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.

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.

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).

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

• Al-Faruque F. EMA launches stepwise ‘PIP’ pilot. 2023. [March 12, 2024]. https://www​.raps.org​/news-andarticles/news-articles​/2023/2/ema-launches-stepwise-pip-pilot .
• Bere N, Garcia J. Patient engagement at EMA. 2020. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/presentation​/presentation-patient-engagement-ema-progressing-conceptpatient-centered-development-practice-nbere-jgarcia-ema_en.pdf .
• Critical Path Institute. Rare Disease Clinical Outcome Assessment consortium. [August 6, 2024]. n.d.-a. https://c-path​.org/program​/rare-disease-clinical-outcome-assessment-consortium/
• Critical Path Institute. Rare Disease Cures Accelerator-Data and Analytics Platform. [March 7, 2024]. n.d.-b. https://c-path​.org/program​/rare-disease-cures-accelerators-data-and-analytics-platform/
• EMA (European Medicines Agency). Points to consider on application with 1. Meta-analyses; 2. One pivotal study. 2001. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/scientific-guideline​/points-consider-application-1meta-analyses-2one-pivotal-study_en.pdf .
• EMA. Guideline on clinical trials in small populations. 2006. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/scientific-guideline​/guideline-clinical-trials-small-populations_en.pdf .
• EMA. Benefit-risk methodology project. 2009. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/report​/benefit-risk-methodology-project​_en.pdf .
• EMA. ICH guideline E16 on genomic biomarkers related to drug response: Context, structure and format of qualification submissions. 2010. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/scientific-guideline​/ich-guideline-e16-genomic-biomarkers-related-drugresponse-context-structure-and-format-qualification-submissions-step-5​_en.pdf .
• EMA. Guideline on pharmaceutical development of medicines for paediatric use. 2013. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/scientific-guideline​/guideline-pharmaceuticaldevelopment-medicines-paediatric-use_en.pdf .
• EMA. Mandate of the EMA Innovation Task Force (ITF). 2014. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/other​/mandate-european-medicines-agency-innovation-task-force-itf_en.pdf .
• EMA. Workshop on demonstrating significant benefit of orphan medicines: Concepts, methodology, and impact on access. 2015. [August 6, 2024]. https://www​.ema.europa​.eu/en/events/workshop-demonstrating-significant-benefit-orphan-medicines-concepts-methodology-impact-access .
• EMA. Demonstrating significant benefit of orphan medicines: Concepts, methodology and impact on access: Workshop report. 2016. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/report​/workshop-report-demonstrating-significant-benefit-orphan-medicines-conceptsmethodology-and-impact-access_en.pdf .
• EMA. Framework of collaboration between the European Medicines Agency and academia. 2017a. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/regulatory-procedural-guideline​/framework-collaboration-between-european-medicines-agency-and-academia_en.pdf .
• EMA. ICH guideline E17 on general principles for planning and design of multiregional clinical trials. 2017b. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/scientific-guideline​/ich-guideline-e17-general-principles-planning-and-design-multi-regional-clinical-trialsstep-5-first-version_en.pdf .
• EMA. Rare diseases, orphan medicines: Getting the facts straight. 2018. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/other​/rare-diseases-orphan-medicines-getting-facts-straight​_en.pdf .
• EMA. Guideline on the investigation of subgroups in confirmatory clinical trials. 2019. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/scientific-guideline​/guideline-investigation-subgroupsconfirmatory-clinical-trials_en.pdf .
• EMA. EMA starts first rolling review of a COVID-19 vaccine in the EU. 2020. [August 15, 2024]. https://www​.ema.europa​.eu/en/news/ema-starts-first-rolling-review-covid-19-vaccine-eu .
• EMA. Guideline on registry-based studies. 2021a. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/scientific-guideline​/guideline-registry-based-studies_en​.pdf-0 .
• EMA. A vision for use of real-world evidence in EU medicines regulation. 2021b. [August 15, 2024]. https://www​.ema.europa​.eu/en/news/vision-use-real-world-evidence-eu-medicines-regulation .
• EMA. Complex clinical trials—Questions and answers. 2022a. [August 1, 2024]. https://health​.ec.europa​.eu/system/files​/2022-06/medicinal_qa​_complex_clinical-trials_en.pdf .
• EMA. Concept paper on platform trials. 2022b. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/scientific-guideline​/concept-paper-platform-trials_en.pdf .
• EMA. Engagement framework: EMA and patients, consumers and their organizations. 2022c. [August 1, 2024]. https://www​.ema.europa​.eu/system/files/documents​/other/updated​_engagement_framework​_-_ema_and_patients​_consumers_and_their​_organisations_2022-en.pdf .
• EMA. European Medicines Agency guidance for applicants seeking scientific advice and protocol assistance. 2022d. https://www​.ema.europa​.eu/en/documents/regulatory-proceduralguideline​/european-medicines-agency-guidance-applicants-seeking-scientific-advice-andprotocol-assistance_en.pdf .
• EMA. Good practice guide for the use of the metadata catalogue of real-world data sources. 2022e. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/regulatory-procedural-guideline​/goodpractice-guide-use-metadata-catalogue-real-world-data-sources_en​.pdf .
• EMA. ICH guideline M10 on bioanalytical method validation and study sample analysis. 2022f. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/scientific-guideline​/ich-guidelinem10-bioanalytical-method-validation-step-5_en​.pdf .
• EMA. Data quality framework for EU medicines regulation. 2023a. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/regulatory-procedural-guideline​/data-quality-framework-eu-medicinesregulation_en​.pdf .
• EMA. Guidance for stepwise PIP pilot. 2023b. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/regulatory-procedural-guideline​/guidance-stepwise-pip-pilot​_en.pdf .
• EMA. Procedural advice for post-orphan medicinal product designation activities. 2023c. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/other​/procedural-advice-post-orphan-medicinal-product-designation-activities-guidance-sponsors_en.pdf .
• EMA. Reflection paper on establishing efficacy based on single arm trials submitted as pivotal evidence in a marketing authorisation. 2023d. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/scientific-guideline​/reflection-paper-establishing-efficacy-based-single-arm-trialssubmitted-pivotal-evidence-marketing-authorisation_en.pdf .
• EMA. Cluster activities. 2024a. [August 15, 2024]. https://www​.ema.europa​.eu/en/partners-networks​/international-activities​/cluster-activities .
• EMA. Real-world evidence provided by EMA. 2024b. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/other​/guidance-real-world-evidence-provided-ema-support-regulatory-decisionmaking_en.pdf .
• EMA. United States. 2024c. [August 15, 2024]. https://www​.ema.europa​.eu/en/partners-networks​/internationalactivities​/bilateral-interactions-non-eu-regulators​/united-states .
• EMA. Accelerated assessment. [August 15, 2024]. n.d.-a. https://www​.ema.europa​.eu/en/human-regulatory-overview​/marketing-authorisation​/accelerated-assessment .
• EMA. Accelerating Clinical Trials in the EU (ACT EU). [August 1, 2024]. n.d.-b. https://www​.ema.europa​.eu/en/human-regulatory-overview​/research-development​/clinical-trials-human-medicines​/accelerating-clinical-trials-eu-act-eu .
• EMA. Applying for orphan designation. [February 20, 2024]. n.d.-c. https://www​.ema.europa​.eu/en/humanregulatory-overview​/research-development​/orphan-designation-research-development​/applying-orphan-designation .
• EMA. Class waivers. [August 6, 2024]. n.d.-d. https://www​.ema.europa​.eu/en/human-regulatory-overview​/research-development​/paediatric-medicines-research-development​/paediatricinvestigation-plans​/class-waivers .
• EMA. Class waiviers. [August 15, 2024]. n.d.-e. https://www​.ema.europa​.eu/en/human-regulatory-overview​/research-and-development​/paediatric-medicines-research-and-development​/paediatricinvestigation-plans​/class-waivers .
• EMA. Clinical efficacy and safety: General. [August 6, 2024]. n.d.-f. https://www​.ema.europa​.eu/en/humanregulatory-overview​/research-and-development​/scientific-guidelines​/clinical-efficacysafety-guidelines​/clinical-efficacy-safety-general .
• EMA. Conditional marketing authorization. [February 20, 2024]. n.d.-g. https://www​.ema.europa​.eu/en/humanregulatory-overview​/marketing-authorisation​/conditional-marketing-authorisation .
• EMA. Data Analysis and Real World Interrogation Network (DARWIN EU). [August 6, 2024]. n.d.-h. https://www​.ema.europa​.eu/en/about-us/how-we-work​/big-data/real-world-evidence​/data-analysis-real-world-interrogation-network-darwin-eu . [PubMed: 39532529]
• EMA. EU Innovation Network (EU-IN). [July 10, 2024]. n.d.-i. https://www​.ema.europa​.eu/en/committees/working-parties-other-groups​/eu-innovation-network-eu .
• EMA. European Medicines Agency (EMA). [August 15, 2024]. n.d.-j. https:​//european-union​.europa.eu/institutionslaw-budget​/institutions-and-bodies​/search-all-eu-institutions-and-bodies​/europeanmedicines-agency-ema_en#:~:text​=The​%20European%20Medicines​%20Agency%20(EMA,European​%20Economic%20Area%20(EEA)
• EMA. Exceptional circumstances. [March 10, 2024]. n.d.-k. https://www​.ema.europa​.eu/en/glossary/exceptional-circumstances .
• EMA. Getting involved. [March 15, 2024]. n.d.-l. https://www​.ema.europa​.eu/en/partners-networks​/patients-andconsumers​/getting-involved .
• EMA. Oprhan incentives. [February 19, 2024]. n.d.-m. https://www​.ema.europa​.eu/en/human-regulatory-overview​/research-and-development​/orphan-designation-research-and-development/orphanincentives .
• EMA. Orphan designation: Overview. [June 25, 2024]. n.d.-n. https://www​.ema.europa​.eu/en/human-regulatoryoverview​/orphan-designation-overview .
• EMA. Paediatric investigation plans. [August 15, 2024]. n.d.-o. https://www​.ema.europa​.eu/en/human-regulatoryoverview​/research-development​/paediatric-medicines-research-development​/paediatricinvestigation-plans .
• EMA. Patients’ and Consumers’ Working Party. [August 6, 2024]. n.d.-p. https://www​.ema.europa​.eu/en/committees/working-parties-other-groups​/comp-working-parties-other-groups​/patientsconsumers-working-party .
• EMA. PRIME: Priority Medicines. [August 15, 2024]. n.d.-q. https://www​.ema.europa​.eu/en/human-regulatoryoverview​/research-development​/prime-priority-medicines .
• EMA. Qualification of novel methodologies for medicine development. [August 6, 2024]. n.d.-r. https://www​.ema.europa​.eu/en/qualification-novel-methodologies-medicine-development .
• EMA. Scientific advice and protocol assistance. [March 10, 2024]. n.d.-s. https://www​.ema.europa​.eu/en/humanregulatory-overview​/research-development​/scientific-advice-protocol-assistance .
• EMA. Support to SMEs. [August 7, 2024]. n.d.-t. https://www​.ema.europa​.eu/en/about-us/support-smes .
• EMA. Supporting innovation. [July 10, 2024]. n.d.-u. https://www​.ema.europa​.eu/en/human-regulatoryoverview​/research-development​/supporting-innovation .
• EMA. Who we are. [July 9, 2024]. n.d.-v. https://www​.ema.europa​.eu/en/about-us/who-we-are .
• EMA and FDA (U.S. Food and Drug Administration). General principles: EMA-FDA parallel scientific advice. 2021. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/other​/general-principles-european-medicines-agency-food-and-drug-administration-parallel-scientific-advice_en.pdf .
• European Commission. European Partnership on Rare Diseases. 2022. [August 6, 2024]. https://cordis​.europa​.eu/programme/id/HORIZON​_HORIZON-HLTH-2023-DISEASE-07-01 .
• European Commission. Guideline on the format and content of applications for designation as orphan medicinal products and on the transfer of designations from one sponsor to another. 2014. [August 1, 2024]. https://health​.ec.europa​.eu/system/files​/2016-11/2014-03_guideline_rev4_final_0​.pdf .
• European Joint Programme on Rare Diseases. European Joint Programme on Rare Diseases. [August 6, 2024]. n.d. https://www​.ejprarediseases.org/
• European Union. The EU Decentralised Clinical Trials project (EU DCT project). 2022. [August 1, 2024]. https://www​.hma.eu/fileadmin​/dateien/HMA_joint​/00-_About_HMA​/03-Working_Groups/CTCG​/2022_08_CTCG_EU_DCT_project.pdf .
• FDA. Providing clinical evidence of effectiveness for human drug and biological product: Guidance for industry. 1998. [August 1, 2024]. https://www​.fda.gov/media/71655/download .
• FDA. Formal meetings between the FDA and sponsors or applicants. 2009. [August 1, 2024]. https://www​.fda.gov/media/72253/download .
• FDA. Guidance for the use of Bayesian statistics in medical device clinical trials: Guidance for industry and FDA staff. 2010. [August 1, 2024]. https://www​.fda.gov/media/71512/download .
• FDA. E16 biomarkers related to drug or biotechnology product development: Context, structure, and format of qualification submissions. 2011. [August 1, 2024]. https://www​.fda.gov/media/81311/download . [PubMed: 21834216]
• FDA. Best practices for communication between IND sponsors and FDA during drug development guidance for industry and review staff: Good review practice. 2017. [August 1, 2024]. https://www​.fda.gov/media/94850/download .
• FDA. Biomarker qualification: Evidentiary framework: Guidance for industry and FDA staff. 2018a. [August 1, 2024]. https://www​.fda.gov/media​/122319/download .
• FDA. Biomarker qualification: Evidentiary framework: Guidance for industry and FDA staff. 2018b. [August 1, 2024]. https://www​.fda.gov/media​/122319/download .
• FDA. Breakthrough therapy. 2018c. [August 6, 2024]. https://www​.fda.gov/patients​/fast-track-breakthroughtherapy-accelerated-approval-priority-review​/breakthrough-therapy .
• FDA. Clinical trial endpoints for the approval of cancer drugs and biologics. 2018d. [August 1, 2024]. https://www​.fda.gov/media/71195/download .
• FDA. E17 general principles for planning and design of multiregional clinical trials. 2018e. [August 1, 2024]. https://www​.fda.gov/media/99974/download .
• FDA. Fast track. 2018f. [August 7, 2024]. https://www​.fda.gov/patients​/fast-track-breakthrough-therapy-accelerated-approval-priority-review​/fast-track .
• FDA. Meta-analyses of randomized controlled clinical trials to evaluate the safety of human drugs or biological products: Guidance for industry. 2018g. [August 1, 2024]. https://www​.fda.gov/media​/117976/download .
• FDA. Priority review. 2018h. [March 5, 2024]. https://www​.fda.gov/patients​/fast-track-breakthrough-therapyaccelerated-approval-priority-review​/priority-review .
• FDA. Rare diseases: Early drug development and the role of pre-IND meetings. 2018i. [August 1, 2024]. https://www​.fda.gov/media​/117322/download .
• FDA. Adaptive designs for clinical trials of drugs and biologics: Guidance for industry. 2019a. [August 1, 2024]. https://www​.fda.gov/media/78495/download .
• FDA. Demonstrating substantial evidence of effectiveness for human drug and biological products: Guidance for industry. 2019b. [August 1, 2024]. https://www​.fda.gov/media​/133660/download .
• FDA. Rare diseases: Natural history studies for drug development: Guidance for industry. 2019c. [August 1, 2024]. https://www​.fda.gov/media​/122425/download .
• FDA. Rare pediatric disease priority review vouchers guidance for industry. 2019d. [August 1, 2024]. https://www​.fda.gov/media/90014/download .
• FDA. CURE ID app lets clinicians report novel uses of existing drugs. 2020a. [August 6, 2024]. https://www​.fda.gov/drugs​/science-and-research-drugs​/cure-id-app-lets-clinicians-report-novel-usesexisting-drugs .
• FDA. Interacting with the FDA on complex innovative trial designs for drugs and biological products: Guidance for industry. 2020b. [August 1, 2024]. https://www​.fda.gov/media​/130897/download .
• FDA. Patient-focused drug development: Collecting comprehensive and representative input. 2020c. [August 1, 2024]. https://www​.fda.gov/media​/139088/download .
• FDA. Pediatric study plans: Content of and process for submitting initial pediatric study plans and amended initial pediatric study plans: Guidance for industry. 2020d. [August 1, 2024]. https://www​.fda.gov/media/86340/download .
• FDA. Qualification process for drug development tools: Guidance for industry and FDA staff. 2020e. [August 1, 2024]. https://www​.fda.gov/media​/133511/download .
• FDA. About CDER small business and industry assistance (SBIA). 2022a. [August 6, 2024]. https://www​.fda.gov/drugs​/cder-small-business-industry-assistance-sbia​/about-cder-small-business-andindustry-assistance-sbia .
• FDA. Externally-led patient-focused drug development meetings. 2022b. [August 7, 2024]. https://www​.fda.gov/industry​/prescription-drug-user-fee-amendments​/externally-led-patient-focused-drugdevelopment-meetings .
• FDA. General clinical pharmacology considerations for pediatric studies of drugs, including biological products. 2022c. [August 1, 2024]. https://www​.fda.gov/media/90358/download .
• FDA. Master protocols: Efficient clinical trial design strategies to expedite development of oncology drugs and biologics: Guidance for industry. 2022d. [August 1, 2024]. https://www​.fda.gov/media​/120721/download .
• FDA. Multiple endpoints in clinical trials. 2022e. [August 1, 2024]. https://www​.fda.gov/media​/162416/download .
• FDA. Patient-focused drug development: Methods to identify what is important to patients: Guidance for industry, Food and Drug Administration staff, and other stakeholders. 2022f. [August 1, 2024]. https://www​.fda.gov/media​/131230/download .
• FDA. Patient-focused drug development: Selecting, developing, or modifying fit-for-purpose clinical outcome assessments. 2022g. [August 1, 2024]. https://www​.fda.gov/media​/159500/download .
• FDA. Benefit-risk assessment for new drug and biological products: Guidance for industry. 2023a. [August 1, 2024]. https://www​.fda.gov/media​/152544/download .
• FDA. Clinical outcome assessment (COA) qualification program. 2023b. [August 6, 2024]. https://www​.fda.gov/drugs​/drug-development-tool-ddt-qualification-programs​/clinical-outcome-assessmentcoa-qualification-program .
• FDA. Complex innovative trial design meeting program. 2023c. [March 19, 2024]. https://www​.fda.gov/drugs​/development-resources​/complex-innovative-trial-design-meeting-program .
• FDA. Considerations for the design and conduct of externally controlled trials for drug and biological products: Guidance for industry. 2023d. [August 1, 2024]. https://www​.fda.gov/media​/164960/download .
• FDA. Considerations for the use of real-world data and real-world evidence to support regulatory decision-making for drug and biological products. 2023e. [August 1, 2024]. https://www​.fda.gov/media​/171667/download .
• FDA. Data standards for drug and biological product submissions containing real-world data. 2023f. [August 1, 2024]. https://www​.fda.gov/media​/153341/download .
• FDA. Decentralized clinical trials for drugs, biological products, and devices. 2023g. [August 1, 2024]. https://www​.fda.gov/media​/167696/download .
• FDA. Demonstrating substantial evidence of effectiveness with one adequate and well-controlled clinical investigation and confirmatory evidence: Guidance for industry. 2023h. [August 1, 2024]. https://www​.fda.gov/media​/172166/download .
• FDA. FDA-EMA Parallel Scientific Advice (PSA) program. 2023i. [August 6, 2024]. https://www​.fda.gov/drugs​/news-events-human-drugs​/fda-ema-parallel-scientific-advice-psa-program-03162022 .
• FDA. Formal meetings between the FDA and sponsors or applicants of PDUFA products. 2023j. [August 1, 2024]. https://www​.fda.gov/media​/172311/download .
• FDA. Frequently asked questions (FAQ) about designating an orphan product. 2023k. [March 19, 2024]. https://www​.fda.gov/industry​/designating-orphan-product-drugs-and-biological-products​/frequently-asked-questions-faq-about-designating-orphan-product .
• FDA. International agreements & information sharing. 2023l. [August 6, 2024]. https://www​.fda.gov/drugs​/cder-international-program​/international-agreements-information-sharing .
• FDA. 2023m. Orphan products grants program. [August 6, 2024]. https://www​.fda.gov/industry​/medicalproducts-rare-diseases-and-conditions​/orphan-products-grants-program .
• FDA. Patient-focused drug development: Incorporating clinical outcome assessments into endpoints for regulatory decision-making: Guidance for industry, Food and Drug Administration staff, and other stakeholders. 2023n. [August 1, 2024]. https://www​.fda.gov/media​/166830/download .
• FDA. Rare diseases: Considerations for the development of drugs and biological products: Guidance for industry. 2023o. [August 1, 2024]. https://www​.fda.gov/media​/119757/download .
• FDA. Real-world data: Assessing registries to support regulatory decision-making for drug and biological products: Guidance for industry. 2023p. [August 1, 2024]. https://www​.fda.gov/media​/154449/download .
• FDA. Support for clinical Trials Advancing Rare disease Therapeutics pilot program; program announcement. 2023q. [August 1, 2024]. https://www​.federalregister​.gov/documents​/2023/10/02/2023-21235​/support-for-clinical-trials-advancing-rare-disease-therapeutics-pilot-program-program-announcement .
• FDA. Using Bayesian statistical approaches to advance our ability to evaluate drug products. 2023r. [August 1, 2024]. https://www​.fda.gov/drugs​/cder-small-business-industry-assistance-sbia​/using-bayesian-statistical-approaches-advance-our-ability-evaluate-drug-products .
• FDA. About the FDA patient representative program. 2024a. [March 10, 2024]. https://www​.fda.gov/patients​/learn-about-fda-patient-engagement​/about-fda-patient-representative-program .
• FDA. Accelerated approval program. 2024b. [August 6, 2024]. https://www​.fda.gov/drugs​/nda-and-bla-approvals​/accelerated-approval-program .
• FDA. Accelerating Rare disease Cures (ARC) program. 2024c. [February 20, 2024]. https://www​.fda.gov/aboutfda​/center-drug-evaluation-and-research-cder​/accelerating-rare-disease-cures-arc-program .
• FDA. Advancing real-world evidence program. 2024d. [August 7, 2024]. https://www​.fda.gov/drugs​/development-resources​/advancing-real-world-evidence-program?utm_medium​=email&utm​_source​=govdelivery#:~:text=As​%20announced%20in​%20the%20Federal%2cnew​%20indications%20of​%20approved%20medical .
• FDA. Biomarker qualification program. 2024e. [August 6, 2024]. https://www​.fda.gov/drugs​/drug-developmenttool-ddt-qualification-programs​/biomarker-qualification-program .
• FDA. CDER patient-focused drug development. 2024f. [March 05, 2024]. https://www​.fda.gov/drugs​/development-approval-process-drugs​/cder-patient-focused-drug-development .
• FDA. CDER pilot grant program: Standard core clinical outcome assessments (COAs) and their related endpoints. 2024g. [August 7, 2024]. https://www​.fda.gov/drugs​/development-approval-processdrugs​/cder-pilot-grant-program-standard-core-clinical-outcome-assessments-coas-andtheir-related-endpoints .
• FDA. Clinical pharmacology considerations for the development of oligonucleotide therapeutics. 2024h. [August 1, 2024]. https://www​.fda.gov/media​/159414/download .
• FDA. Designating an orphan product: Drugs and biological products. 2024i. [August 15, 2024]. https://www​.fda.gov/industry​/medical-products-rare-diseases-and-conditions​/designating-orphan-productdrugs-and-biological-products .
• FDA. FDA-led Patient-Focused Drug Development (PFDD) public meetings. 2024j. [August 7, 2024]. https://www​.fda.gov/industry​/prescription-drug-user-fee-amendments​/fda-led-patient-focused-drug-development-pfdd-public-meetings .
• FDA. FDA Patient-Focused Drug Development guidance series for enhancing the incorporation of the patient’s voice in medical product development and regulatory decision making. 2024k. [August 7, 2024]. https://www​.fda.gov/drugs​/development-approval-process-drugs​/fda-patient-focused-drug-development-guidance-series-enhancing-incorporation-patients-voice-medical .
• FDA. FDA patient listening sessions. 2024l. [August 1, 2024]. https://www​.fda.gov/patients​/learn-about-fdapatient-engagement​/fda-patient-listening-sessions .
• FDA. FDA patient listening sessions. 2024m. [August 7, 2024]. https://www​.fda.gov/patients​/learn-about-fdapatient-engagement​/fda-patient-listening-sessions .
• FDA. Guidance documents for rare disease drug development. 2024n. [August 6, 2024]. https://www​.fda.gov/drugs​/guidances-drugs​/guidance-documents-rare-disease-drug-development .
• FDA. LEADER 3D: Learning and Education to Advance and Empower Rare Disease Drug Developers: Public report of external stakeholder analysis. 2024o. [August 15, 2024]. https://www​.fda.gov/media​/176557/download?attachment=
• FDA. Model-informed drug development paired meeting program. 2024p. [August 6, 2024]. https://www​.fda.gov/drugs​/development-resources​/model-informed-drug-development-paired-meetingprogram .
• FDA. Patient listening session summaries. 2024q. [August 7, 2024]. https://www​.fda.gov/patients​/learn-aboutfda-patient-engagement​/patient-listening-session-summaries#​:~:text=Patient​%20Listening​%20Sessions%20can​%20either,advocates​%20participate%20in%20the%20session .
• FDA. Project Orbis. 2024r. [August 6, 2024]. https://www​.fda.gov/about-fda​/oncology-center-excellence​/project-orbis .
• FDA. Rare Disease Endpoint Advancement pilot program. 2024s. [August 6, 2024]. https://www​.fda.gov/drugs​/development-resources​/rare-disease-endpoint-advancement-pilot-program .
• FDA. Rare pediatric disease designation and priority review voucher programs. 2024t. [August 15, 2024]. https://www​.fda.gov/industry​/medical-products-rare-diseases-and-conditions​/rare-pediatric-disease-designation-and-priority-review-voucher-programs .
• FDA. Support for clinical Trials Advancing Rare disease Therapeutics (START) pilot program. 2024u. [August 6, 2024]. https://www​.fda.gov/science-research​/clinical-trials-and-human-subject-protection​/support-clinical-trials-advancing-rare-disease-therapeutics-start-pilot-program .
• Flynn R, Plueschke K, Quinten C, Strassmann V, Duijnhoven RG, Gordillo-Maranon M, Rueckbeil M, Cohet C, Kurz X. Marketing authorization applications made to the European Medicines Agency in 2018-2019: What was the contribution of real-world evidence? Clinical Pharmacology & Therapeutics. 2022;111(1):90–97. [PMC free article: PMC9299056] [PubMed: 34689339]
• GAO (U.S. Government Accountability Office). Pediatric cancer studies: Early results of the Research to Accelerate Cures and Equity for Children Act. 2023. [August 1, 2024]. https://www​.gao.gov/products​/gao-23-105947 .
• ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use). Statistical principles for clinical trials E9. 1998. [August 1, 2024]. https://database​.ich​.org/sites/default/files/E9_Guideline​.pdf .
• ICH. E10 choice of control group and related issues in clinical trials: Guidance for industry. 2001. [August 1, 2024]. https://www​.ema.europa​.eu/en/documents/scientific-guideline​/ich-e-10-choicecontrol-group-clinical-trials-step-5_en.pdf .
• ICH. Final concept paper - E20: Adaptive clinical trials. 2019. [August 1, 2024]. https://database​.ich​.org/sites/default/files​/E20_FinalConceptPaper_2019_1107_0​.pdf .
• ICH. General considerations for clinical studies E8(R1). 2021. [August 1, 2024]. https://database​.ich​.org/sites/default/files​/ICH_E8-R1_Guideline​_Step4_2021_1006.pdf .
• Ionan AC, Clark J, Travis J, Amatya A, Scott J, Smith JP, Chattopadhyay S, Salerno MJ, Rothmann M. Bayesian methods in human drug and biological products development in CDER and CBER. Therapeutic Innovation & Regulatory Science. 2023;57(3):436–444. [PMC free article: PMC9718464] [PubMed: 36459346]
• Lee KJ, Bent R, Vaillancourt J. Selected FDA programs on rare disease: Processes to Evaluate the Safety and Efficacy of Drugs for Rare Diseases or Conditions in the United States and the European Union (Meeting 1 - Virtual). 2023.
• Michaeli T, Jürges H, Michaeli DT. FDA approval, clinical trial evidence, efficacy, epidemiology, and price for non-orphan and ultra-rare, rare, and common orphan cancer drug indications: Cross sectional analysis. BMJ. 2023;381:e073242. [PMC free article: PMC10167557] [PubMed: 37160306]
• Thirstrup S. Orphan medicines in EU: Processes to Evaluate the Safety and Efficacy of Drugs for Rare Diseases or Conditions in the United States and the European Union (Meeting 2 - Hybrid). 2023.
• Thor S, Vetter T, Marcal A, Kweder S. EMA-FDA parallel scientific advice: Optimizing development of medicines in the global age. Therapeutic Innovation & Regulatory Science. 2023;202357(4) CC BY 4.0. [PMC free article: PMC9985489] [PubMed: 36871110]
• Ungstrup E, Vanags D. Aligning global drug development for pediatric populations. 2023. [August 15, 2024]. https://www​.pharmalex​.com/thought-leadership​/blogs/aligning-global-drug-development-for-pediatric-populations/