Key Takeaways of FDA and CRCG 2024 DDCP Workshop: When Might "Other Design Differences" Be Justified Without a Comparative Use Human Factors Study (CUHF)?

Summary and Key Takeaways of FDA and Center for Research on Complex Generics (CRCG) 2024 Drug-Device Combination Product Public Workshop (Symposium III, Topic 2 Interactive Working Sessions) When Might “Other Design Differences” Be Justified Without a Comparative Use Human Factors Study (CUHF)? Corresponding to FDA's 2017 Guidance for Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device Combination Product Submitted in an ANDA.

On March 14th and 15th, 2024, our HFUX Research founder, Heidi Mehrzad, had the privilege and honor to be invited by FDA and the Center for Research on Complex Generics (CRCG) to attend and co-facilitate at their March 2024 Drug-Device Combination Product (DDCP) Workshop titled:

Drug-Device Combination Products: 

Updates and Challenges with Demonstrating Generic Substitutability

Complex drug-device combination products (DDCP) provide end-users with important drug treatment options. Availability of high quality generic DDCPs is essential for making these therapies accessible to more Americans, but there are challenging regulatory and scientific obstacles that may hinder the development and timely approval of generic DDCPs. As DDCP complexity increases, so do the challenges of product development and establishing therapeutic equivalence. From a user interface (UI) standpoint, ANDAs for DDCPs should include comparative analyses (CA).

When CA identify “Other Design Differences” between the user interface of the proposed generic combination product as compared to its reference listed drug (RLD), the applicant may need to provide data and/or information to justify that potential use errors related to the design differences do not preclude a finding that the proposed generic combination product and the RLD can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.

WORKSHOP and WORKING SESSIONS OVERVIEW

The workshop intended to discuss the myriad of challenges currently impacting the development and assessment of generic DDCPs. The event included five symposia, and as part of Symposium III, in-person attendees were divided into four interactive working sessions (Topics 1 to 4) to address four challenging aspects of identifying and assessing design differences in user interfaces between a proposed generic product and its reference listed drug (RLD).

The 2-day hybrid (virtual and in-person) workshop was focused on addressing current challenges associated with developing complex generic drug- device combination products (DDCPs).

The first day of the event included three symposia:

• Symposium I: Understanding the Landscape and Challenges for Development of Generic Drug-Device Combination Products,

• Symposium II: Assessment of “Other Design Differences” for Generic DDCPs: Current Challenges and Future Opportunities, and

• Symposium III: Setting the Course for the Generic DDCP Future.

During the Symposium III interactive working sessions, each in-person attendee participated in two interactive working sessions, i.e., two topics, to identify challenges, knowledge gaps, and resources needed to address four challenging aspects of comparative user interface (UI) assessments:

1. Topic 1: Minor vs. Other Design Difference – Learning to speak the same language.

2. Topic 2: When Might "Other Design Differences" Be Justified Without a Comparative Use Human Factors (CUHF) Study?

3. Topic 3: Designing and Executing CUHF Studies - Choosing Study Population(s) and Statistical Methods.

4. Topic 4: Building a More Informed and Flexible Comparative User Interface Assessment Landscape.

Topic 2: When Might "Other Design Differences" Be Justified Without A CUHF Study was co-facilitated by our founder Heidi Mehrzad, together with Claire McDiarmid and FDA’s very own esteemed Irene Chan and Michelle Lin.

The working sessions were intended to help define an approach to resolve major issues in each topic area, as well as identify the challenges, gaps, and next steps to inform a “roadmap” for the activities of a future CRCG expert committee that will work collaboratively with the FDA to address the challenges and knowledge gaps in comparative user UI assessment through research and other means.

SUMMARY of TOPIC 2 WORKING SESSIONS

At the beginning of Topic 2 'When Might “Other Design Differences” Be Justified Without a CUHF Study' interactive working sessions, co-facilitators clarified that the primary goal of such was for the group to aim together at answering the question: What are the drug product factors and use context factors that inform the types of data and information that can support an “Other Design Difference?” by sharing and discussing ideas freely with co-facilitators and attendees, whilst not focusing on CUHF (study) methodologies.

FDA's 2024 GDUFA Topic 2 Working Sessions Goal: What are the drug product factors and use context factors that inform the types of data and information that can support an “Other Design Difference?”

To begin the discussion on when might “Other Design Differences” be justified without a Comparative Use Human Factors Study, co-facilitators initially presented FDA’s official definition of “Other Design Differences.”

FDA's 2017 ANDA Guidance for Comparative Analyses and Related Comparative Use Human Factors Studies

Co-facilitators continued by asking attendees to share examples of “Other Design Differences" they might have worked on previously as well as list some of the most common ones they have encountered, e.g., difference in number of steps to administer/ use the drug product. Some attendees provided instances where multiple differences could be at play, e.g., shape/size, visual/audio cues, etc. The in-depth discussion on what is an “Other Design Difference” and what it constituted, functioned to provide attendees the framework to continue in individual breakout groups in which each group selected one “Other Design Difference” that was raised and brainstormed on what type of information and/ or data might support the justification of such a design difference without the need for a comparative use human factors study (CUHF).

Attendees were given a list of context questions to help facilitate their breakout sessions:

• Is the product being used in an emergency use vs. chronic use scenario?

• Who are the users?

• Where would the DDCP be used? What is the environment of use?

• Regarding risks: Did the drug product (drug constituent part) have a narrow therapeutic index?

• What are the potential use errors for this difference?

• How would you apply this information/data?

• Why do you think this is scientifically supportable?

• Would this apply to all use scenarios and all user groups (e.g., emergency vs chronic use, adult vs pediatric population)

• Are there other considerations that we should account for?

TOPIC 2 WORKING SESSIONS OUTCOMES

FDA 2024 GUDFA 'When Might "Other Design Differences" be Justified without a CUHF Study?'

What were participant drivers for attending this session, and what were they most interested to learn from it?

• Make sure we are conducting CUHF correctly.

• What is changing regarding DDCP.

• Learn about “Other” differences, how to approach and test it.

• Share experiences and explore options.

• Increase confidence of doing something other than CUHF.

• How to derive at other approaches.

• Parameters around CUHF: cost and time.

• Understand peers’ challenges across the field.

• Align/find consensus in language used.

• Learn about alternatives to CUHF.
  

Why would they want to seek alternatives for a CUHF study?

• To meet customer timelines/requests (e.g., using off the shelf devices),

• To potentially save time and cost,

• To understand why CUHF is needed when alternative data is available (data provided was not accepted by FDA), and

• To commercialize DDCP faster and/ or at all.

What were examples of “Other Design Differences” they worked on or encountered?

(Ones bolded and in blue below were selected for the breakout sessions.) 

1. Resetting Button (proposed generic does not need reset)

2. Extension of Dose Button on Pen Injector when the reference does not extend

3. Number of Activation Use Steps (Autoinjector)

4. Different Graduation Marks

5. Different Color Coding (of graduation marks/ or device overall)

6. Autoinjector (reference) to PFS

7. Pen Injector – Pull Push vs Push or Slide Button

8. Pen Injector – Change the number of Steps to Dial Dose

9. Autoinjector – Cap vs. No Cap

10. Pen Injector – Different Locking Mechanism (to avoid accidental injection)
    

What were the main findings of the breakout groups during their discussion of selected examples?

(Points below directly reflect attendees feedback and do not represent any type of priority or analysis of research value and/ or views or opinions of FDA or co-facilitators.)

2. Extension of Dose Selection Button Difference impacts multiple tasks: (1) Selecting dose, (2) administration. One consideration is looking at device performance: Under-dial vs. Over-dial. Use Anthropometric/Biomechanics data to support difference – studies on hand strength, breaking down movement into subsystems are available. Use FOIA Review/Study Data on Similar Device. Specific details (e.g., sample size, study design, etc.) of the available data is important to determine whether it can support the difference. Is post-marketing data meant to answer regulatory questions around substitutability? What about real world data on safety? Looking at public medication error data. Available clinical data error may demonstrate that the difference does not impact risk. 6. Autoinjector to PFS Considerations: cost, dose window, plunger vs. button to administer dose, training, feedback when injection done, needle gauge and length. Alternative approach: use existing real-world data, validation study, performance study, and biomechanical data (rate of dose delivery and force). 9. Autoinjector – Cap vs. No Cap Cap vs. no cap (omit a task): assumption is the RLD has a cap, while the T has no cap. This design difference for the emergency use product will be an “Other.” But if it’s a standard and chronic use product, it can be “minor” depending on the context of use (environment, patient population). Note: that there will be a learning effect (1st time will takes more time to figure out for proper use but will reduce the time of delay) with assuming any training is not provided for the patient (illustrated instructions will be helpful). Use error includes device damage and patient harm (needle stick). Alternative approach: 2-Arm study between the focus groups of RLD user vs. naïve. If risk identified, the validation study can be a steppingstone for the next step (whether will be go the CUHF study or not, or redesign). Use real world/published/adverse event data to show the safety data. Heuristic analysis informing URRA.

3. Number of Activation Use Steps (Autoinjector) RLD has 4 steps vs 2 steps generic. If same use scenario; same user representation, then use other supplemental data such as: Rely on another ANDA’s approval that evaluated similar scenario. Could there be a research project in this space (BAA)? 4. Different Graduation Marks Considerations: The End-user (Healthcare Professional vs Patient vs Caregiver). Patient age perspective with the cognitive abilities (adolescent, caregivers, senior). Disease state could impact reading of graduation marks (diabetic, vision). Other co-morbidities that could impact the use of reading the graduation marks. Looking at public data available with similar generic products on the market. Some caveats to this and depend on the specific details of the paper/data. Use biomechanics/anthropometric data. Data gathering to power statistical study to specifically look at this attribute and gather data on negative transfer. Fill in the gaps with other data (supplemental data) to justify this “Other Design Difference.” Conduct “rigorous” formative study using theoretical sampling of the most sensitive population in respect to not do a CUHF study. Have your parameters set and structured to see if it was employed in real life, there’s a strong confidence you’d see the same result in the real-world setting. Include supportive data built on the risk analyses. 7. Pen Injector – Push Pull, Push, or Slide Button Whether the difference is an “Other Design Difference” depends on the context of use. Perform URRA to inform risk and guide next steps. If it improves the user interface, CUHF study may not be required. Analytical data (e.g., in vitro study) to support the “improvement.” Alternative approach: validation study (recruit existing user), results help inform next step: Residual risk study for informing decisions regarding safety and usability.

KEY TAKEAWAYS of TOPIC 2 WORKING SESSIONS DISCUSSIONS

• Context is IMPORTANT.

  • Participants noted that for any of the examples, they could be considered “Other Design Differences” depending on the context for use of the product. For example, for emergency use products, all tasks might be considered critical, so a difference that impacts any of the tasks would be an “Other Design Difference.”

• Use-Related Risk(s) Should be a Key Driver in Strategy Selection for Alternative Approach.

  • Participants noted that understanding the use related risks associated with “Other Design Differences” is important to informing how much and/ or what type of evidence or data may need to be submitted to support the “Other Design Difference.”

• Considering Multiple Types and Sources of Data or Information to Support “Other” Differences is Important.

  • Participants discussed that when using multiple types or sources of data or information, it’s important to provide a comprehensive and cohesive story for FDA to follow your reasoning for classifying a difference as “other” and why your corresponding data provision is appropriate.

• Can a 2-Arm Human Factors Summative (Validation) Study be Used?

  • This was a question that participants were interested in exploring. They wanted to know whether FDA would be open to this. Some discussion noted that in some cases, a validation study plus a residual risk analysis should be sufficient to support the “Other Design Difference.” Others noted that depending on the findings of the validation study, additional steps may be needed, such as re-designing the user interface or proceeding to another study such as a CUHF study.

• Other Types of Data Should be Allowable.

  • Participants were interested in exploring how data collected in clinical trials, real-world data, or postmarket surveillance data might also be used to justify the acceptability of “Other Design Differences.” The conversation also noted that in some cases, sponsors should be able to rely on data generated by other sponsors or based on the agency’s awareness of data from other sponsors. This raised questions about reliance and rights of reference, and it was noted that this may raise some legal implications.

Access to the workshop recordings and slides and to learn more about the entire event, including its speakers' and facilitators' biographies, can be found HERE.

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DISCLAIMER: The outcomes of the working sessions directly reflect attendees feedback and do not reflect any type of priority, analysis, or research value; nor do they reflect any opinions by FDA or HFUX Research LLC or its affiliates. Neither FDA or HFUX Research LLC, nor any of its employees or representatives make any representation or warranty, express or implied, as to the accuracy or completeness of any information contained herein (in this post). The information and examples provided in this post originate directly from individual experience of workshop attendees and shall be used as examples for discussion purposes only. Nothing contained within this post is, or should be relied upon as, a promise or representation as to the future and HFUX Research LLC expressly disclaims any obligation to update the information if it should change.