DRUG REVIEW AND APPROVAL

In the EU, EMA is responsible for assessing the benefits and risks of medicines. The 27 member states of the EU each have their own regulatory authority for licensing drugs, but EMA provides a centralized procedure that allows a sponsor to apply to one authority, undergo one scientific evaluation, and receive one marketing authorization (EMA, n.d.-s). Once the Committee for Medicinal Products for Human Use (CHMP), which is convened by EMA and made up of experts selected from the 27 member states, issues a positive opinion on a marketing authorization application, the European Commission (EC) makes a final legally binding decision on whether a medicine can be marketed in the EU. This authorization is legally binding and valid in all 27 member states, as well as the other states of the European Economic Area (Iceland, Norway, and Liechtenstein) (EMA, n.d.-e, n.d.-s).

This centralized procedure through EMA is mandatory for certain categories of products, including orphan medicines, advanced therapies (e.g., tissue-engineered medicines, cell- and gene-therapy), medicines derived from biotechnology processes, and medicines with new active substances to treat human immunodeficiency virus (HIV), cancer, diabetes, neurodegenerative diseases, auto-immune and other immune dysfunctions, and viral diseases (EMA, n.d.-e).¹

The CHMP is responsible for assessing drug marketing authorization applications and making recommendations regarding those applications to the European Commission (EMA, n.d.-k). The CHMP works with other EMA committees, including the “Committee for Advanced Therapies, which leads the assessment of advanced therapy medicines (gene therapy, tissue engineering and cell-based medicines); the Pharmacovigilance and Risk Assessment Committee for aspects related to the medicine’s safety and risk management; the Paediatric Committee (PDCO) for aspects related to the medicine’s use in children; and the Committee for Orphan Medicinal Products (COMP) for orphan-designated medicines” (EMA, n.d.-r). During an assessment of a marketing authorization application, the CHMP is supported by a team of assessors from membership state agencies with relevant expertise (e.g., pharmaceutical, clinical, statistical), and the EMA secretariat provides technical, scientific, and administrative support (EMA, n.d.-r). See Figure 3-1 for an illustrative overview of the EMA process and the committees involved in each stage.

FIGURE 3-1

EMA committees in human medicines regulatory process. SOURCE: Adapted from European Medicines Agency: Presentation—Centralised procedure at the European Medicines Agency, https://www.ema.europa.eu/system/files/documents/presentation/wc500201043_en.pdf (more...)

The EMA secretariate is required to publish a European public assessment report (EPAR) for all medicines that have been granted or refused marketing authorization² (European Union, 2004). The EPAR includes information about the drug product, including how the marketing authorization submission was assessed, reasons for the committee’s conclusions, and a public-friendly overview (see Table 3-1).

TABLE 3-1

Components of European Public Assessment Reports.

Standards of Evidence

EMA’s decision about whether to recommend a drug for marketing is based on whether its benefits outweigh its risks. This benefit–risk assessment can be complex due to the large amount of data involved and the inherent uncertainty around whether the available evidence is sufficient to assess benefits and risks (EMA, n.d.-f). For products aimed at rare disease, there are two types of “benefit” assessed. First, COMP may give the product orphan designation if the product offers a “significant benefit” compared with other treatments; this means that it offers an advantage in terms of efficacy, safety, or mode of use (EMA, n.d.-u; Thirstrup, 2023). Next, CHMP evaluates the application for marketing approval; the product can be approved if the benefits outweigh the risks (EMA, n.d.-k). The benefit–risk assessment framework allows EMA review to account for factors like small patient populations and limited data within the context of the specific rare disease.

EMA has not issued guidance on drug development for rare diseases and conditions. However, EMA has issued several disease-specific guidelines, many of which concern rare diseases, and held a workshop in 2015 on the demonstration of significant benefit of orphan medicines (EMA, 2016). In addition, there are EMA guidelines and reflection papers on a number of topics that are relevant to the collection of data on rare disease drug development. The details of these guidelines are discussed further in Chapter 4. Table 3-2 includes some guidelines:

TABLE 3-2

EMA Guidelines on Collection of Data.

ORPHAN MEDICINE DESIGNATION

In 1999, the European Parliament adopted Regulation (EC) 141/2000, which established the COMP, laid out the process for the designation of orphan medicines, and identified the incentives available to designated products. An “orphan medicine” is defined as one that is intended to treat a life-threatening or chronically debilitating condition for which there is no satisfactory method of diagnosis or treatment available, and which affects not more than 5 in 10,000 people in the European Union community. Alternatively, if it is intended to treat a condition that affects more than 5 in 10,000 people, it can still be eligible for orphan designation if the market is unlikely to generate sufficient return on the investment without incentives (European Commission, n.d.).

To receive orphan designation, a drug usually must be targeted at a disease or condition for which there is no treatment available; if a treatment is available, a drug may still be eligible if it provides “significant benefit” to those affected by the condition. Significant benefit is defined as either a “clinically relevant advantage” or “a major contribution to patient care.” A clinically relevant advantage means that compared with previously approved treatments, the product offers either improved efficacy or improved safety and there is a reasonable probability that the patient will actually experience this benefit³ (Thirstrup, 2023). A product that represents a “major contribution to patient care” is one with improved availability or ease of use. For example, a product that does not require refrigeration would be an improvement over one that does require refrigeration, or a product that can be taken by pill would be an improvement over one that requires an injection. As noted in a presentation to the committee, the determination of “major contribution to patient care” can be more difficult than the determination of a “clinically relevant advantage” because it depends in part on what patients consider to be important (Thirstrup, 2023). A “significant benefit” cannot be claimed based on an “alternative mode of action per se, an increase in supply or availability due to a shortage of existing products, or higher pharmaceutical quality” (Thirstrup, 2023).

The condition at which an orphan drug is targeted must be clearly distinct from other conditions; differences in severity or stages do not make a condition distinct from others. “Condition” is defined under EC Guideline (ENTR/6283/00) as “any deviation(s) from the normal structure or function of the body, as manifested by a characteristic set of signs and symptoms (typically a recognized distinct disease or a syndrome)” (European Commission, 2014b). If the targeted condition is a subtype of a more common condition, there must be justification for restricting the medicine to the subgroup of patients. The patients must have “distinct and unique evaluable characteristics,” and such characteristics must be essential for the action of the medicine such that the medicine would not be effective in the larger group of patients with the common condition (European Commission, 2014a). According to Steffan Thirstrup, chief medical officer of EMA, in open session with the committee, differences in biomarkers are currently not accepted as evidence of a distinct condition (Thirstrup, 2023). The determination of whether a condition is considered distinct enough to qualify for orphan designation may change over time as the understanding of disease progresses and new therapies are developed (Thirstrup, 2023).

Process

Orphan medicine designation is a separate process from marketing authorization, with the orphan designation coming before marketing authorization. Sponsors submit a request for orphan medicine designation to the COMP, which examines applications for orphan designation from EMA (EMA, n.d.-d). During the 90-day evaluation process, the COMP reviews the application to assess whether the drug product meets the criteria for orphan medicine designation. The COMP examines whether the condition is life-threatening or chronically debilitating, determines the prevalence of the condition, assesses the medical plausibility that the product will treat the condition, and compares the proposed treatment with existing treatments, if any (EMA, n.d.-u). Typically, products are designated as orphan early in the drug development process, although designation may happen as late as the marketing authorization application (see Figure 3-2). The COMP will adopt a positive opinion or provide a list of questions and invite the sponsor to provide an oral explanation at the next COMP meeting (EMA, n.d.-d). There is an appeals process if the COMP opinion is negative. Following a COMP positive opinion, EMA sends the opinion to the European Commission, which is responsible for issuing a decision within 30 days of receipt (EMA, n.d.-d).

FIGURE 3-2

Orphan product designation and maintenance along drug life cycle. NOTES: I = Phase 1 clinical trials; II = Phase 2 clinical trials; III = Phase 3 clinical trials; MAA = marketing authorization application; Pharm = pharmacology studies; PhV = pharmacovigilance; (more...)

Once a product is designated as orphan, it undergoes the same quality, safety, and efficacy assessment as any other medical product. The CHMP is responsible for assessing the product for authorization, while the COMP is responsible for determining whether an orphan product can maintain its orphan designation (EMA, n.d.-k, n.d.-r). A product could lose its orphan designation if, for example, another product received marketing authorization first and the second product cannot demonstrate a significant benefit over the already-authorized product (EMA, n.d.-c; Thirstrup, 2023).

Approvals of Drugs with Orphan Designation

In the 20 years that EMA has issued orphan designation, over 2,730 products have received orphan designation, and over 230 of these have been recommended for marketing authorization (see Figure 3-3). As of 2023, 142 orphan designations are still active (Thirstrup, 2023). Of the active orphan designations, 98 received full authorization, 26 are under conditional authorization pending confirmatory data, and 18 were approved under “exceptional circumstances” in which the applicant is unlikely to be able to generate more data (Thirstrup, 2023). The largest number of orphan product designations are for congenital, familial, and genetic disorders, with significant numbers of products for blood and lymphatic systems disorders as well as neoplasms (Thirstrup, 2023). Orphan designations are published on the EMA website, along with minutes and agendas of the scientific committee meetings. Reports are published for both the initial assessment of orphan designation, and the assessment of orphan maintenance (Thirstrup, 2023).

FIGURE 3-3

Designation and authorization of orphan medicines in the EU from 2001 to 2022. NOTE: EU = European Union. SOURCES: Presented to the Committee by Steffan Thirstrup, EMA, on December 4, 2023; adapted from European Medicines Agency: Orphan medicines in the (more...)

As described in Chapter 2, the committee examined the approval rates for orphan and non-orphan medicine applications between 2015 and 2020 (see Appendix D for full methodology). Overall, there was little difference in EMA approval rates for orphan and non-orphan medicine applications (see Figure 3-4) and no discernable differences in approval rates across therapeutic areas (see Figure 3-5).

FIGURE 3-4

EMA approval rates for orphan and non-orphan drugs using expedited approval pathways from 2015 to 2020. NOTES: EMA = European Medicines Agency; NAS = new active substance. SOURCE: CIRS Data Analysis, 2024.

FIGURE 3-5

Approval rates for non-orphan and orphan NAS applications submitted to EMA from 2015 to 2020 per therapeutic area. NOTES: EMA = European Medicines Agency; NAS = new active substance; Other = other therapeutic areas not described in the top 5 therapeutic (more...)

EXPEDITED REGULATORY PROGRAMS

There are four expedited authorization pathways for drugs available through EMA. Each program has its own eligibility criteria, process, and benefits. While these pathways are available for any medicine that meets the criteria, they may be particularly relevant for products with orphan designation because orphan products are more likely to meet the criteria of the programs (e.g., meeting an unmet need, intended to treat a life-threatening disease, extremely rare indication). Expedited pathway programs and orphan medicine designation may be used separately or in combination; medicines targeted at rare, serious diseases—particularly those that have no existing treatment—may be eligible for multiple programs.

Accelerated Assessment

Medical products that are expected to be of “major public health interest,” particularly with respect to therapeutic innovation, may be approved for accelerated assessment, which reduces the timeframe for assessment and approval. There is no specific definition of “major public health interest;” each application is reviewed on a case-by-case basis. In general, a product eligible for accelerated assessment is one that involves new methods of therapy or improves on existing methods in order to address unmet needs (EMA, n.d.-a).

Process

Applicants must apply for accelerated assessment at least 2 or 3 months before submitting the application for marketing authorization. EMA recommends that applicants request a pre-submission meeting several months before requesting accelerated assessment in order to discuss their proposal and plan. Applicants who have already received PRIME status may receive confirmation during the clinical development phase that their product is eligible for accelerated assessment (EMA, n.d.-a).

Benefits

Assessment of a marketing authorization application typically takes 210 days (excluding “clock stops” for requests of additional information). Under accelerated assessment, this timeframe is reduced to 150 days (EMA, n.d.-a).

Impact

A study of orphan medicinal product (OMP) approvals in the EU between 2010 and 2022 found that about 24 percent of OMPs were eligible for accelerated assessment, and that use of accelerated assessment for OMPs increased significantly around 2015 (see Figure 3-6). The study found that the use of accelerated assessment is more frequent in OMPs than in nonorphan medicinal products (Bouwman et al., 2024).

FIGURE 3-6

Evolution of the number of orphan medicinal products that have received a non-standard marketing authorization, are non-small molecules, and have benefited from accelerated assessment. NOTE: MA = marketing authorization. SOURCE: Bouwman et al., 2024. (more...)

STAKEHOLDER ENGAGEMENT

Patient Engagement

Organizations, patients, and caregivers interact with EMA in a variety of ways all along the regulatory pathway (EMA, n.d.-q) (see Figure 3-7), a practice that is underpinned by EMA’s broader engagement framework for engaging patients and consumers throughout a medical products lifecycle (EMA, 2022a). Depending on the activity, patients may interact as representatives of their community, as representatives of an organization, or as individual experts. Specific opportunities for engagement include serving on EMA’s management board,⁶ scientific committees, and initiatives, such as the Accelerating Clinical Trials in the EU initiative (EMA, n.d.-b), which aims to further develop innovative clinical research in the European Union; attending consultations and workshops, assisting with providing advice on science and protocols, and involvement in the Patients’ and Consumers’ Working Party (PCWP) (EMA, n.d.-q). The PCWP was established in 2006 to provide a platform for the exchange of information and discussion of issues between EMA and patients. The group consists of representatives from patient and consumer organizations, representatives of EMA scientific committees, and observers. Organizations currently represented include the European Organisation for Rare Diseases, the Thalassemia International Federation, and the World Duchenne Organization among others (EMA, n.d.-w).

FIGURE 3-7

Patient involvement along the medicines lifecycle at EMA. SOURCE: Adapted from European Medicines Agency: Getting involved, https://www.ema.europa.eu/en/partners-networks/patients-and-consumers/getting-involved (accessed March 15, 2024).

Organizations and individuals can apply to work with EMA if they meet certain requirements. Among other criteria, organizations must be registered in the EU, have a clear mission and objectives, be representative of patients or consumers throughout the EU, and be transparent. Individual patients may also register to have an opportunity to use their real-life experiences to inform EMA’s work. EMA maintains a database⁷ of patients and calls upon them to provide their expertise in various EMA groups and in reviewing EMA documents prepared for the public (EMA, 2022a).

From January 2021 to May 2022, EMA ran a pilot program that explored how patients and organizations could be involved in the early stages of evaluation for orphan product applications. The pilot program included 37 products and involved identifying applications with orphan status; contacting organizations and inviting them to share information about aspects likely to be useful for evaluation (e.g., quality of life, unmet needs); and sharing this information with rapporteurs and product leads. Rapporteurs and product leads assessed whether the information provided added value, whether it was useful for assessing the application, and whether it should be included in the assessment report. An EMA assessment of the pilot program found that patient input highlighted new and valuable information and contributed to interim assessment reports in the marketing authorization process. This pilot program is being expanded to include health care professionals (EMA, 2022b).

RARE DISEASE INITIATIVES

EMA does not currently have programs specific to rare disease drug development. However, one of EMA’s stated goals is to encourage and facilitate the use of innovative methods in the development of medicines (EMA, n.d.-ac). To this end, EMA has several initiatives that support the development of innovative methods by fostering collaboration with academia and across the regulatory network. In addition to PRIME (described above), two of these initiatives are particularly relevant to rare diseases: the Innovation Task Force (ITF) and the EU Innovation Network (EU-IN).

TRANSPARENCY

Under EU law and its own regulations, transparency is an important feature of EMA’s operations. EMA is required by law¹⁰ to publish an EPAR for each medicine that it approves or denies a marketing authorization. The EPAR is made up of several documents including a “public friendly” overview; information about the marketing authorization holder; details about the product, labeling, and indications; and the history of EMA’s assessment (e.g., orphan designation assessment, procedural steps taken) (EMA, n.d.-p). The EPAR also includes information on uncertainties about benefits and risks of the product (EMA, 2009). The EPAR is published after the EC issues a decision on an application as well as whenever product information is updated. Prior to the EC decision and EPAR publication, the relevant EMA committee (CHMP or the Committee for Veterinary Medicinal Products) publishes a “summary of opinion” following their adoption of the scientific opinion. Both the summary of opinion and the EPAR are available on the EMA website, and some components are published in multiple languages (EMA, n.d.-p).

A CHMP report in 2007 made recommendations about how CHMP could improve its methodology and could increase the transparency, consistency, and communication of its benefit–risk assessment (EMA, 2007). In 2009, EMA partnered with experts in decision theory on a 3-year project aimed at identifying decision-making models that could be used to make the agency’s work more consistent, transparent, and easier to audit (EMA, n.d.-f). In a 2012 commissioned report, EMA made a recommendation that the agency employ a two-level approach: first, a qualitative analysis using PrOACT-URL (problem formulation, objectives, alternatives, consequences, trade-offs, uncertainties, risk attitude, and linked decisions) along with an MCDA (multiple criteria decision analysis) model for quantitative assessment of more complex situations (EMA, 2012).

Starting in 2016, EMA has published clinical data submitted by sponsors to support marketing applications for human medicines (EMA, n.d.-i). EU law (Article 81 of No 536/2014) mandates that EMA make clinical trial data publicly available while also protecting personal data and commercially confidential information. In accordance with this law, EMA launched the Clinical Trial Information System (CTIS) in January 2022. At the time of the CTIS launch, transparency rules allowed sponsors to apply redactions or defer the publication of certain documents for a certain period of time depending on the type of clinical trial (EMA, 2015; Zhuleku and Preinfalk, 2023). EMA has revised its regulations on clinical data publication through the adoption of EMA/263067/2023 in October 2023. Major changes to the rules include (See EMA (2023b) for a detailed description):

• Selected data will be published using structured data fields that include information on study design, inclusion and exclusion criteria, primary and secondary endpoints, details on the product, and authorization status. These fields were chosen based on relevance for the public and researchers and cannot be redacted.
• The deferral mechanism is removed entirely for every trial category. Timing of document and data publication depends on a number of factors.
• The number of documents published will be rationalized in order to reduce complexity and workload.

In addition to the EPAR and clinical trial data, EMA makes other information available to improve transparency, including dates, agendas, minutes, and outcomes of its scientific committee meetings; information about staff and experts’ conflicts of interest; information about manufacturing inspections; pediatric investigation plans; and orphan designations (EMA, n.d.-ab).

Transparency, on the part of regulators, can be an important component in building trust in regulatory processes. At the same time, transparency must be balanced with the protection of personal and commercially confidential information. The introduction of clinical trial publications by EMA was accompanied by public debate (before and around 2016) about potential downsides of transparency, including the risks of damaging industry competitiveness, false health scares (due to publication of safety data that could be misinterpreted), and compromised patient privacy (Bonini et al., 2014; O’Donnell, 2016). As far as can be ascertained by the committee, none of these risks have materialized. Information provided by EMA may help inform drug developers about the successes and failures of past programs and studies, but it is not possible to quantify the benefits for the drug development ecosystem.

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