence that demonstrates the product’s value.
Similar early advice can also be offered at G-BA (HTA authority in Germany) and TLV (HTA authority in Sweden), both with a formal structure in place to offer early payer scientific advice to manufacturers. Additionally, HAS in France, AIFA in Italy, as well as regional HTA authorities in Spain can offer informal HTA advice.
As of 2022, the European Network for Health Technology Assessment (EUnetHTA) consortium offers parallel joint scientific consultations (JCS) with the EMA. The EUnetHTA 21 (years 2021-2023) is a joint consortium including HTA authorities from 12 countries in the EU. Only two calls for applicants were planned for the EUnetHTA 21 period (the second will remain open till 31 August 2022). However, the medium-term goal is to establish a regular, legally acceptable procedure in view of the new HTA Regulation 2021/2282, which sets to harmonize the HTA process at an EU level. The aims of this regulation include unifying HTA methodology and providing an equal basis for decision-making for member states across the entire EU (e.g., regarding reimbursement eligibility) through joint clinical assessments of health technologies. This new HTA Regulation 2021/2282 came into force in January 2022 and will apply from January 12, 2025. In this line, EMA strategic objectives for 2025 acknowledge that they are willing to improve communication with HTA authorities and payers regarding therapeutic context, comparison vs. placebo/active-control and/or patient perspective, and support bridging from benefit-risk to relative effectiveness assessment.
Figure 1. Different HTA authorities offer the possibility of early consultations during clinical development. Joint scientific consultations are provided by the EMA together with EUnetHTA, as well as the MHRA with NICE
The best time to seek early advice on the clinical development and evidence generation to support an HTA evaluation can vary from product to product. As a general rule, advice should be asked for when:
This time frame often corresponds to the end of the exploratory Phase I/II studies and prior to starting the pivotal Phase IIb/Phase III clinical trials. In such cases, preliminary data on safety and efficacy in the target population will be available, and a recommended dose for future commercialization may even be defined. However, the design of the pivotal clinical trials could still accommodate considerations by the HTA authorities regarding e.g., choice of comparator(s), relevant outcomes of efficacy, quality of life assessments and/or specific subgroup assessments.
Early consultation with the HTA authorities can potentially benefit all new therapeutics for which clinical effectiveness needs to be demonstrated. However, we see two scenarios where these consultations are strongly recommended:
In those cases when cost-effectiveness should be discussed within a therapeutic area of special interest, HTA authorities can provide recommendations on which comparators should be considered relevant. In addition, potential efficacy gaps identified during the effectiveness assessment of the comparators could be covered during the ongoing development of the new product.
Moreover, early consultations with HTA authorities are recommended when the clinical development is limited by number of patients (e.g., orphan diseases), or when the timelines for real clinical efficacy and safety assessment cannot be covered in a clinical trial (e.g., when efficacy is based on surrogated biomarkers, or data on long-term safety is missing).
Noteworthy is a scenario where the targeted indication is an orphan condition and the clinical trials do not cover long-term efficacy and safety, which is common to the development of cell and gene therapy products. In such cases, consultations with HTA authorities and payers are strongly encouraged, both due to the significant cost of these therapies and the high degree of product innovation and limited real-world experience associated with them.
ProPharma Group is a unique partner to support early engagement with HTA authorities since our teams of clinical regulatory experts and market access specialists closely collaborate to help you streamline the development and launch of new products. We strongly believe that to accelerate patients’ access to innovative therapies, a full alignment of the expectations from all stakeholders, including patients, clinicians, pharma industry, regulators, and payers, is required. The clinical development phase of a medicine is the context where these inputs should be addressed to maximize the possibilities for faster market access and product launch.
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