Procedures for the development of orphan drugs

While the regulatory definition in the European Union classifies a disease as “rare” if it affects fewer than 5 people in 10,000, the epidemiological reality is massive. Collectively, these diseases affect millions of patients in Europe and France. For these individuals, the lack of treatment is often a daily reality, resulting in critical unmet needs. In response to this market failure, orphan drug status was introduced as a strategic lever. However, transforming a promising molecule into a marketing authorization (MA) cannot be improvised. Indeed, the development of drugs for rare diseases differs radically from conventional standards.

 

 

Orphan drug designation: criteria and procedure

The “orphan” designation is the first hurdle to overcome. It does not equate to marketing authorization, but it is the key that unlocks access to incentives.

 

Strict eligibility criteria

For a product to obtain this designation from the Committee for Orphan Medicinal Products (COMP) and the European Commission, the sponsor must prove:

• Prevalence: the condition must affect no more than 5 in 10,000 people in the EU.
• Severe condition: the condition must be life-threatening or cause chronic serious disability.
• No alternative or significant benefit: if an authorized treatment already exists, the new drug must offer a “significant benefit” to patients.

 

The application dossier submitted to the EMA

The application is evaluated by the EMA’s Committee for Orphan Medicinal Products (COMP). This dossier requires absolute scientific rigor, combining bibliographic data and preliminary results. The schedule is strict: once the application has been administratively validated, the procedure lasts 90 days.

Interactions with the COMP (questions/answers, oral hearings) are frequent and decisive. The possibility of requesting a meeting/teleconference prior to submission is also strongly recommended: the EMA strongly encourages sponsors to request this meeting as it allows for an initial regulatory assessment of the application and provides advice on possible improvements to the application that will be submitted.

 

Validation steps and average timeframes

Once the evaluation is done, the COMP gives its opinion. If it’s positive, the European Commission then has 30 days to approve the decision and add the product to the Community list of orphan designations.

 

Regulatory and financial benefits

Once designation has been obtained, the benefits are tangible:

• 10-year marketing exclusivity after marketing authorization;
• Protocol assistance: scientific advice at reduced cost or free of charge;
• Reduction in administrative fees charged by the EMA;
• Access to specific funding for European research.

 

 

Regulatory stages of development

The development of an orphan drug does not follow a conventional straight line. The scarcity of available data means that each stage must be optimized.

 

Preclinical and clinical: adapting to rarity

From the preclinical development stage of a drug, it is necessary to anticipate the transition to human trials. In the clinical phase, the small number of patients affected makes large randomized trials difficult. The EMA therefore encourages innovative study designs. It is therefore crucial to be aware of the EMA’s requirements for clinical trials so as not to invalidate years of research with a protocol that does not comply with European regulatory standards.

 

Strategic interactions with the EMA

To ensure a smooth process, dialogue with agencies is based on several key mechanisms:

• Scientific Advice: a major risk mitigation tool. It allows developers to submit questions to the agency regarding quality development.
• Protocol Assistance: a version of Scientific Advice dedicated to orphan drugs. It allows the relevance of planned studies to be validated with the EMA.
• PRIME (PRIority MEdicines) program: if the drug meets a major unmet medical need, it can benefit from enhanced support and accelerated assessment.

 

Documents to prepare and recommendations for each phase

Regulatory success depends largely on anticipating the documentation required, which acts as validation milestones.

• Early phase (ODD designation dossier): this stage requires the compilation of a solid scientific argument proving medical plausibility and compliance with prevalence criteria.
• Preclinical and clinical development; protocol assistance, PRIME if applicable.
• Clinical development: even for a rare disease, a PIP (Pediatric Investigation Plan) must be submitted to the EMA, usually after the first pharmacokinetic studies. If the disease only affects children, the EMA may also request that the PIP be submitted at the end of the preclinical phase before clinical studies begin.
• Marketing authorization application: the final dossier (Common Technical Document¹) compiles all the modules.

 

 

Evaluation and authorization procedures (MA)

Unlike conventional medicines, which can sometimes go through national procedures, orphan drugs must follow the centralized procedure with the EMA. A single MA opens the doors to all 27 EU countries.

 

Assessment by the CHMP and COMP

The MA application is reviewed by the CHMP (Committee for Medicinal Products for Human Use) for a benefit/risk assessment. At the same time, the COMP reassesses whether the orphan designation criteria are still met at the time of authorization. These committees rely on internal expert groups for in-depth data analysis.

To understand the complexity of the application, it is useful to refer to the basics: how to obtain marketing authorization (MA) for a new drug.

 

Conditional marketing authorization and exceptional circumstances

In the field of rare diseases, waiting for complete data is not always ethical or possible. Conditional marketing authorization therefore allows approval based on less complete data, if the benefit of immediate availability outweighs the risk inherent in the lack of data. Marketing authorization under exceptional circumstances applies when the rarity of the disease makes it impossible to obtain complete data, even in the long term.

These procedures have a direct impact on the EMA’s approval times for new drugs, which can be shortened to speed up access to care.

 

Post-authorization monitoring and obligations

Obtaining marketing authorization does not mark the end of regulatory oversight. For orphan drugs, monitoring is even more rigorous.

 

Pharmacovigilance and risk management

Any uncertainties accepted at the time of marketing authorization must be resolved after the drug is placed on the market. The Risk Management Plan (RMP) is therefore particularly detailed. Laboratories must strictly comply with post-marketing pharmacovigilance obligations in Europe. These often include post-authorization safety studies (PASS) or patient registries².

 

Reassessment of orphan status

The granting of orphan status confers on the holder ten years of market exclusivity from the date of marketing authorization. However, this exclusivity may be lifted after five years if the COMP considers that the drug has become sufficiently profitable to cover all research and development investments.

The “orphan” designation may also be reassessed at any time if the initial conditions are no longer met, particularly in the event of a change in the prevalence of the disease, or if the significant benefit of the product is called into question.

The arrival of a competing drug does not automatically result in the loss of exclusivity, unless it is demonstrated that it provides a superior clinical benefit or that the existing drug no longer meets medical needs.

 

 

The role of expert regulatory support

Developing an orphan drug is a race against time. Every regulatory error results in months of delay, or even refusal of approval. The complexity of the dossiers, the specific nature of the arguments to be provided for “significant benefit,” and the management of interactions with EMA require a 360° view.

Alhena Consult supports biotech companies and pharmaceutical laboratories. We help transform scientific innovation into regulatory success. We do this in several ways:

• Strategic structuring: analysis of eligibility for orphan designation and drafting of a well-argued dossier for the COMP.
• Interactions with agencies: preparation and support during Scientific Advice or Protocol Assistance (PIP) meetings.
• Operational drafting: handling of regulatory modules (CTD) for marketing authorization applications.
• Post-marketing authorization support: pharmacovigilance management and maintenance of authorizations.

In a sector where regulations evolve as quickly as science, surrounding yourself with experts allows you to secure your most valuable asset: time to market.

Are you developing a molecule for a rare disease? Do you want to secure orphan status for your drug? Contact Alhena Consult for an audit of your regulatory strategy.

 

 

¹ Common Technical Document (CTD): internationally standardized mandatory format used to submit a Marketing Authorization Application.

² Specific obligation required in the Risk Management Plan (RMP) to collect, over the long term and in real-world settings, the safety and effectiveness data that were lacking at the time of Marketing Authorization.