The EU pharma package: meeting unmet medical needs

The proposed revision of the EU medicines regulatory framework is aimed at strengthening investment in medicinal products where research is most needed but investment is riskier. This aims to address the needs of patients groups that are overlooked and that may therefore fall in the category of patients with an Unmet Medical Need (UMN). Also, it targets areas of High Unmet Medical Needs (HUMN) in orphan medicines.

This revision is part of the implementation of the Pharmaceutical Strategy for Europe, with the overarching aim to offer a balanced and coordinated system of incentives to the development and marketing of medicines in particular those responding to UMN.

1. What is an UMN or a High UMN and the perception of stakeholders

UMN typically refers to situation where patients do not have access to treatment needed to address highly specific patient needs. The term UMN is used by various stakeholders (such as patients, prescribers, payors, health insurance providers) who will have a different perspective of when a medical need is unmet and will have different preferences to cater for their needs.

Commonly, the following elements will be seen in definitions of UMN¹:

• Availability of treatment;

• Adequacy of treatments;

• Severity of a disease or burden on life;

• Patient population size; and

• Burden of available treatment.

Absence of treatment option(s) is not necessarily a result of inability of research and investigation or lack of innovative power. Whereas a marketing authorisation is the first step for any product to be marketed, the actual availability on patient level may vary per Member State and will depend on availability of other treatments both in terms of presence as affordability.

Typically, designated orphan medicines would fall within scope of UMN (proposed Directive article 83, subclause 2) but the scope is not limited to such medicinal products. The proposed legislation offers a criterion based approach in determining whether or not an UMN or HUMN will be addressed.

The varying interpretations of the concept of UMN has prompted the European Medicines Agency (EMA) to further clarify the scope of UMN and facilitate development of medicines to address this need. 

2. Criterion-based approach of UMN and involvement of stakeholders

The legislator is introducing criterion-based definitions of UMN and High UMN. With regard to UMN: Proposal for a Directive of the European Parliament and of the Council on the Union code relating to medicinal products for human use, and repealing Directive 2001/83/EC and Directive 2009/35/EC (Proposed Directive), article 83:

"Medicinal products addressing an UMN:

(a) there is no medicinal product authorised in the Union for such disease, or, where despite medicinal products being authorised for such disease in the Union, the disease is associated with a remaining high morbidity or mortality;

(b) the use of the medicinal product results in a meaningful reduction in disease morbidity or mortality for the relevant patient population"

With regard to HUMN

Proposal for a Regulation of the European Parliament and of the Council laying down Union procedures for the authorisation and supervision of medicinal products for human use and establishing rules governing the European Medicines Agency, amending Regulation (EC) No 1394/2007 and Regulation (EU) No 536/2014 and repealing Regulation (EC) No 726/2004, Regulation (EC) No 141/2000 and Regulation (EC) No 1901/2006 (Proposed Regulation), article 70:

"Orphan medicinal products addressing a high unmet medical need

1. An orphan medicinal product shall be considered as addressing a high unmet medical need where it fulfils the following requirements:

(a)there is no medicinal product authorised in the Union for such condition or where, despite medicinal products being authorised for such condition in the Union, the applicant demonstrates that the orphan medicinal product, in addition to having a significant benefit, will bring exceptional therapeutic advancement;

(b)the use of the orphan medicinal product results in a meaningful reduction in disease morbidity or mortality for the relevant patient population."

Both the definition of UMN products (in the Proposed Directive) as well as orphan products in the Proposed Regulation require for a medicinal product to have a  meaningful reduction in disease morbidity or mortality (in the Proposed Regulation) This criterion is included to ensure that only most effective medicinal products are covered.

The Agency should specify elements relevant to give meaning to the rather sweeping yet opaque criteria established to identify underserved therapeutical areas. This is necessary though in order to do justice to the fact that unmet needs are personal often and a narrow definition may have been problematic in serving all various stakeholder who use UMN as investment or policy instrument².

These criteria will there need further development and guidance as established in the Proposed legislation  (article 83, subclause 3 proposed Directive and article 95 European Network and 162 Consultation proposed Regulation process) and the Regulation (EU) 2021/2282 on Health Technology Assessment (HTAR).

In doing so, the voice of stakeholders will be given more prominence.

European Network addressing paediatric indications

On the basis of article 95 of the Proposed Regulation, the Agency shall set up a European network composed of different academics, patient representatives, medicines developers, investigators and research centres based in the EU in order to discuss priority in the development of medicinal products, particularly with regards to UMNs for children. 

Consultation procedure

In addition, through a consultation process the Agency should seek input from a broad range of authorities or bodies active along the lifecycle of medicinal products. Pursuant to article 162 of the Proposed Regulation, the Agency may extend the consultation process to (amongst others) patients and health care providers as relevant. The Agency should take into account scientific initiatives at EU level or between Member States related to analysing UMNs, burden of disease and priority setting for research and development. The criteria for UMN can then subsequently be used by Member States to identify specific therapeutic areas of interest. 

3. Rewards and incentives to enhance development of medicines addressing UMN

The system rewards innovation in areas of (H)UMNs by offering financial incentives as well as regulatory support. Of particular relevance are:

• Early Access and Conditional Approvals: to facilitate early patient access for medicines that demonstrate significant clinical benefit based on preliminary data, with the requirement for further evidence collection. Based on article 19 of the Proposed Regulation, to meet an UMN a conditional marketing authorisation or a new conditional therapeutic indication to an existing marketing authorisation authorised under the Proposed Regulation may be granted by the Commission to a medicinal product that is likely to address the UMN in accordance with Article 83 (1) point (b), of the Proposed Directive, prior to the submission of comprehensive clinical data. However, this is on the condition that the benefit of the immediate availability on the market of that medicinal product outweighs the risk inherent in the fact that additional data are still required.

• Health Technology Assessment (HTA): to enhance cooperation and coordination among EU Member States in HTA evaluations, addressing UMN in the context of reimbursement and access. In light of this, the above-mentioned consultation process (within the meaning of article 162 of the Proposed Regulation) shall also include bodies responsible for HTA as referred to in the HTAR as well as national bodies responsible for pricing and reimbursement.

• PRIME: Companies may benefit from an enhanced scientific and regulatory support scheme and from accelerated assessment mechanisms. Pursuant to article 60 of the Proposed Regulation, the Agency may offer scientific and regulatory support for certain medicinal products that, based on preliminary evidence submitted by the developer fulfil the following conditions:

  (1) are likely to address an UMN as referred to in article 83 of the Proposed Directive;

  (2) are orphan medicinal product and are likely to address a HUMN within the meaning of article 70 (1) of the Proposed Regulation; and

  (3) are expected to be of major interest from the point of view of public health, in particular as regards therapeutic innovation, taking into account the early stage of development, or antimicrobials with any of the characteristics mentioned in article 40 (3) of the Proposed Regulation.

• Market exclusivity: a step-up system granting market exclusivity aimed at predictability where highest investments in medicines addressing HUMN, should benefit from the longest market exclusivity³. Under the Proposed Regulation it is possible to apply for an orphan marketing authorisation (based on article 69). If such authorisation is granted, pursuant to article 71 (1) and (2) sub (b) of that Proposal, the Union and the Member States shall not grant a marketing authorisation or extend an existing marketing authorisation for the same therapeutic indication for the duration of ten years for orphan medicinal products addressing a HUMN within the meaning of article 70 of the Proposed Regulation.

4. A bright future ahead?

The EU Pharmaceutical package as proposed by the Commission contains many new and/or improved elements to induce all stakeholders involved in the life time of medicinal products to prioritise underserved patient needs.

Hopefully, the initiatives to improve alignment on the meaning and relevancy of UMN will accelerate the actual availability of medicines addressing this broad but neglected area of (H)UMN throughout Europe.

¹ Unmet Medical Need: An Introduction to Definitions and Stakeholder Perceptions, Value in Health, Volume 22, Issue 11 https://www.sciencedirect.com/science/article/pii/S1098301519323034

² As strongly advocated by EFPIA:  https://www.efpia.eu/about-medicines/development-of-medicines/unmet-medical-need

³ See also our article The EU pharmaceutical package: Data and market protection as rewards