Appendix I

FDA and EMA Resources, Policies, and Programs Relevant for Drug Development for Rare Diseases and Conditions

This appendix summarizes a non-exclusive list of resources, polices, and programs that the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have in place to support drug development for rare disease and conditions. Each section provides a brief summary on the topic and lists relevant FDA and EMA resources (e.g., guidance, program websites, and other publications).

While FDA and EMA are considered regulatory counterparts, there are a few key differences in their jurisdiction and authority as well as how the organizations operate. FDA is a centralized regulatory body that oversees the evaluation of safety and efficacy of drugs approved in the United States and has a dedicated workforce and authority to issue guidance and make regulatory decisions on medications and medical devices. EMA is a decentralized agency of the European Union (EU) that is responsible for evaluating the safety and efficacy of drugs in Europe. However, it does not have the authority to approve medications. Instead, EMA can issue guidance and make authorization recommendations on medical products that the European Commission ultimately approves for marketing in the European Union (EMA, n.d.-j). Day-to-day operations at EMA are carried out by dedicated staff that rely on a network of experts from across Europe and collaboration with member states to pool resources and coordinate work to regulate medicines for use in humans (EMA, n.d.-v).

FDA and EMA each have regulatory policies in place to support and incentivize drug development for rare diseases and conditions, including

mechanisms for facilitating expedited regulatory review, and opportunities for engagement with sponsors and people with lived rare disease experience.

ORPHAN DRUG DESIGNATION

Both FDA and EMA offer an orphan designation for drugs that are targeted at rare diseases. The criteria are similar but not identical. FDA offers orphan designation to products that treat conditions affecting fewer than 200,000 individuals in the United States, or that affect more than 200,000 individuals but there is no reasonable expectation that the cost of developing a drug for the condition would be recovered by sales of the drug. EMA offers orphan designation to products that treat conditions affecting not more than 5 in 10,000 individuals in the European Union, or that affect more than 5 in 10,000 individuals but the market is unlikely to generate sufficient return on the investment. EMA further requires that the product targets a condition for which there is either no treatment available, or the product provides a “significant benefit” over available treatments. This significant benefit may be related to either improvements in clinical outcomes or patient care (e.g., ease of use). FDA also has a program for Rare Pediatric Disease Designation (FDA, 2024t), while EMA does not have a designation specifically for rare pediatric conditions.

For the purposes of orphan designation, FDA and EMA define “condition” slightly differently. FDA requires that a product be targeted at a distinct condition, as determined by a variety of factors. A product targeted at a subset of a more common condition may be eligible if the drug itself has properties that make it inappropriate for patients with the more common version of the condition; for example, a drug that is only effective in patients with a specific biomarker may be eligible, whereas those without the biomarker or drug-target would not be expected to respond (for example, mutationally-defined cancers).¹ EMA also specifies that the targeted condition must be clearly distinct from other conditions, and notes that differences in severity or stages do not make a condition distinct (European Commission, 2014). A treatment targeted at a subtype of the condition may be eligible if the characteristics of the subtype make the treatment ineffective for patients with the more common version of the condition; biomarkers of a subtype are not currently accepted as evidence of a distinct condition (Thirstrup, 2023). For these reasons, it can be more difficult for a drug product to be granted and keep an orphan designation by EMA.

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¹ 78 FR 35117.

As stated in Chapter 1, orphan designation in the United States qualifies sponsors for incentives (see Box 1-1). Similarly, in the European Union, sponsors may also receive incentives including (EMA, n.d.-m):

• Reduced fees for regulatory activities, which may include reduced fees for protocol assistance, marketing-authorisation applications, inspections before authorisation, applications for changes to marketing authorisations made after approval, and reduced annual fees; and
• Potential 10 years market exclusivity after approval.

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.

INCENTIVES FOR ORPHAN DRUG DEVELOPMENT

Once designated as an orphan drug by FDA, sponsors receive the following incentives (Michaeli et al., 2023):

• Tax credits worth 25 percent of costs for qualified clinical trials;
• Waiver of the Prescription Drug User Fee ($4 million for FY 2024); and
• Potential 7 years of market exclusivity after approval.

In addition, the Orphan Drug Act established the Orphan Product Grants Program to provide funding for developing products for rare diseases

or conditions. Products that receive EMA orphan designation can access a number of incentives (EMA, n.d.-m). First, sponsors can request protocol assistance from EMA at a reduced fee; this allows sponsors to get answers to questions about what types of studies are necessary to demonstrate the quality, benefits, risks, and significant benefit of the drug. Second, a product with orphan designation is mandated to use the centralized marketing approval process conducted by EMA. Third, products maintaining orphan designation at the time of approval receive 10 years of market exclusivity; this is extended to 12 years for products with an approved pediatric investigation plan. Fourth, sponsors applying for orphan designation pay reduced fees for regulatory activities, including marketing authorization application fees, inspections before authorization, and applications for post-approval changes. In addition, sponsors may be eligible for incentives available through individual EU member states. For companies classified as small and medium-sized enterprises (SMEs) that are developing a product with orphan designation, there may also be administrative and procedural assistance from EMA’s SME office and fee reduction.

EVIDENTIARY STANDARDS

As discussed in Chapters 2 and 3, FDA and EMA each define standards of evidence in different ways. By statute, FDA approval of a drug product requires a demonstration of “substantial evidence of effectiveness,” which has generally been interpreted as requiring at least two adequate and well-controlled studies (FDA, 2019b). However, amendments have clarified that substantial effectiveness may be demonstrated with one adequate and well-controlled study along with confirmatory evidence (FDA, 2023h). FDA and EMA approval processes require a risk-benefit assessment that requires consideration of many complex factors (e.g., therapeutic context, seriousness of condition). FDA has published a number of guidance documents that are relevant to rare disease drug development, including Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products (FDA, 2019b), Rare Diseases: Considerations for the Development of Drugs and Biological Products (FDA, 2023o), Benefit–Risk Assessment for New Drug and Biological Products (FDA, 2023a), Demonstrating Substantial Evidence of Effectiveness with One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence (FDA, 2023h), and Rare

Diseases: Natural History Studies for Drug Development (FDA, 2019c). EMA has not issued general guidance on drug development for rare diseases and conditions, but there are a number of publications that apply to issues involved in rare disease drug development, including clinical trials in small populations, real-world evidence, registry-based studies, single arm trials, and use of one pivotal study in drug application.

EXPEDITED REGULATORY PATHWAYS

FDA and EMA both offer a number of expedited pathways that allow products to be approved on a shorter timeline and/or with preliminary or limited data.

Approval on a Shortened Review Timeline

FDA’s breakthrough therapy designation and EMA’s Priority Medicines (PRIME) scheme are similar programs; they are both designed to assist sponsors of products developed for conditions with an unmet need and

offer the potential for shortened review. Breakthrough therapy designation is for products that are intended to treat a serious or life-threatening condition, and where preliminary clinical evidence indicates a substantial improvement on a clinically significant endpoint over available therapies (FDA, 2018c). For PRIME designation, an applicant must provide data that demonstrate a meaningful improvement of clinical outcomes (EMA, n.d.-q). Breakthrough therapy designation offers intensive guidance on drug development, meetings and communication with FDA staff, and the potential for accelerated approval or priority review. PRIME offers similar benefits including meetings with EMA experts, iterative and expedited scientific advice, and the potential for accelerated assessment.

FDA has one program that shortens review time, called Priority Review (FDA, 2018h). EMA also has one program, called Accelerated Assessment (EMA, n.d.-a). Priority Review is for products aimed at a serious condition that demonstrate a significant improvement in safety or effectiveness and offers review of the application in 6 months. EMA’s Accelerated Assessment is for products that are of “major public health interest,” particularly ones that involve innovations or improvements for unmet needs. The program reduces the timeframe for application assessment from 210 days to 150 days.

Approval Based on Preliminary Data

Both agencies have a mechanism that allows a product to be approved with preliminary data which is to be followed by confirmatory data after approval. FDA’s Accelerated Approval pathway can be used when a product has a meaningful advantage over available therapies, and evidence demonstrates an effect on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit (FDA, 2024b). This pathway allows for a shorter development timeline and requires sponsors to collect data after approval to confirm the clinical benefit. EMA’s Conditional Marketing Authorization is used when there is an unmet need and the benefits of making the product available to the public outweigh the risks; sponsors are required to collect additional data after approval to confirm the benefit-risk analysis (EMA, n.d.-g).

Approval Based on Limited Data

Only EMA has a mechanism for approving a product for which comprehensive data on safety and efficacy are not available. Under the Exceptional Circumstances pathway, EMA may grant approval to a product if it is not possible to collect comprehensive data because of the current state of scientific knowledge, the condition is too rare, or it would be unethical (EMA, n.d.-k).

Both agencies have the legal authority to exercise a great degree of flexibility in the amount and type of data necessary for rare disease product approval.

RARE DISEASE PROGRAMS

FDA has several programs dedicated to rare diseases, several of which are in pilot form:

• Accelerating Rare disease Cures (ARC) program: CDER launched the ARC Program in 2022; its mission is “to drive scientific and regulatory innovation and engagement to accelerate the availability of treatments for patients with rare diseases” (FDA, 2024c)
• Learning and Education to Advance and Empower Rare Disease Drug Developers (LEADER 3D): ARC launched the LEADER 3D initiative in 2023. Through LEADER 3D, FDA seeks input from stakeholders who design and conduct rare disease drug development programs in order to identify gaps in knowledge about the regulatory process (FDA, 2024o).

• Rare Disease Endpoint Advancement (RDEA) pilot program: The RDEA pilot program is a joint CDER and CBER program that seeks to advance rare disease drug development by providing a mechanism for sponsors to collaborate with FDA throughout the efficacy endpoint development process (FDA, 2024s).
• Support for clinical Trials Advancing Rare disease Therapeutics (START) pilot program: START is a joint CBER and CDER pilot program that was launched in late 2023. It augments currently available formal meetings by addressing issues through more rapid, ad hoc communication mechanisms (FDA, 2023q; Lee et al., 2023).
• The Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP^®): RDCA-DAP^®, funded by FDA and operated by the Critical Path Institute in collaboration with the National Organization for Rare Disorders, is a centralized database and analytics hub that contains standardized data on a growing number of rare diseases and allows secure sharing of data collected across multiple sources, including natural history studies/patient registries, control arms of clinical trials, longitudinal observational studies, and real-world data. Since RDCA-DAP^® was launched in 2021, the platform has enabled access to data from over 30 rare disease areas with more data being added over time (Critical Path Institute, n.d.-b).

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.-m). 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).

There are two rare disease programs funded by the European Commission:

• The European Partnership on Rare Diseases is an implementation tool of Horizon Europe, a broad research and innovation funding scheme by the European Commission. The Rare Disease Partnership seeks to advance innovation for rare diseases by coordinating local, national, and regional research activities. It will succeed the European Joint Programme on Rare Diseases (European Comission, 2022).
• The European Joint Programme on Rare Diseases (EJP RD) facilitates rare disease research collaboration across the EU member

• states as well as associated states and the UK & Canada (European Joint Programme on Rare Diseases, n.d.).

SPONSOR ENGAGEMENT

Sponsors developing new drugs must navigate a range of complex challenges when designing and conducting a study for regulatory submission. Clinical trials for regulatory submission require a combination of clinical, safety, biostatistical, and regulatory expertise, as well an understanding of the patient populations a drug is intended to treat to maximize the likelihood that study results meet regulatory requirements to gain market approval. These challenges are heightened when it comes to rare diseases and conditions. Additionally, many companies developing rare disease drugs are small and medium-sized enterprises, which may have fewer resources and less in-house expertise than large pharmaceutical companies. For these reasons, it is critically important for sponsors developing rare disease drug products to engage with the agency early and often.

Both agencies offer sponsors the opportunity to engage throughout the development and approval process. Sponsors may request a meeting with FDA at any time during drug development. In general, communication with the agency is through the regulatory project manager and sponsors are discouraged from contacting reviewers directly (FDA, 2017). Sponsors may solicit advice on a variety of topics and may also request a formal meeting at critical junctures of development. EMA offers preparatory meetings for sponsors early in the development process in order to avoid major issues, and sponsors are encouraged to reach out at any time for feedback. Scientific advice is available from EMA for a fee; the fee can be waived for orphan medicines, smaller sponsors, and in the case of public emergencies (EMA, n.d.-s).

PATIENT ENGAGEMENT

FDA and EMA both have several mechanisms for engaging with patients, caregivers, and patient groups. FDA uses the Patient-Focused Drug Development (PFDD) program as a systematic approach for incorporating patient perspectives into drug development (FDA, 2024f), while EMA utilizes the Patients’ and Consumers’ Working Party (PCWP) to provide a platform for the exchange of information between the agency and patients (EMA, n.d.-p). Individual patients can serve on FDA advisory committees and provide advice to FDA through the Patient Representative Program (FDA, 2024a), while at EMA patients and organizations can apply to be part of a database of patients that can be called on by EMA during the drug evaluation process (EMA, 2022c). Although there are differences in how each agency engages with patients there is no evidence that one agency’s methods are superior.

• Methodological Guidance Series: A series of guidance that is intended to promote the use of systematic approaches for incorporating patient and caregiver input in medical product development and regulatory decision-making (FDA, 2024k).
• Clinical Outcome Assessments (COA) and their Related Endpoints Pilot Grant Program: A pilot grant program to support the development of publicly available COAs and their related endpoints. In 2021, a grant was awarded for a project developing an observer measure of communications abilities of individuals with rare, neurodevelopmental disorders (FDA, 2024g).

FDA’s PFDD initiative, which was established under the fifth authorization of the Prescription Drug User Fee Act (PDUFA), is a systematic approach to help ensure that patients’ experiences, perspectives, needs, and priorities are meaningfully incorporated into drug development and evaluation” (FDA, 2024f). Patient listening sessions, similar to PFDD meetings, serve to inform FDA on the concerns of the patient community. However, patient listening sessions are nonpublic and only FDA, patients, caregivers, advocates, and community representatives can participate in the session, and they are non-interactive, in that the agency participants are listening but not conversing with other participants (FDA, 2024l).

Organizations, patients, and caregivers interact with EMA in a variety of ways all along the regulatory pathway (EMA, n.d.-l), a practice that is underpinned by EMA’s broader engagement framework to engage patients and consumers throughout a medical product’s lifecycle (EMA, 2022c). Depending on the activity, patients may interact as representatives of their community, representing an organization, or as individual experts. Specific opportunities for engagement include serving on EMA’s Management Board and scientific committees, attending consultations and workshops, assisting with providing advice on science and protocols, and involvement in the PCWP (EMA, n.d.-l).

EMA also has several avenues to promote patient engagement, including public hearings, participation on review, scientific advice, and other consultative committees, and involvement in preparing guidelines.

INCLUSION OF PEDIATRIC POPULATIONS

In 2012, the Food and Drug Administration Safety and Innovation Act added a provision to section 505B of the FD&C Act,² often referred to by the acronym of the legislation that created section 505B, the Pediatric Research Equity Act (PREA), that requires sponsors to submit an initial pediatric study plan (iPSP) “before the date on which the sponsor submits the required assessments or investigation and no later than either 60 days after the date of the end-of-Phase 2 meeting or such other time as agreed upon between FDA and the sponsor” (FDA, 2020d). The iPSP must include the following: (1) “an outline of the pediatric study or studies that the sponsor plans to conduct (including, to the extent practicable, study objectives and design, age groups, relevant endpoints, and statistical approach); (2) “any request for a deferral or waiver . . . if applicable, along with any supporting information; and (3) “other information specified in the regulations promulgated under paragraph (7).”³

A sponsor should not submit a marketing application or supplement until FDA confirms agreement on the iPSP, and the total review period for iPSPs should not exceed 210 days. PREA provides an exemption from iPSP requirements for applications for drugs that have orphan designation.⁴ In 2017, PREA was amended by the FDA Reauthorization Act of 2017,⁵ by including the RACE for Children Act⁶ to lift the orphan exemption for rare pediatric cancers, requiring sponsors to submit iPSPs for these indications. This amendment has required that sponsors submit a planned approach for studying drugs in pediatric populations if they intend to apply for approval of adult cancer drugs (GAO, 2023).

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² Public Law 112-144, 126 Stat. 993 (July 9, 2012).

³ 21 U.S.C. § 355c(e)(2)(B).

⁴ 21 U.S.C. § 355c(k)(1).

⁵ P. L. 115-52, § 504. FDA Reauthorization Act of 2017 (August 18, 2017).

⁶ H.R.1231—RACE for Children Act—115th Congress (2017–2018).

In EMA, the paediatric investigation plan (PIP) serves to ensure all needed data to support a marketing authorization for children are collected. PIPs are required to be submitted when the Phase 2 dose is selected at the end of Phase 1 (Ungstrup and Vanags, 2023). All medicines seeking marketing authorization have to include a PIP unless the treatment is exempt due to referral or waiver (EMA, n.d.-e). Typically, waivers are provided to treatments that are likely to be ineffective or unsafe in children, intended for adult-only conditions, or unlikely to provide significant benefit over current treatment available to children (EMA, n.d.-e). The PIP is reviewed and agreed upon by the drug sponsor and EMA’s Paediatric Committee (EMA, n.d.-o). In early 2023, EMA launched a stepwise PIP pilot program which is designed to allow greater flexibility for sponsors that are developing innovative treatments (EMA, 2023b). The stepwise PIP will allow sponsors to continue with development with a partial PIP in place rather than waiting for more data to support a full PIP (Al-Faruque, 2023). Sponsors indicated that the PIP can be restrictive to drug development and expect the stepwise program to ease some of the issues.

FDA has a program for Rare Pediatric Disease Designation, while EMA does not have a designation specifically for rare pediatric conditions.

INNOVATIVE CLINICAL TRIAL DESIGN

Due to the complex biology underpinning rare diseases and conditions, low disease prevalence, and patient heterogeneity, it is often challenging to design traditional randomized controlled trials (RCTs) for studying drugs that treat rare diseases or conditions. As such, clinical trials for rare diseases and conditions are often smaller than for other more prevalent conditions and may require the use of novel design elements to meet evidentiary standards.

In general, both agencies have demonstrated an openness to the use of alternative and confirmatory data (e.g., natural history studies), as well as novel approaches for data analysis (e.g., Bayesian statistical methods).

To assist sponsors, FDA’s Complex Innovative Trial Design Meeting program (also referred to as the Complex Innovative Trial Paired Meeting Program) offers sponsors up to two meetings with FDA to discuss their proposed complex innovative design elements during late-stage clinical development (FDA, 2023c). In guidance, FDA explains that there is no fixed definition of a complex innovative design because what is considered innovative may change over time, and that the determination of whether a specific novel design is appropriate for regulatory use is made on a case-by-case basis (FDA, 2020b). The guidance provides examples of innovative design approaches (e.g., adaptive designs, Bayesian inference), and gives sponsors suggestions on common elements that should be included in a proposal for this program (FDA, 2020b). EMA, in collaboration with the European Commission and member state heads of medicines agencies, launched the Accelerating Clinical Trials in the EU (ACT EU) program to improve regional clinical trials infrastructure in the European Union through several action areas (EMA, n.d.-b). Those most relevant to rare diseases are: (1) Implementation of the Clinical Trial Regulation, (2) Clinical Trial Methodologies, (3) Scientific Advice, and (4) Clinical Trials Training Curriculum.

ENDPOINT SELECTION AND BIOMARKER DEVELOPMENT

Attributable to the small number of patients with rare diseases, an inherent challenge is accruing study sample sizes large enough to adequately power all endpoints. This commonly translates to disproportionate focus on the primary endpoint and concomitant emphasis on the population most relevant for that endpoint. Criteria that focus on power to detect a difference for the study primary endpoint may obfuscate statistical efficacy measurement on important secondary endpoints. Conversely, study eligibility criteria attempting to enroll patients for all endpoints often slows accrual. For these reasons, endpoint selection and utilization of biomarkers are particularly crucial in rare disease treatment development where small sample sizes impact statistical power for efficacy and safety determinations.

FDA guidance acknowledges that, given limited sample size, flexibility may be needed in qualifying biomarkers (FDA, 2018a) and that such strategies as exit interviews or surveys may be needed for COAs (FDA, 2023n) to add greater depth to data for rare diseases (FDA, 2022f). EMA’s 2006 Guideline on Clinical Trials in Small Populations has several pertinent statements related to the choice of endpoints that indicate regulatory flexibility (EMA, 2006):

• Recognition that there may be too few patients to validate endpoints and test treatments.
• Adequate follow-up in time to progression or time to remission can be obtained in open-label extension studies.
• Given that the mode of action of the treatment may not be sufficiently well known, EMA states that “the usual approach of pre-specifying the primary endpoint may be too conservative, and more knowledge may be gained from collecting all sensible/possible endpoints and then presenting all the data in the final study report. Still, every effort should be made to identify an appropriate

• hierarchy in the endpoints. If, collectively, the data look compelling, then a Marketing Authorisation may be grantable” (EMA, 2006).

STATISTICAL ANALYSIS AND USE OF REAL-WORLD DATA

Beyond the choice in study design, researchers must consider the analytical challenges that arise when sample sizes are small and data are limited. It is often more difficult to achieve the statistical power necessary to demonstrate substantial evidence of effectiveness for a drug to treat a rare vs a common disease or condition. Innovative statistical methods (e.g. Bayesian analysis, extrapolation of adult data for pediatric uses, and network meta-analysis) and the use of real-world sources of data (e.g. expanded access programs, open label extension studies, natural history data, and patient

registries) are additional tools that can be applied for studying rare disease drug products.

Bayesian statistics enable the incorporation of prior and external information, which may be a useful approach for the study of drugs to treat rare diseases or conditions. For example, a Bayesian approach could apply information from a study of a drug in adult populations towards understanding the effect of the same drug in children. Though FDA does not have guidance solely focused on the use of Bayesian methods in drug trials, it does cover this topic in guidance for adaptive trial designs and dedicates it as a focal point in the Complex Innovative Trial Design Paired Meeting Program (FDA, 2023r). Furthermore, it is documenting instances in which Bayesian methods have been used within CBER and CDER, with the aim of issuing draft guidance on applying them in drug trials by the end of the fiscal year 2025 (Ionan et al., 2023). EMA briefly covers Bayesian methods in guidance on clinical trials in small populations (EMA, 2006) and more thoroughly in a 2022 Q&A on complex clinical trials (EMA, 2022a).

External sources of data can help supplement RCT data for rare disease drug development and strengthen the evidence base for regulatory decision-making. FDA has issued several guidance, such as draft guidance on the design and conduct of externally controlled trials (FDA, 2023d), as well as draft guidance on the utilization of natural history studies (FDA, 2019c) and patient registries (FDA, 2023p). EMA has issued guidance on choice of control groups (ICH, 2001), including external control groups, and registry-based studies (EMA, 2021a). Additionally, EMA has outlined the role of real-world evidence in regulatory decision-making (Flynn et al., 2022).

FDA AND EMA COLLABORATIVE EFFORTS

Despite some key differences, FDA and EMA have similar approaches to the evaluation and approval of drugs for rare diseases. Given this overlap, there are many existing mechanisms for close collaboration between the two agencies, as well as opportunities for enhanced collaboration in the future. Since the signing of a confidentiality agreement in 2003, which permits the agencies to share nonpublic information, including confidential commercial information, FDA and EMA have created multiple formalized mechanisms to facilitate communication and collaboration. These collaborations cover a wide range of topics and activities, including scientific advice, orphan designations, marketing authorizations, post-authorization requirements, inspections, pharmacovigilance, guidance documents, and other topics (EMA, 2024c) (see Figure 5-7).

One of the primary formal mechanisms for collaboration between EMA and FDA are so-called “clusters”—regular virtual meetings between EMA and FDA staff, which are focused on specific topics and therapeutic areas that would benefit from an “intensified exchange of information and collaboration” (EMA, 2024a). Documents exchanged within clusters may include draft guidances/guidelines; assessment reports; review memos; and meeting minutes. The agencies typically set the agenda for what is discussed at a cluster meeting. However, sponsors also have the option of asking that a drug program or topic be discussed. Topics discussed within clusters range from emerging scientific and ethical issues to challenges in product development to issues with the review of marketing authorization applications.

Established in 2005, the Parallel Scientific Advice (PSA) program is a voluntary mechanism through which FDA and EMA can concurrently provide scientific advice to sponsors during the development of new drugs, biological products, vaccines, or advanced therapies (EMA and FDA, 2021). The goals of the PSA program are to: (1) increase dialogue early on in the product lifecycle, (2) deepen understanding of regulatory decisions, (3) optimize product development, and (4) avoid unnecessary or duplicative testing (Thor et al., 2023). The program does not guarantee EMA and FDA alignment, but can offer a number of potential benefits for sponsors, including agency convergence on approaches to development, a better understanding of each agency’s concerns and requirements, and opportunity for sponsors and agencies to ask and answer questions (Thor et al., 2023).

REFERENCES

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