How To Navigate The EU's New Interim PSA Program

By Geneviève Michaux and Georgios Symeonidis, King & Spalding, Brussels

In 2010, the European Medicines Agency (EMA) launched a pilot program to enable drug and biologic product developers to receive “parallel scientific advice.” The agency wanted developers to be provided with simultaneous scientific input from national-level health technology assessment bodies (HTAbs). The advice would support both marketing authorization activities and health technology assessments (HTAs) required for pricing and reimbursement purposes. Armed with this information, sponsors could adapt their clinical development plans accordingly.

In 2021, the European Union (EU) adopted the HTA regulation, an EU-wide law that formalized cooperation among individual member states’ HTAbs, both for consultative and assessment purposes. Anticipating formal application of the HTA regulation in January 2025, the European Commission and the EMA recently published a guidance setting forth an interim EMA/HTAbs consultation approach similar to the one set out by the HTA regulation. 

The EMA/HTAbs consultation procedure begins this month, in September 2023. It is especially relevant for biologics and other advanced technology products, as national HTAbs are generally less equipped to address novel and complex medicinal products. This can lead to evidentiary demands for pricing and reimbursement that are not only very stringent and different from EU country to country but also vary from marketing authorization requirements.

U.S. companies active in the EU should take advantage of this coordination opportunity — and should consider it sooner rather than later as this consultation program will be very popular.

Background On The Authorization Of Medicinal Products

In the EU, placing medicinal products on the market is subject to very strict rules that are similar to the U.S. rules. The applicant must submit scientific data to demonstrate the quality, safety, and efficacy of its product, as well as a positive benefit-risk ratio to be granted a marketing authorization (MA). Biologics are typically approved through the centralized procedure, which involves a scientific assessment by the EMA and an EU-wide authorization from the European Commission.

Pricing And Reimbursement

The MA is not the end of the story, however. After approval, a sponsor must apply for a price and reimbursement level in each EU country where it wants to market its product. The 27 EU member states have broad social security systems, including national health insurance systems. The costs of most prescription medicinal products are supported by the state, either entirely or partly, depending on the reimbursement level allocated to the product. Medicinal products, especially for high unmet needs, are increasingly developed based on their anticipated pricing and reimbursement (P&R).

P&R systems greatly vary from EU country to country, but they generally rely on the added value and relative cost-effectiveness of the product. Relative effectiveness is judged via the HTA conducted by a national HTAb such as the Haute Autorité de Santé in France, the G-BA in Germany, or NICE in the United Kingdom. HTA is based on several clinical and non-clinical evaluation criteria and seeks to ensure an optimal use of limited national health budgets. Manufacturing is important for HTA since it is intrinsically connected to quality and consistency (clinical) and to cost-effectiveness (non-clinical).¹

Importantly, national HTAbs may require clinical data to support a requested P&R that differ from the scientific data required by the EMA to support marketing authorization. The underlying criteria are different: regulatory data answer the questions, "Does the product work?" and "Is its benefit-risk balance acceptable?" while P&R data must answer the questions, "Does the product work in practice?" and "How does it compare with existing products in terms of costs and outcome?" If a sponsor does not hold adequate P&R data, it will have to generate them after approval, which will delay marketing of the medicinal product and be detrimental to patient access.

Furthermore, the criteria for HTA purposes differ from EU country to country and can lead to different evidence requirements from national HTAbs, reducing the usefulness of separate advice from individual HTAbs obtained through expensive and time-consuming meetings.

Parallel Scientific Advice

EU and member states’ national pharmaceutical laws provide for scientific advice (SA), meaning that EMA or the national regulator answers a company’s questions about the scientific data that EMA or the national regulator expects to receive in support of MA application. It is fairly standard for companies to seek EMA’s SA concerning the design of their clinical trial programs.

In 2010, the EMA launched a pilot program to associate national HTAbs with their regulatory SA so that companies could learn about the clinical expectations of EMA and national HTAbs simultaneously and early enough to adapt drug development plans accordingly. So, elements important to both regulatory approval and HTA include choice of comparators, clinical endpoints, duration of trial, and patient populations. If one or more HTABs disagree with the EMA on the appropriate endpoint or comparator, they should try aligning and the sponsor should know before designing its pivotal clinical trial. Although not all national HTAbs participated, some regularly did, which made the scheme, then called "parallel SA," worthwhile for companies. Parallel SA was carried out on a purely voluntary basis for more than 10 years.

HTA Regulation

On Dec. 15, 2021, the EU adopted Regulation 2021/228 on Health Technology Assessment. This formalized joint HTA assessment and scientific consultations concerning clinical aspects of P&R. The objective is to regulate the cooperation among national HTAbs and to harmonize and systematize HTA assessments at the EU level. 

The HTA Regulation will become applicable in stages, starting with new oncology and advanced therapy medicinal products on Jan. 12, 2025, followed by orphan products on Jan. 12, 2026, and, finally, all new medicinal products on Jan. 12, 2028. 

Why Is Parallel Scientific Advice Important For Biologics?

An early dialogue with national HTAbs, even only a few of them, is generally useful for sponsors, despite drawbacks such as additional costs. National HTAbs may not yet have developed tools and methods adapted to highly innovative and expensive products. This scenario can lead to evidence requirements for P&R purposes that are not only very stringent and different from EU country to EU country but also vary from MA requirements, imposing additional studies on companies. 

Interim Parallel EMA/HTAb Scientific Advice

The HTA regulation sets up joint scientific consultations so that companies may simultaneously consult several HTAbs and exchange information on their development plans for a given medicinal product. In order to prepare for those joint scientific consultations, the EMA and HTAbs agreed to offer an interim consultation approach, on a rolling basis and using the same selection criteria and a similar procedure as the HTA Regulation.

On July 3, 2023, the European Commission and the EMA published Guidance on Parallel EMA/HTAb Scientific Advice for the Interim Period leading up to 2025.

Scope — Parallel EMA/HTAb scientific advice (PSA) focuses on advice before the start of pivotal clinical trials, on initial evidence generation for MA applications and HTA assessments, and on post-licensing evidence generation (PLEG). However, discussions on PLEG can be facilitated only in conjunction with a request for discussion of pivotal trial design and when contextualized with clinical data from the pivotal (Phase 2/3) studies.

Application Period — PSA will be provided from September 2023 until the HTA Regulation becomes applicable in January 2025.

Actors — The procedure involves: 

• the EMA through its Scientific Advice Working Party (SAWP);
• the national HTAbs that may, at their discretion, participate or not in a PSA as active participants or observers;
• the Gemeinsamer Bundesausschuss (G-BA), the German HTAb, which acts as the HTA Coordination Contact for the centralized recruitment and practical coordination of participant HTAbs(The HTA Coordination Contact acts as the sole HTAb contact for all PSA for EMA and companies.); and
• as the case may be, experts and patient representatives.

There must be at least two actively participating HTAbs per PSA. Otherwise, the application will continue as an EMA-only SA.

A sponsor may not choose the HTAbs to be involved — selection criteria of the HTA regulation apply. Acceptance into the program will depend on available resources of the interested HTAbs, which should push companies to apply for PSA sooner rather than later given HTAbs’ generally limited resources. There is no HTAb assessor. Each HTAb is responsible for its recommendations and provides its national position individually.

Application For PSA

Companies are invited to flag their interest in PSA by sending an email to the HTA Coordination Contact, copying EMA.

Companies must complete an application form and submit it with annexes, if applicable, to the HTA Coordination Contact. This application should be submitted three months earlier than the standard submission deadline for applications (e.g., application before May 5 for a start of PSA on July 3).

Product Selection Criteria — HTAbs in the interim procedure will apply the same selection criteria as in the HTA Regulation. The HTA Coordination Contact communicates the outcome of the selection to an applicant company and the EMA within four weeks of receipt of an application.

A prerequisite for a PSA is that the pivotal clinical trial (Phase 2/3) has not yet started. This timing indeed is the most suited for PSA purposes since enough information is available to enable HTAbs to provide more detailed and tailored advice. 

Promising candidates must meet the following criteria to be considered:

• unmet medical need (no treatment or only unsatisfactory treatment),
• first in class,
• potential impact on patients, public health, or healthcare systems
• significant cross-border dimension,
• major EU-wide added value, or
• EU clinical research priorities.

Oncology products, ATMPs, and indications for which there is no established guidance for clinical development (i.e., absence of recent HTA evaluation in a similar indication) are also given preferred consideration.

Medicinal products that are not selected for a PSA can pursue a regular SA procedure with the EMA and may be eligible for national advice from some HTAbs. In any case, even companies whose products have been selected for the interim procedure should continue engaging with national HTAbs to discuss the non-clinical aspects of HTA.

Format — There is one single procedure for PSA. Due to the limited timeframe, follow-up consultation for the same indication is not anticipated; hence, all relevant questions should be submitted in a single application.

Consultations will take place in a discussion meeting format allowing for a direct exchange between the participating HTAbs, EMA, and the company. 

Timing — The entire procedure will last approximately 3½ to 4½ months starting from receipt of the draft briefing package. 

Process — The guidance details the PSA process and timeline.

An applicant who receives notification of selection should notify the EMA by means of an application and send the draft briefing package to the EMA and the HTA Coordination Contact. The submission deadline is 30 days before the formal procedure start date (day 0 or SAWP 1) and three months before the intended discussion meeting (day 60 or SAWP 3 meeting). For accurate submission deadlines, see the relevant 2023 and 2024 submission deadlines on the EMA website. 

Thereafter, EMA and the HTA Coordination Contact will agree on the allocation of discussion meeting slots, and EMA will confirm the date and time of the discussion meeting to the HTA Coordination Contact and the applicant.

Outcome — As an outcome of the PSA, the company receives an EMA scientific advice letter and individual written recommendations from each of the participating HTAbs.

SA provided by the EMA is not legally binding, but, in practice, it is taken into consideration during the scientific assessment of the MA application and a company must justify any deviations from SA given.

Individual Written Recommendations are not binding either, including on the HTAbs, since they are based on documentation provided by a company and only reflect the state-of-the-art of medical science and national requirements at the time of advice. They are not consolidated, but an attempt is made to establish mutual understanding and ideally consensus among HTAbs.

Fees — The EMA charges fees for this procedure, which are the same as for standard SA, and the participating HTAbs' fees depend on each HTAb’s national rules on fees. A sponsor will be informed about fees by the HTA Coordination Contact as soon as HTAb participation is confirmed.

Confidentiality — By submitting an application for PSA, the sponsor agrees to the exchange of information between EMA and participating HTAbs. The PSA process, however, is confidential.

References:

1. J.Enzing et al., Do health technology associations consider manufacturer’s costs in relation to drug price? A study of reimbursement reports, Cost Effectiveness and Resource Allocation (2022) 20:46.

About the Authors:

Geneviève Michaux is a partner at King & Spalding, based at the Brussels and Paris offices. She specializes in life sciences, and companies with regulatory strategy for pediatric development, approval and protection of orphan products and ATMPs, and other complex issues. She also helps companies with issues under EU and national (French and Belgian) food and drug laws and regulations, such as forming patient/compassionate use programs in Europe, negotiating and drafting consortia-related agreements, reviewing clinical trial and clinical investigation agreements, interacting with healthcare professionals in connection with advertising and promotion efforts, and classifying borderline products. Genevieve regularly interacts with European and national regulators and leads international projects with the assistance of local regulatory counsels.

Georgios Symeonidis is an associate in King & Spalding’s life sciences practice and focuses on EU regulatory matters for companies in the pharmaceutical, medical devices, cosmetic, and food sectors. Georgios advises clients on clinical research, compliance, product classification, marketing authorization, patient/compassionate use programs, labeling and packaging requirements, and advertising and promotion in the EU. Prior to joining King & Spalding, Georgios was involved in the implementation of the EU Clinical Trials Regulation, the application of the EU Transparency Directive, the regulation of ATMPs and the revision of the EU legislation for blood, tissue, and cell-based medicinal products.