The EU Pharmaceutical Package: Introduction to Changes

The revised regulations impact all industry stakeholders for marketed and drug development, with the extent dependent on the type and stage of development. (An important note for stakeholders: There is still a window opportunity to provide additional comments and suggest improvements before final adoption.)

The EU Pharmaceutical Package looks to “all patients across the EU have timely and equitable access to safe, effective, and affordable medicines,” and includes:

• One new regulation that merges:
  • Commission Regulation No 726/2004
  • Orphan Medicinal Products (OMP) Regulation No 141/2000
  • Pediatric Regulation No 1901/2006
• One new directive that replaces:
  • Directive 2001/83/EC
  • Directive 2009/35/EC

What does this mean for the regulatory landscape?

In our latest series of articles, “A Deep Dive into the EU Pharmaceutical Package Changes,” Alira Health’s Regulatory experts explore how the proposed package will disrupt the European regulatory landscape and what it means for companies.

This first article outlines the key changes that the package introduces. You can also read the full details of the Reform of the EU pharmaceutical legislation.

1. Modular definition of unmet medical need
2. Regulatory data protection changes
3. Modification of incentives for orphan and pediatric medicines
4. New launch conditionality
5. New Environmental Risk Assessment for market authorizations
6. Hospital exemptions for Advanced Therapy Medicinal Products
7. Incentives to prevent the spread of antimicrobial resistance
8. Drug shortage requirements and notifications
9. Other regulatory provisions

1. Modular definition of unmet medical need (UMN)

These definitions are critical as they determine the duration of data protection and the eligibility to some incentives.

1.1. Revision of the existing UMN

UMN for medicinal products is currently defined as “no satisfactory method of diagnosis, prevention, or treatment authorized in the union exists, or, even if such a method exists, the medicinal product concerned will be of major therapeutic advantage to those affected.”

Under the new definition, a product addresses UMN if it:

• Relates to a “life threatening or severely debilitating disease” and there is no medicinal product authorized in the Union for such disease, or
• Where despite medicinal products, the disease is associated with a “remaining high morbidity or mortality”, and
• The use of the medicinal product results in a “meaningful reduction in disease morbidity or mortality” for the relevant patient population

And according to Article 67 of [revised Regulation (EC) No 726/2004], all orphan drugs will address UMN.

1.2. New concept of high unmet medical need (HUMN)

The EU Pharmaceutical Package also introduces the concept of HUMN for orphan medicinal products (OMP). For an OMP to address a HUMN:

• There must be no medicinal product authorized in the EU for such condition or if there is one, the applicant demonstrates that, in addition to having a significant benefit, the product will bring exceptional therapeutic advancement
• The use of the OMP that results in a meaningful reduction in disease morbidity or mortality for the relevant patient population

2. Regulatory data protection (RDP) changes

Data protection is the period when an applicant for biosimilar, generic, or hybrid application cannot rely on the data of the original applicant to support their marketing application.

Whereas market protection is the period when a biosimilar, generic, or hybrid cannot be placed on the market, even if the medicinal product has already received a marketing authorization.EU Pharmaceutical Package

Under the , RDP has been shortened from 8 years to 6 years. There are certain conditions where it can be extended to a maximum of 10 years:

• Launch across all EU Member States (2 years)
• Addresses UMN (6 months)
• Running comparative clinical trials (6 months)
• New indication with Significant Benefit (1 year)

This extension of data protection doesn’t modify the duration of market protection, which can be an additional protection of 2 years.

So, with all RDP extensions and market protection, a maximum of 12 years of protection could be obtained for new molecules.

For repurposed products, an RDP of 4 years can be granted if the product hasn’t been previously protected or if it’s been 25 years since the initial product authorization.

3. Modification of incentives for orphan and pediatric medicines

3.1 Orphan Medicines Exclusivity (OME)

A modulation of market exclusivity has been introduced for OME. The new exclusivity proposed is 9 years with the possibility to extend to 13 years for:

• HUMN products (1 year)
• Launch across all EU Member States within a certain timeline (1 year)
• Each new orphan therapeutic indication (1 year) – this year exclusivity extension for global orphan marketing authorization (GOMA) can be executed a maximum of two times)

A developer cannot receive the RDP extension for moving into new indications. And for well-established use OMEs, the market exclusivity is reduced to 5 years with no possibility of extension as less investment is required.

3.2 Orphan designation criteria

In addition to exclusivity, criteria to meet orphan designation has also been modified.

3.3 Pediatrics

For pediatric medicines, supplementary protection certificates (SPCs) are an intellectual property right that extend the patent right’s 20-year protection.

Patent and extension of protection:

With the current regulation, the Marketing Authorization Holder (MAH) can benefit from a 6-month SPC when they have fully implemented the measures of the Pediatric Investigation Plan (PIP).

The EU Pharmaceutical Package keeps the 6-month SPC (including OMP) and proposes two new incentives:

• Medicines that are not under patent or SPC can qualify for “pediatric use marketing authorization” to secure their own regulatory data protection
• Introduction of a 5-year referral cap for the PIP, with the potential for extension if solid justifications are made

However, the market exclusivity of 2 years for Pediatric OMPs has been removed.

4. New launch conditionality

Under the EU Pharmaceutical Package, a launched product is “released and continuously supplied into the supply chain in a sufficient quantity and in the presentations necessary to cover the needs of the patients in the Member States.”

To benefit from the incentive in the new package, the launch obligation is influenced by the size of the company and the designation of the product.

Launching in all 27 Member States within 2 years (and in certain cases like SMEs, 3 years) from marketing authorization provides extension options:

• Data protection (2 years)
• OME (1 year)

Confirmation of compliance must be issued by Member States.

5. New Environmental Risk Assessment (ERA) for market authorizations

The new regulations include a reinforcement of the ERA with additional requirements connected to market authorization. The ERA must include the human and environmental risks and mitigation strategies, and if it’s incomplete or unsatisfactory, market authorization can be refused.

ERAs can also be requested by Member States after authorization, so companies must maintain current ERAs. The scope of the ERA now also covers new protection goals such as the risk of antimicrobial resistance (AMR).

6. Hospital exemptions (HE) for Advanced Therapy Medicinal Products (ATMP)

The HE rule aims to guarantee patient access to novel therapies based on the use of ATMPs in the Member States.

The EU Pharmaceutical Package includes significant updates:

• Removes proposal to implement an adaptive framework for less complex ATMPs.
• Mandates that HE product delivery must be non-routine, in a single Member State hospital, and under the exclusive responsibility of a medical practitioner
• Products must meet GMP standards, ATMP traceability, and pharmacovigilance requirements
• Data on use, efficacy, and safety will be collected by Member States
• New guidelines that streamline:
  • HE application details
  • Data collection format and reporting
  • Knowledge exchange modalities across Member States
  • Consistent preparation and use guidelines for advanced therapy products

7. Incentives to prevent the spread of antimicrobial resistance (AMR)

To promote development of “priority antimicrobials,” the new package includes a transferable exclusivity voucher that can be sold and used to extend the RDP for one year. These vouchers are only good for 15 years once the directive begins—or when 10 vouchers have been granted.

8. Drug shortage requirements and notifications

The increasing drug shortages in many EU/EEA countries means a decline in treatment quality and more pressure on health professionals to identify and obtain other treatments.

In response, the EU Pharmaceutical Package includes guidelines for managing shortages:

• Companies must develop and maintain a shortage prevention plan (SPP)
• The EMA or other national agency may request a shortage mitigation plan
• Establishment of a critical medicines list with supply chain support
• 12-month notification requirement for marketing authorization withdrawal for permanently discontinued products
• 6-month notification requirement for temporary disruption

9. Other regulatory provisions

The EU Pharmaceutical Package also provides additional guidelines for regulatory and authorization:

• Pharmaceuticals are exempt from genetically modified organism (GMO) regulation
• The ERA will include provisions for developers who use GMOs
• Replacement of EMA groups COMP and CAT with scientific working parties and advisory groups to create more efficient decisions
• Simplified regulatory framework, including EMA assessment reduced to 180 days and EC authorization reduced to 46 days
• For (PRIME) scheme, clarification and narrowing of eligible therapies to focus on UMN, HUMN, and public health priorities
• Phased review of therapies that offer an exceptional benefit
• Acknowledgement of RWE as an important factor in regulatory authorization