Appendix E

Qualitative Interview Summary and Methodology

PURPOSE

The National Academies Committee on Processes to Evaluate the Safety and Efficacy of Drugs for Rare Diseases or Conditions in the United States and the European Union sought qualitative information from biopharmaceutical and biotechnology companies to better understand:

• How regulatory flexibilities have been applied by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) towards drugs to treat rare diseases or conditions.
• The use of alternative and confirmatory data (e.g., open label extension studies, expanded access programs, natural history studies, and patient registries) for informing regulatory decision-making.
• The impact of collaboration between FDA and EMA on review/approval of drugs for rare diseases or conditions.

TYPE OF RESEARCH

A series of semi-structured qualitative interviews were conducted by National Academies staff to supplement information gathered from the published literature and public statements made by industry representatives and other stakeholders. All interviewees were asked the same set of starting questions (see methodology), which covered the following topics:

• Regulatory flexibilities, authorities, and mechanisms
• Use of alternative and confirmatory data during the review process
• Collaborative efforts between FDA and EMA
• Inclusion of pediatric populations in rare disease trials
• Use of patient and caregiver input

Coverage of these topics varied depending on time available and breadth of interviewee expertise. Information shared by interviewees was collected and summarized in this document by National Academies staff. Interviewee responses to questions were anonymized and statements were not attributed to specific interviewees or companies to protect the identification of individuals who agreed to participate and enable more open sharing of information. A more in-depth description of the methodology is located at the end of this document.

Aggregated, de-identified results of the semi-structured interviews may help inform deliberations of the committee on the study statement of task and may be included in the final published report of the committee.

Exemption from Institutional Review Board (IRB) approval for this work was obtained February 19, 2024, from the Committee to Review Human Subjects, acting as the National Academies of Sciences, Engineering, and Medicine’s IRB (#IRB00000281; expires February 17, 2026).

INFORMATION ON INTERVIEWEES

Companies represented: AMO Pharma; AbbVie; Affinia Therapuetics; Agios; Bayer; BioMarin Pharmaceuticals; Biogen; BridgeBio; Dyne Therapeutics; GlaxoSmithKline; Glycomine; Janssen Pharmaceutical Companies of Johnson & Johnson; Mahzi Therapeutics; Prilenia Therapeutics; Reata; Recordati; Roche; Sanofi; Stealth BioTherapeutics; Takeda; Ultragenyx Pharmaceutical Inc.

Roles: Clinical Development and Operations; Medical; Regulatory Policy; Patient Advocacy; Product Development; Research and Development

Invitation Summary

Company Type

FDA/EMA Experience

Therapeutic Area

INTERVIEWEE RESPONSES RE: REGULATORY FLEXIBILITIES, AUTHORITIES, AND MECHANISMS

Interview Questions

• What has been your experience engaging with FDA and/or EMA on drugs to treat rare diseases or conditions? What worked well? What could be improved upon and how?
• Based on your experience, how have regulatory flexibilities been applied by FDA and/or EMA for marketing applications for drugs to treat rare diseases or conditions?
• If you could wave a magic regulatory wand, what would you like to see change as it relates to the review and approval of drugs to treat rare diseases and conditions?

Summary of Responses Organized by Theme

Agency Structure

FDA

• Interviewees said that FDA engagement with drug sponsors seems inconsistent across divisions. They pointed to differences at the division-level when it comes to whether or not FDA grants a meeting requested by a sponsor.
• There seem to be differences in the level of engagement between individual FDA employees and a given sponsor.
• Interviewees appreciate the overall structure of the agency, which enables the same FDA staff to support sponsor engagement throughout a program’s lifespan.
• Interviewees indicated that FDA provides predictable timelines for sponsors, but the advice provided by the agency can be unpredictable.

EMA

• Interviewees said that EMA’s organizational structure and procedures for sponsor engagement can be difficult for companies to navigate.
• The decentralized structure of EMA was described by one interviewee as a “daunting and difficult process.”
• Interviewees pointed to the requirement of first engaging national regulatory bodies within the European Union before EMA as a barrier to regulatory submission.
• Interviewees suggested that smaller, pre-revenue companies may be particularly vulnerable to these types of organizational/structural barriers.
• The rapporteur process employed by EMA Committee for Medicinal Products for Human Use (CHMP) may add another layer of difficulty for sponsors.

Alignment between FDA and EMA

• Interviewees said that FDA and EMA both understand unmet medical need for rare indications and appreciate the difficulties that accompany rare disease drug development.
• At the same time, interviewees said that approaches for facilitating rare disease drug development varies between the agencies. For

• example, FDA seems to provide clearer guidance documents on rare disease drug development while EMA seems to provide more feedback to an individual sponsor.
• Interviewees who have worked with FDA and EMA described inconsistencies that may be the result of differences between the organization/structure of the agencies.
• There are cases in which the two agencies have diverging guidance – specifically statistical methodology.
• Interviewees noted that the two agencies often arrive at the same regulatory decision.

Sponsor Support

• Interviewees said that current mechanisms for interacting with FDA are generally favored by sponsors. In part, this may be due to well-defined and shorter timelines for advice from FDA compared to EMA, which may be seen as more formal and rigid in their approach.
• Interviewees noted that both FDA and EMA employ helpful sponsor support strategies. They also suggested that both agencies provide an appropriate level of guidance to help bring treatments to market.
• Interviewees said that EMA provides more detail and clarity in their advice than FDA.
• Interviewees said that meetings with regulators are helpful and can make the drug development process easier. It was specifically stated that the best alignment between sponsors and regulators come out of formal meetings. However, interviewees also pointed out that FDA seems to have made a shift away from granting meetings in recent years.
• Interviewees expressed frustration at being ‘stuck’ with a written response from FDA. A written response feedback from FDA can make it difficult for sponsors to understand the nuance of the response, which can lead to delays in bringing treatments to market.

Wish List

• Interviewees called for greater transparency in decision making and consistency in reasoning for FDA and EMA decision making, both internally and between the agencies. This type of information could cut out some of the ambiguities that slow drug development, help guide future product development, better inform the research and patient community on strategies sponsors plan to take, reduce

• duplicative efforts, and document examples of drug products that received marketing authorization approval.
• It was stated that, “readily accepting the qualification of biomarkers for accelerated approval using scientific and pharmacologic criteria would transform rare disease drug development.”
• Interviewees expressed a desire for the pediatric voucher to not sunset.
• Interviewees indicated a need for more in-person or teleconference meetings with FDA throughout the development process, timely explanations for why flexibilities were or were not applied, and increased expertise in rare diseases among reviewers.
• Interviewees noted the following changes to regulatory flexibility and the acceptance of alternative and confirmatory data:
  • Increased consistency within FDA;
  • Increased use of data from other development programs;
  • Increased use of the patient’s voice; and
  • New ways to get promising products to market.
• Consistency in the application of regulatory flexibilities within FDA was the most common request for change. Interviewees suggested that better resources for FDA reviewers and other staff would help increase consistency across the agency and acceptance of these data.
• Interviewees called for greater acceptance of real-world data (RWD) and less dependence on p-values.
• Interviewees suggested the following data resources would also be helpful:
  • Use of data from other drug development programs and repurposing of data;
  • Curated natural history data, registry data, and control data to inform the development and use of external controls; and
  • Patient experience data.
• Interviewees said increased regulatory flexibility around the use of endpoints (e.g., decreasing rigor; validating/accepting endpoints) would help to bring promising products to market.
• Interviewees said the substantial evidence needed for drugs to treat rare diseases and conditions could be altered to allow more flexibility.

INTERVIEWEE RESPONSES RE: USE OF ALTERNATIVE AND CONFIRMATORY DATA DURING THE REVIEW PROCESS

Interview Questions

• Have you incorporated “supplemental data” (e.g., data from open label extension studies, expanded access programs, natural history studies, or use of real-world data (RWD)) in submission materials to FDA or EMA? Why or why not?
• If you could wave a magic regulatory wand, what would you like to see change as it relates to the review and approval of drugs to treat rare diseases and conditions?

Summary of Responses Organized by Theme

Variability Between FDA and EMA

• Interviewees suggested that FDA and EMA are both flexible in accepting alternative and confirmatory data (ACD).
• Interviewees provided conflicting examples and perspectives that highlighted variability between the agencies on their application of flexibility and acceptance of ACD for specific drug development programs.
• Interviewees said that FDA has been less likely to use RWD, specifically for labeling decisions, than EMA.
• FDA tends to rely on placebo controls more heavily than EMA.
• Interviewees recounted instances of FDA leadership impacting agency decisions. In contrast, there seems to be limited opportunity for sponsors to engage EMA leadership.

Intra-FDA Variability

• Within FDA, there are inter-center and inter-divisional differences in the application of flexibility and acceptance of ACD.
• Interviewees expressed that FDA’s Center for Biologics Evaluation and Research (CBER) tends to be more flexible in its acceptance of ACD than the FDA’s Center for Drug Evaluation and Research (CDER). Interviewees identified neurology and oncology as areas within FDA with the greatest application of regulatory flexibilities.
• Differences in regulatory flexibility were attributed to a lack of experience with regulating rare disease products. The endocrinology

• division was specifically called out for a lack of experience in the rare disease space and lack of flexibility.
• Several interviewees noted that increased application of regulatory flexibility and acceptance of ACD seems to be spreading throughout FDA. However, there are still issues with FDA decisions and data being siloed by divisions, which may limit the ability of divisions to learn from one another.
• The lack of consistency and reliance on precedence can lead to issues for drug development given that sponsors design programs based on regulatory certainty.
• Interviewees raised the issue of inconsistency between individual reviewers. Interviewees suggested that less experienced reviewers seemed less flexible. Some sponsors have been able to circumvent this issue by engaging FDA leadership, particularly within FDA/CBER.
• Interviewees suggested that the thoughts and beliefs of FDA leadership do not seem to trickle down to the reviewer level.

INTERVIEWEE RESPONSES RE: COLLABORATIVE EFFORTS

Interview Questions

• Have you used or considered the FDA–EMA Parallel Scientific Advice (PSA) Program? Why or why not?
• If you could wave a magic regulatory wand, what would you like to see change as it relates to the review and approval of drugs to treat rare diseases and conditions?

Summary of Responses Organized by Theme

Collaborative Efforts – Parallel Scientific Advice (PSA)

• Interviewees expressed that the usefulness of PSA seems dependent on timing and need for advice. For example, PSA may not be useful for sponsors if accessed too early in development and the product is too far from the market.
• Sponsors are trying to “ask the right question at the right time to the right agency,” meaning that sponsors may need to ask a specific question to only one agency and PSA could hinder that ability.
• Interviewees said that the opportunity to harmonize feedback would be beneficial, but this would need to result in a more efficient development plan.

• One interviewee provided a favorable perspective of PSA, noting that PSA can be used to streamline the regulatory process and the company used that PSA given the significant investment in the drug development process.
• Interviewees listed issues with PSA that stem from the timing of the program, non-binding nature of PSA, misalignment of advice, and the influence of one agency on the other:
  • PSA utilizes EMA timelines for scientific advice, which are less favored than FDA timelines. Thus, sponsors view PSA as adding steps to the development process that slows the time to getting approval;
  • PSA is also non-binding which does not decrease sponsors’ uncertainty in the development process, a key aspect to PSA usefulness;
  • The distinction was made that PSA is not joint, only parallel. Thus, the agencies often provide their own advice; and
  • The misalignment of advice further exacerbates issues with timing and speed.
• Sponsors are able to leverage the differences in flexibilities employed by agencies to their advantage. They can strategically plan development in the more flexible region to improve the issues with rigidity in the other region.
• Interviewees suggested there is fear on the part of sponsors that the agencies may influence each other in a negative way:
  • There is the perception that through PSA, the more rigid (less flexible) opinion tends to prevail, resulting in a less flexible development in both regions; and
  • There is a general perception that the ‘worst common denominator’ will dominate the advice.
• Interviewee quote: “PSA meetings can be protracted, discordant, and non-binding. Sponsors need them to be rapid, concordant, and binding.”

Wish List

• Interviewees said that concordance between the two agencies is important and divergent feedback leads to fear/uncertainty on the part of sponsors.
• Interviewees specifically called for alignment on approvable endpoints and harmonization for validated biomarkers and standards for rare disease drug development. For example, a joint EMA/FDA group that validates biomarkers could be helpful, but there is concern that the “worst common denominator” may dominate

• decision making and limit flexibility on the part of the regulatory agencies. Interviewees noted that it can cost almost a million dollars to go through the steps to validate measures and noted that companies have gone out of business pursing this to “please the FDA with validation.”

INTERVIEWEE RESPONSES RE: INCLUSION OF PEDIATRIC POPULATIONS IN RARE DISEASE TRIALS

Interview Question

• Have you included or considered the inclusion of pediatric populations as part of your submission to FDA or EMA? Why or why not?

Summary of Responses Organized by Theme

Pediatric Inclusion

• Interviewees indicated that the type of disease and age of onset is the largest driver for pediatric inclusion. They said they have no issues following the regulatory pathways for pediatric studies for submission to either agency.
• Interviewees indicated that the process of starting in adults to collect data and ensure safety before moving into pediatrics works well for sponsors, but this may not always be practical in practice.
• For indications primarily among adults, it is seen as helpful to determine if the drug works before being required to conduct a study in a pediatric population by EMA.
  • Both agencies have adequate scrutiny of safety data before entering into pediatric populations.
• FDA often prefers to see RCTs in pediatrics and do not question whether children can burden a placebo control
• early on in the drug development process, sponsors submitting for approval in EMA for adult or pediatric populations are required to submit a Pediatric Investigation Plan (PIP). PIPs are a binding agreement between the sponsor and EMA which outline a development plan and identify the particular studies needed to gather the necessary data to support the authorization of a drug for children.
• One interviewee suggested that EMA uses PIPs to avoid massive off-label use of drugs and ensure sponsors complete post-approval studies to protect children from more unregulated use.

• Interviewees noted the involvement of EMA’s Paediatric Committee (PDCO), and the Committee for Medicinal Products for Human Use (CHMP) can be burdensome as they are not always aligned.
• PIP requirements are often viewed as inefficient and procedural, with interviewees stressing the requirements often cause delays in authorization by EMA which is not always advantageous for sponsors. Interviewees suggested that some issues surrounding PIPs may be a result of EMA binding PIPs to incentives (rewards linked with obligations).
• For pediatric inclusion, interviewees noted FDA has a more pragmatic approach for pediatric study development while EMA has a more conversative approach. This is in part due to the exemption from needing a pediatric plan within FDA for orphan products
• One interviewee drew upon a specific experience in which, based on recommendations from FDA, they included an additional study for pediatric safety concerns that EMA flagged as unnecessary. The interviewee noted that EMA and FDA have a mechanism to discuss and work out these types of issues.

INTERVIEWEE RESPONSES RE: USE OF PATIENT & CAREGIVER INPUT

Interview Question

• Have you invited patients and/or caregiver representatives to participate in meetings with FDA? Why or why not?

Summary of Responses Organized by Theme

Patient Inclusion

• In seeking input on how the agencies tend to approach the use of patient and caregiver input, interviewees said that their inclusion in some manner is important as it allows discussions to become more personal and the patient voice to be considered by reviewers.
• Patient input may be better utilized when it is preplanned (e.g., prospective rather than post-hoc).
• Patient involvement with FDA is sometimes seen as complicated because FDA does not require sponsors to incorporate the patient voice.

• EMA seems more formal with patient inclusion as the agency selects patient groups to be present for certain meetings and requires that sponsors verify that they have included the patient voice.

FDA

• Interviewees shared mixed opinions on the value of including patient input during program specific meetings.
• Some interviewees stated it was clear how FDA incorporated patient input into their decision making account, others noted that it is not clear, especially for written responses.
• Interviewees commented on their success with patient inclusion and noted that FDA is amenable, acknowledges the importance of inclusion, and that it helped enlighten the agencies’ thinking on topics such as unmet need and the impact of available treatment on risk-benefit ratios.
• Interviewees highlighted the potential benefit of public Patient Focused Drug Development (PFDD) meetings. Interviewees also said benefit comes from product-specific meetings, which include FDA, the sponsor, as well as patients who can provide valuable input and added context for a particular treatment.
• Interviewees expressed that they do not include patients in meetings with FDA, holding the belief that meetings with FDA and sponsors should be data driven and objective and patients may not have the expertise needed for these conversations. Instead, these interviewees opt to include key opinion leaders or clinicians and suggested that the PFDD and listening sessions are adequate mechanisms for FDA to gather patient input.
• Interviewees also suggested that meetings between patients and FDA, without sponsors present, work better than PFDD and listening sessions, given potential concerns that FDA may view sponsor-invited patients as biased.
• PFDD meetings and listening sessions are becoming the more common form of patient inclusion for FDA.
• Interviewees shared that there seems to be an overall lack of clarity on how these meetings are considered during the review process, noting that FDA could do a better job of applying the knowledge gained form these meetings.
• PFDD meetings may not be as effective as intended.
• Interviewees suggested that PFDD meetings listening sessions can be a waste of advocacy group resources as a great number of patients are needed to provide a comprehensive perspective and it may cost up to $100,000 for a PFDD meeting and $25,000 for a listening session.

METHODOLOGY

Interview Question and Guide Development

Semi-structured interview questions were developed by the committee to better understand (1) how regulatory flexibilities have been applied by FDA and EMA towards drugs to treat rare diseases or conditions, (2) the use of “supplemental data” (e.g., open label extension studies, expanded access programs, natural history studies, and patient registries), and (3) the impact of collaboration between FDA and EMA on drug review/approval for rare diseases or conditions.

The use of pre-determined questions included flexibility for follow-up questions to allow for further clarification of interviewee experiences as needed. Information gathered on the interviewees (e.g., organization type, products approved, and circumstances surrounding product approval) also helped inform follow-up questions.

During the interview, National Academies staff asked interviewees the following questions:

• Of the rare disease drug products that you have worked on:
  1. Which disease/condition or therapeutic area(s) were these products intended to treat?
  2. Do you have experience submitting a marketing authorization application for a rare disease drug product to FDA or EMA?
• What has been your experience engaging with FDA and/or EMA on drugs to treat rare diseases or conditions?
• Based on your experience, how have regulatory flexibilities been applied by FDA and/or EMA for marketing applications for drugs to treat rare diseases or conditions?
• Have you incorporated “supplemental data” (e.g., data from open label extension studies, expanded access programs, natural history studies, or use of real-world data) in submission materials to FDA or EMA? Why or why not?
• Have you used or considered FDA-EMA Parallel Scientific Advice (PSA) Program? Why or why not?
• Have you included or considered the inclusion of pediatric populations as part of your submission to FDA or EMA?
• Have you invited patients and/or caregiver representatives to participate in meetings with FDA? Why or why not?
• If you could wave a magic regulatory wand, what would you like to see change as it relates to the review and approval of drugs to treat rare diseases and conditions?

These interview questions were included in a note-taking template to standardize response recording to and simplify the analysis.

Selection of Interviewees

Recruitment of interviewees was purposive, based on their expertise in leading clinical development and regulatory submission of rare disease drug products. The following criteria were used to identify and select interviewees:

• Individuals with expertise in FDA and/or EMA regulatory policy and who have direct experience working with one or both regulatory agencies (e.g., through submitting marketing approval packets for drug products that treat rare diseases and conditions).
• Individuals who serve in a clinical development, R&D strategy, and/or regulatory affairs leadership/decision making role within a company.
• Individuals who work at companies that have applied for FDA or EMA marketing authorization for a drug to treat a rare disease or condition within the past 5 years.
• Individuals who led the clinical development and marketing authorization submission of rare disease drug products that used “supplementary data” (e.g., open label extension studies, expanded access programs, natural history studies, and patient registries) to demonstrate evidence for effectiveness.

After identifying the final list of interviewees, National Academies staff will contact selected individuals by email to inform them of the study and qualitative interview process and gauge interest in participation. The invitation email will include a subject line which clearly states that it is an interview invitation to provide input for the study. National Academies staff will attach an interview process overview and FAQ document to ensure all interviewees understand the purpose and process for participation. Interviewees will be made aware that their participation is voluntary and that they have the opportunity to retract responses up to when the committee holds its last meeting on May 23, 2024. They will also be made aware upfront that should they choose to retract their responses, all materials related to their interview will be deleted immediately.

National Academies staff assembled an initial list of 89 individuals who represent companies based in the United States and European Union and cover a range of rare disease therapeutic areas. These individuals were contacted by email to inform them of the study, the qualitative interview process, and gauge interest in participation. National Academies staff provided

documentation on the interview process and FAQs to ensure all interviewees understood the purpose and process for interview participation. An additional 6 individuals were identified from a snowballing process – individuals who received an invitation to participate in the interview process were asked for suggestions of other people who might be added to the list.

A total of 95 individuals received an email invitation to participate in the interview process. 28 of the individuals responded to the invitation and 21 individuals were interviewed by National Academies staff.

Interview Process

Once interviewees agreed to participate, 45-minute Zoom interviews were scheduled via a Calendly account with each interviewee. Prior to invitation emails being sent, all interviewees were assigned a unique identification (ID) number using the RAND function in Microsoft Excel. This enabled all internal references to individual interviewees to be anonymized after they agreed to participate.

Interviews were conducted via videoconference between February 23, 2024, and March 22, 2024, by at least two National Academies staff—one to facilitate the interview and one to capture notes in the note-taking template. When conducting each interview, National Academies staff followed an interview guide, which included an overview of the interview process and efforts taken to anonymize responses. National Academies staff obtained verbal consent to proceed with the interview and saved an audio recording for note-taking purposes if interviewees explicitly agreed to this request. If an interviewee did not agree to recording, staff would verify statements with the interviewee to ensure the notes taken during the interview were accurate. Prior to each interview, note-taking templates were labeled by interviewee unique IDs to help protect interviewee identification and anonymization of their responses.

Qualitative Analysis

Following each interview, National Academies staff reviewed notes taken during the interview and confirmed the content based on available audio recordings. After reviewing three randomly selected interview notes, National Academies staff developed a set of common themes and subthemes for each set of questions (see Interview Themes and Sub-Themes for list and description of themes). Once themes and subthemes were developed, National Academies staff reviewed and organized all interviewee responses into a filterable Excel file based on these themes and subthemes. To add context for each interviewee, the following additional information was included in the Excel file: type of company (clinical stage/pre-revenue/-

biotech/pharma), FDA experience, EMA experience, and therapeutic area. To aggregate responses, National Academies staff used the Excel file to filter responses to a particular theme and subtheme. All responses for a particular theme and subtheme were then aggregated.

Data Anonymization

All interviewees were assigned a unique identification (ID) number using the RAND function in Microsoft Excel. The key for anonymization of interviewees will be stored on the private drive of a National Academies study staff member whose laptop is password protected and requires a personal identification number and VPN application to access.

Interviews were conducted by two individuals and, as such, data could not be blinded. However, all interview materials (audio, transcript, notes, and rubric analysis) were tagged with a unique ID to anonymize responses. The following steps were used to help protect interviewee identification:

1. Once interviewees use Calendly to schedule an interview, all zoom meetings will be updated such that their name is tagged with the interviewee’s unique ID. This will help ensure that audio transcripts will be saved with the appropriate file name. Passcodes and waiting rooms will be used for each meeting to prevent unwanted third parties from joining.
2. Note taking templates will be pre-saved with interviewee’s assigned unique IDs. Within the document, only the unique ID will be used to refer to the interviewee.
3. At the beginning of each Zoom meeting, National Academies staff will change the interviewees name in Zoom to their unique ID.
4. After notes are taken, staff will delete all references to the name of an interviewee’s employer. Names of specific products discussed (both generic and trade names) will be also deleted from notes. Product names will not be mentioned in aggregate analysis to prevent external audiences from tracing responses back to the interviewee.
5. Note-taking templates will be pre-saved with interviewee’s assigned unique ID.

Data Storage and Destruction

Interview audio recordings, transcripts and notes will be stored on a private folder on SharePoint, accessible only to the National Academies study team.

Zoom audio recordings will be stored on a local drive before being moved to SharePoint. All local drive recordings will be promptly deleted after being moved to SharePoint. Following the development of interview analysis (using an inductive approach), audio recordings will be deleted permanently.

After the release of the pre-publication version of the report in August 2024, all materials containing identifiable information (e.g., the anonymization key) and de-identified meeting transcripts will be deleted permanently. The original notes and analysis will be deleted after the final electronic version of the report, prepared by the National Academies Press, is submitted to the sponsor in October 2024.

Any identifying information on interviewees will be anonymized. Only aggregated, de-identified information will be made available to the full committee. Only a summary of key themes will be included in the study’s public access file.

Interview Themes and Subthemes

Themes: The themes below were identified by using three randomly selected interview notes to identify common topics raised by interviewees in response to each question.

Subthemes: The subthemes below were identified by using the same process as above, but serve to further categorize responses within a theme. The subthemes were used to review and organize interviewee responses to each question.

Themes and subthemes identified based on interviewee responses to questions on regulatory flexibilities, authorities, and mechanisms:

Themes and subthemes identified based on interviewee responses to questions on FDA and EMA use of regulatory flexibilities and acceptance alternative and confirmatory data

Themes and subthemes identified based on interviewee responses to questions on FDA and EMA collaboration

Themes and subthemes identified based on interviewee responses to questions on inclusion of pediatric populations in trials

Themes and subthemes identified based on interviewee responses to questions on use of patient and caregiver input

Themes and subthemes identified based on interviewee responses to questions on changes to the rare disease regulatory processes

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