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Industry Survey on The Health Authority Query Management Process

The drug and biologic Health Authority (HA) application process requires submission to local HAs to secure approval for product marketing authorization. Across global HAs, the number of filings of original applications/ Novel Active Substances (NAS) and their supplements/variations is on a constant rise. At the same time, approval times have shown an overall reduction.

As a case in point, in 2022, the Centre for Innovation in Regulatory Science (CIRS) annual analysis of new active substance (NAS)¹ demonstrated that the FDA had seen a reduction in achieving review timelines to 91% of the PDUFA (Prescription Drug User Fee Act) scheduling in 2021 and an overall median approval time of 245 days according to CIRS. This is the fastest across the 6 major markets, with corresponding approval times of 428 days for EMA, 329 days for Swiss Medic, 350 days for Australia’s TGA, and 301 days for Health Canada as well as PMDA Japan. This acceleration assists the industry in reducing time to market once HAs meet all requirements.

Regardless of this positive traction, drug/ biologic application reviewers at the HA have the responsibility to look for clarifications in the application. Common problems include unexpected safety issues, failure to demonstrate a drug's effectiveness, a need to conduct additional studies, or product quality/ analytical/ manufacturing issues. HAs such as the European Medicines Agency have even issued Best Practices Guides² similar to US FDA³ to help the industry with the correct procedural approaches to respond to HA requirements.

HAs have maintained diligence in the application review process even during COVID and have since adapted to approaches in collaboration and communication with applicants. The review process includes further requests for information or clarifications required for a complete review, which can further delay approval timelines. The HAs are additionally hesitant to issue Refuse to File letters as they prefer to work with sponsor companies to ensure that the applications have full opportunity to secure a complete response and potentially approval where warranted.

These Health Authority Queries (HAQ) are also known as List of Questions/List of Outstanding Issues (LoQ/LoOI) issued by the Committee for Medicinal Products for Human Use (CHMP). HAQs (whether from the FDA, EMA, TGA, Health Canada, or other agencies) can be extensive and time-consuming for the sponsor organization to investigate and address. The process of aggregating inputs, compilation, reviewing, and preparing responses or even preparing additional analysis can vary in time and effort depending on the observation/query.

To achieve a deeper understanding, the Regulatory Affairs Digital Council conducted a survey on HAQs with pharmaceutical organizations in 2022. The survey was designed to explore how various organizations, from small to large, manage HAQs and overall effort, efficiency challenges, and foreseen opportunities from technology. This report provides insights on the survey results as potential opportunities, where a strategic approach to maximize the value of the data from these communications with HAs can aid preparedness for the future.

The survey results yielded the following key findings:

1. Across survey respondents, it is anticipated that 500 - 3,500 man-hours per year are spent responding to queries on each application filing to HAs. This range is primarily due to the scope (single country / global), volume, and type of application. Still, it can also be attributed to the effort to prepare information provided in the application. This reflects a significant amount of effort for each submission to each HA at a pharmaceutical or biologic company

2. There are 4 top challenges in preparing a response to an HA query.

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The ability to leverage pertinent insight from historical responses of products belonging to a similar drug class

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Availability of relevant subject matter experts to support a response

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Stringent HA timelines

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The question from an HA may require further clarification to ensure a correct response

With capabilities of natural language processing and learning systems growing, we are starting to see real improvements in our ability to learn from the past and respond more quickly and consistently or even prevent questions. Double Quotes

Paul Nitschmann

Senior Vice President and Global Head of Regulatory Affairs, Intercept Pharma

3. 'Manufacturing process and controls (Module 3 Quality/CMC)' is the specific functional/work area within the submission package that results in more questions. A deeper look reveals that while Module 3 of the CTD application yields the most questions, responding to these queries is less challenging than clinical efficacy and safety queries.

4. Cross-leverage of query responses between HAs is infrequent within these pharma organizations and presents an opportunity to use prior relevant information more adeptly for future potential repurposing.

5. The volume of questions is most prominently produced by the US FDA, followed by EMA and PMDA Japan, compared to other HAs globally.

6. 90% of respondents indicate that their use of technology is not advanced and indicate that basic functionality is applied without the ability to search broadly for relevant prior HAQs.

7. Quality and Compliance are the primary motivators toward improvement and digitization of the Health Authority Query Management process.

Query respondent company demographics

We surveyed respondents from 12 pharmaceutical, vaccine, and biologic organizations across the United States and Europe. The respondent pool was a mix with representation from the director level and above. Over two-thirds of the respondents belong to pharma organizations with over $20 billion US annual revenue (Image 1). Respondents were asked about the number of original applications and their supplements/variations applications filed over the course of the past two years by their organization and to clarify how many countries the applications have been submitted to. 64% of the respondents (Image 2) indicated that their organizations filed over 20 original applications in that timeframe. There is a broad range in the total filings, with half of the respondents indicating they filed at least one original application in 50 or more countries but another 33% in less than 10 countries in the past two years (Image 3).

Image 1: Two-thirds of the survey respondents belonged to organizations with over $20bn US annual revenue

Percentage of survey respondents

Image 2: Most survey respondents reported 20+ original applications filed by their organizations in last 2 years

Percentage of survey respondents

Image 3: Half of survey respondents said their organization filed at least 1 original application in 50+ countries in the last 2 years

Percentage of survey respondents

Submissions by Category and Therapeutic Area

Respondents were asked to clarify the top 3 therapeutic areas and product categories where their organizations prioritized regulatory submissions. This provides insight into which offices of the HAs are fielding more applications and the product categorization.

Overarchingly, the highest response indicated that 26% of respondents are developing for Oncology Therapeutic Areas with Rare Diseases & Haematology, Immunology, Respiratory, and Cardiovascular, all at 12% (Image 4). The recent COVID epidemic might have influenced this.

Image 4: Majority of regulatory submissions were related to oncology

Percentage of survey respondents

Product categories (Image 5) included Small Molecules, Cell & Gene Therapy, Biologics, Biosimilars, Vaccines, and Combination products. Vaccines accounted for most product categories representing 40% of the survey respondents' patterns. It is indicative of the trend due to

COVID-19. Biologics and combination products each represented the second most submissions, with 27% representing that category. Of note, Biologics can additionally be classified as combination products resulting in a recognition that biologics may represent a majority of the applications.

Image 5: Vaccines is the top product category prioritized by organizations for regulatory submissions

Variables contributing to the complexity of HA Query management

A. Submissions by Category and Therapeutic Area

The respondents were asked which HAs they considered in this survey. Respondents were further asked how much effort it takes to respond to HAQs regarding hours spent per query or overall time spent per year. The FDA and EMA were the primary HA bodies (>50 queries each) as per Image 6 that the respondents dealt with and the critical market for their respective companies.

Respondents were asked about the total effort spent by companies attending to HAQs, and from the survey results, this can extend >3500 hours to address a HA Query by some estimates. Overall ~500 - 750 hours per HA query group is most common. It was estimated that, on average, approximately 200 hours per HA query is spent coordinating, preparing, and authoring the response to each question. The wide range can be attributed to the type of question, which might require additional analysis and data preparation to address the HAQ effectively. Overall, respondents confirm that management of HAQ responses consumes significant effort and is an opportunity to drive efficiency.

Respondents clarified that they field a substantial number of queries each year relative to the size of their company and the number of markets they plan to enter. According to one respondent, the number of queries can exceed 200 per year, with an average of around 70 queries per individual application. These insights highlight the opportunities to improve efficiency in responding to queries.

Image 6: USFDA, EMA, and PMDA Japan are the top 3 HAs based on the volume of questions they ask

B. Reason for HA Queries

When asked to rank the top 3 reasons why HAs ask questions, overarchingly, the category of CMC had the most questions in focus, with 30% of respondents. In comparison, 24% of respondents verified that Clinical trial design was also a significant contributor to HAQs. This was followed by Clinical Safety at 18% of respondents (Image 7).

A discussion with respondents concluded that some questions from HAs include clarification for information already included in the applications indicating that HAs either could not locate the information or was inconclusive from their perspective. Additionally, some HA questions could be avoided through planning and preparation, which is an opportunity for the future. It is also concluded that some questions are unavoidable and may require the applicant to produce additional information/insights or sub-analysis from their clinical results.

Image 7: Quality/CMC is the primary reason for receiving HA questions on submissions

Novel approaches toward clinical trial design and submissions (RWE, Fast Track, EUA, EAP, etc.) did not impact the volume of questions. However, for Clinical Queries (Image 8), Study Design was by far the most queried reason when applying fast Track submissions.

This was followed by queries on the Study arms and control, dosing schedule, and data analysis work carried out by the company. The respondents were unanimous in their verdict that conditional/emergency uses do not impact the queries furnished by HAs.

Image 8: Study design was the most commonly queried reason under clinical questions

To further categorize HA query volumes, respondents were asked which specific functional area in the regulatory submission caused the HA to ask the most queries. Insights generated from this can allow companies to zero in on the necessary preparation for upcoming queries and mitigate against future questions. The challenges associated with this can also be further analyzed.

Manufacturing process and controls and stability studies (Module 3 / CMC) were the subjects of most queries. Queries on clinical safety studies and the clinical overview/labeling data followed this. Given the importance of correct labeling information and the heavy focus by the PRAC and US FDA on label requirements, it is not surprising that this is the most common.

Image 9: Under functional area, manufacturing process and controls was the primary area for queries from HAs

C. Impact of Breakthrough, Fast Track, and PRIME submissions on HAQ volumes

Therapies that have the potential to make significant improvements in the treatment of serious and life-threatening diseases may qualify for programs to accelerate their development (e.g., Fast Track and Break Through Therapy in the US or Prime (priority Medicines) in EMA). These programs offer more intensive communication with the HA, such as end-of-phase 1 / 2 meetings to agree on development plans and study protocols. This might lead to an expectation that many queries during the review of the marketing application are pre-empted. 100% of survey respondents have experience filing applications under one of these accelerated pathways and are therefore in an excellent position to state any exceptions. As per the survey, however, there is no impact on the number of HAQs under this category of accelerated approval pathway, which concludes in line with earlier responses that conclusions in the complete submission reveal new information for HAs to consider.

D. Impact of COVID-19 on HA Engagement

The survey asked respondents about the impact on their communications with HAs during COVID-19. Most responded that meetings with HAs were initially more cumbersome and difficult to schedule in the early days of COVID-19. There is also an acknowledgment that there has not been any discernible change in outcomes despite difficulties. Respondents disagreed with the notion that more questions were being posed. Adopting new ways of working has resulted in more effective communication, scheduling with HAs has become easier since the COVID-19 outbreak, and communication has improved. E.g., with the recent release of PDUFA VII, from 2023, the FDA allows for Type D meetings increasing the level of communication with filing organizations ⁴ .

Image 10: More than half of the respondents reported that communications and meetings with HAs were cumbersome and difficult to schedule in the early days of COVID-19

E. Efficiency in the use of HA Query responses

The ability to leverage past HA responses provides an opportunity for efficiency and consistency in creating content, format, and structure of responses. Respondents agreed that often queries addressed to one HA could be used to respond to queries from a different authority or help address queries from subsequent product submissions (Image 11). This requires a complete and accurate database of HAQs that can track the queries in a searchable manner. All respondents indicated the opportunity to repurpose responses with 33% indicating this is Very Common. Additionally, 67% of respondents indicated that insights from HAQs had influenced future product development decision-making (Image 12). The value generated from efficiency can additionally provide greater level of quality and compliance to timelines through this approach.

Image 11: Two-thirds of the respondents confirmed that they periodically use queries raised by one HA in addressing queries from subsequent product submissions or a different authority

Image 12: Future product development decision was influenced by insights from Health Authority questions, according to the majority respondents

F. Challenges in responding to HAQs

Survey respondents highlighted several significant challenges they face when responding to HAQs, including (1) a lack of clarity regarding the objectives of the queries, (2) a lack of insight from previous responses, and (3) resource capacity issues such as SME (Subject Matter Expert) unavailability (Image 13). Respondents indicated that common data sharing between HAs would greatly simplify the process. As determined previously, CMC submissions typically receive a high volume of queries; companies would benefit from standardized CMC submissions and sufficient internal CMC support. These scenarios increase the effort required to interpret, clarify, and justify responses. As a result of these challenges and the often limited time given by HAs to respond, the third most common challenge reported by 17% of respondents was the inability to adhere to timelines.

Image 13: Lack of clarity regarding the objectives of the queries is one of the most common challenges while responding to HA queries

G. Top opportunities to simplify the submission process and reduce the potential for HAQs

Respondents highlighted the desire to standardize CMC requirements and common data/document sharing across applications through a cloud environment. Project Accumulus has reported a similar finding and is progressing with an industry consortium to advance the latter capability across applicants and HAs (Image 14). Additional potential from other recommendations includes standardization of procedural requirements for filing a dossier, elimination of country-specific requirements, and simplifying insights from precedent applications.

Image 14: Standardizing CMC requirements and data/document sharing through a cloud environment were identified by respondents as key opportunities for better alignment across HAs

Future Opportunities through Digital

82% of respondents to the survey answered that Regulatory Information Management systems or similar technologies are currently used to capture, manage, and create insights from HAQs (Image 15). It was also concluded that advanced features are currently not present, and some approaches may be MS Excel (Image 16) based. Most respondents noted they could not get competitive insights or references to HA policy/ regulation.

Image 15: Majority of respondents are using Regulatory Information Management systems or similar technology to manage HA queries

Image 16: 'Enabling a searchable and centralized repository of previous HA queries is the most valued feature in RIM/Digital tools

(Scale: 1 – Not at all useful, 2 – Somewhat useful, 3 - Very useful)

Digital Maturity of HA Query Management

Survey respondents expressed the need for a digitally organized HA Query management solution that provides the following

1. Easy search and reporting capabilities

2. A searchable and centralized repository of previous queries

3. Trend analysis of similar questions

4. Intelligent search capabilities

5. Cross-platform searchability

6. Knowledge management and data integration

7. Efficiency and the ability to upload information from spreadsheets

Complementing this information, 80% of respondents ranked their digital maturity as Basic on a 3-point scale toward a transformational capability in HA Query management (Image 17).

Image 17: The majority of respondents ranked their digital maturity as basic on a 3-point scale in HA Query management

Objectives to Achieve Outcomes

31% of survey respondents confirmed that a clearly defined ROI is needed to support the digitization of HAQ management. The lack of deployment of these functionalities suggests it may be difficult to justify, even in large organizations. However, digital maturity toward connected systems of use and approaches to quantify impact will support a business case for organizations seeking to move toward a transformational HA Query management process (Image 18).

Image 18: Lack of clearly defined ROI is the top organizational constraint in adopting advanced technology for HA query management

Recommendations

Opportunities in the submission process abound with many organizations progressing toward digital regulatory affairs. Three main areas that are being addressed across organizations that will support HAQs include approaches toward (1) Cloud solutions, (2) Collaboration, and (3) Initiatives in automation to deliver efficiently. Forward-looking initiatives to drive further intelligence and insights will also continue to be a focus. In summary, the opportunities are as follows

Cloud Solution examples

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Regulatory agencies and applicants interact with the data and communicate with each other.

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Unified requirements and reviews; standards for data and documents; joint inspections etc.

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Alignment of query process across HAs and sharing questions and responses.

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Cloud-based applications; transparency in operational aspects of the review process

Collaboration examples

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Sequential data availability during development for a rolling review of the development program

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Sharing of questions and responses across different HAs

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Identify recurring themes and avoid questions from future submissions

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Knowledge sharing across organizations to align on the requirements and activation plans

Efficiency / Digital / Automation examples

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Automate the workflow of receipt, classification, and distribution of HAQs

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Catalog queries/responses and include recommendations for actions

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Automate responses and pull relevant data into draft responses

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Identify relevant regulations and guidance

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Analytics from past challenges in submissions

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Standardization of Regulatory requirements across HAs

Conclusion

Collaboration with HAs globally is an essential process toward assurances of the safety, efficacy, and value of products seeking market authorization for commercialization. The exchange of submissions application information for new products and corresponding feedback from HAs post application includes the inevitable response to queries from HAs. Regulatory Affairs Digital Council explored all areas of HA Query management: (1) Root cause of those HA questions, (2) Challenges to respond, (3) Approaches toward addressing the process and information from these questions, and (4) Future opportunities. The detailed survey analysis indicates that HAQs are an inevitable outcome of the HA review feedback. However, approaches to deliver more effective management of the entire process, leverage of insights and precedence information, future approaches toward digital, and ongoing collaboration with HAs provide immense improve this critical regulatory activity. Outcomes of digitalization of this process can provide primary value through efficiency and secondary impact which can drive greater compliance and quality of deliverables.