The information shared here is from a book chapter Melissa co-authored with Dr. Deb Billings Broky on human factors for combination products that will be published later this year in Human Factors Regulations and Standards in Combination Product Development: IEC 62366 and FDA Guidance Documents, within Development of Biopharmaceutical Drug-Device Products.
Chapter on human factors regulatory considerations for combination products
Combination products are increasingly being developed, prescribed and used to treat health conditions within clinical and home settings, including for both healthcare professionals and non-professional patients and caregivers with various abilities, limitations, and prior experience with drug products. The user interfaces of drug delivery products such as syringes, auto-injectors and inhalers may seem relatively simple to design, especially compared to complex medical devices such as diagnostic systems, mobile health apps and web portals, etc. However, combination products often pose unique design challenges due to factors such as diverse use environments and users, potential for negative transfer causing incorrect performance with a new product due to previous or simultaneous use of other drug products, and limited opportunities for manufacturers to provide consistent product training to end users. Furthermore, FDA and other international health authorities have specific expectations regarding human factors pre-market submissions and post-market surveillance for sponsors to demonstrate that a product is safe and effective in the hands of end users. Thus, human factors engineering is a critical part of the product development lifecycle and market success. Implementing a successful human factors program for combination products requires in-depth knowledge of best practices and correct application of principles to avoid the pitfalls that sponsors of combination products often find themselves trapped in.
Applying sound human factors processes to medical device design will optimize safety, effectiveness, and overall user satisfaction with a product. Although human factors engineering is an established science with various standards and guidance specific to medical device development both in the U.S. and internationally, human factors guidance is not prescriptive in nature. Sponsors often incorrectly assume that human factors guidance is a “recipe” that will yield a safe and effective product leading to regulatory and commercialization success. However, human factors guidance is not a “cookie-cutter” approach and should not be blindly followed for the sake of checking off a box, as evidenced by the low percentage of human factors submissions that receive FDA approval the first time (e.g., only 4-10% of human factors 510(k) submissions are approved without deficiencies or requests for further information).
Agilis has nearly 20 years of experience with regulatory human factors submissions, and our clients have never had our human factors methodology rejected by a regulatory reviewer. We work with our clients to achieve a safe and optimized product for end users by correctly implementing human factors methodologies and tailoring the processes to each unique product, which require human factors expertise. Agilis has extensive medical device human factors and instructional design experience and refined best practices that we apply through a sound engineering process to help our clients develop optimized user interfaces as well as successful regulatory submissions. We are always excited to partner with clients in their design efforts to best meet the needs of end users, and here we offer some of our insights from a chapter that I co-authored with Dr. Deb Billings Broky that will be published later this year: Human Factors Regulations and Standards in Combination Product Development: IEC 62366 and FDA Guidance Documents, within Development of Biopharmaceutical Drug-Device Products, edited by Drs. Feroz Jameel, Robert R. Nesbitt, and John W. Skoug.
The chapter discusses foundational human factors principles for sponsors to consider during development of combination products, as well as strategic strategies for implementing successful human factors methodologies. For example, CDER’s definition of critical tasks includes “harm” as compared to CDRH’s definition that includes “serious harm” as a possible outcome for task failures. CDER’s broader definition often translates to a higher number of tasks that are categorized as critical for drug delivery products, which can impact the nature of human factors strategies for regulatory submissions. For example, sponsors may see FDA being concerned with the residual risk analysis or overall conclusion of the safety and effectiveness of a product if data show patients experience a missed dose or incorrect doses of medication, even if these use errors do not necessarily lead to patient injury or hospitalization. Note that U.S. FDA guidance and international standards are aligned in many ways including identifying critical tasks to identifying and describing hazard-related use scenarios, use errors, and tasks (including sequences and severity of harm) to determine which tasks to include in a human factors summative evaluation or validation study. Ultimately, the human factors “story” throughout the development of the product (iterative human factors process) becomes key in establishing to regulatory authorities that the user interface is optimized for use-related safety and effectiveness.
Agilis has extensive experience helping clients navigate the challenges encountered when human factors engineering is applied to the development of drug delivery products, such as accounting for potential negative transfer, conducting studies to ensure effective data-driven design iterations, and creating effective instructions for use, quick reference guides and packaging. Some specific human factors strategies for combination product development that we have found to be helpful for ensuring optimized user interfaces and successful regulatory submissions include:
(1) Start the human factors process early. Implement human factors prior to clinical studies, while selecting device partners, and prior to the summative validation study.
The application of human factors engineering (formative and validation studies) prior to clinical studies is important because designs that users cannot understand or correctly use during a clinical trial may negatively impact or delay the clinical study results. Human factors with the intended clinical user interface will help optimize the labeling, training, and product to help avoid potential adverse events and better ensure the quality of clinical data.
Another important opportunity for early consideration of human factors for combination products is prior to the drug developer selecting the device partner. It is important for sponsors to consider and evaluate prior and ongoing human factors data when selecting device partners, because after a partner is selected it may be too late to effectively address use errors and difficulties that the device design introduces for end users.
Initiating human factors at the point of the summative validation study drastically increases the risk of the validation study turning into an expensive (for both the budget and timeline) formative evaluation due to unmitigated difficulties and use errors. Formative evaluations are a valuable opportunity to test the user interface design mitigations to ensure they are effective in preventing harm to users as well as to assess the summative validation study methodology design.
(2) Leverage applicable prior human factors work when developing multiple combination products that have similar device designs, users, user environments, and uses. Consider conducting threshold analyses to identify gaps in use-related risks.
Oftentimes if sponsors are developing multiple delivery devices for the same or different drugs, there is a good opportunity to leverage prior human factors work and findings throughout the design process. It is important to consider this approach early and to seek out cross-functional approaches to leveraging prior work. The human factors strategy can also be streamlined by using prior use-related risk analyses from similar devices to prioritize human factors evaluation of unique tasks or design features without being excessive or burdensome. However, it is also important to assess if the new product has any unique use cases, use scenarios, or tasks as well as different users or use environments, labeling designs, branding, or other unique features of the user interface that may warrant additional testing with the new product.
Threshold analyses are another type of human factors analysis that can leverage prior applicable human factors work to present an argument to FDA that no summative validation data need to be submitted (if findings support this conclusion). Based on FDA’s recently published draft guidance (September 2018) entitled “Contents of a Complete Submission for Threshold Analyses and Human Factors Submissions to Drug and Biologic Applications,” threshold analyses examine the differences in use-related risks between a new product and existing comparator product(s) (i.e., defined as products on the market with similar intended users, user interface elements, and user-device interactions). Working under the assumption that FDA-approved comparators are both safe and effective for intended users, a sound threshold analysis with adequate comparisons and rationales may be accepted by FDA as evidence of safe and effective use if the new or updated product presents no more use related risk than existing products on the market. Agilis recently presented our successful process and case studies with conducting threshold analyses that were accepted by FDA. (Click here to request the Agilis presentation)
(3) Collect labeling-focused data prior to the human factors summative validation study.
Instructions for use (IFU) and other instructional materials like quick reference guides and product packaging often are important risk mitigations for drug delivery products, especially when sponsors are constrained by device designs that cannot be changed. We also have seen cases where labeling may be an important mitigation for users within nonclinical environments, which makes labeling a critical part of the user interface to support safe and effective use. During human factors validation testing, FDA guidance indicates participants cannot be directed to use any instructional materials to assist them in performing tasks because this is not representative of actual use. Sometimes participants do not look at the instructional materials during simulated use validation testing, which raises the question: How can sponsors ensure the IFU or other instructional materials are safe and effective parts of the user interface?
Agilis recommends confirming if the IFU and other product labeling are safe and effective prior to the human factors summative validation study by conducting formative testing where participants are specifically directed to reference and use the labeling as they complete tasks and answer comprehension questions. With this approach, sponsors can ensure the labeling is optimized and can confidently say that when the labeling is used, it is safe and effective.
Human factors engineering is an important part of combination product development, and regulatory bodies have increasing expectations for human factors data to demonstrate a product user interface is safe and effective in the hands of end users. Although unique issues can emerge during the development of drug delivery product user interfaces, Agilis has helped our clients navigate the dynamic challenges with the application of a variety of human factors formative methods to optimize the user interface and ultimately generate successful human factors summative validation studies and regulatory submissions. We work with our clients to achieve safe and optimized products for end users by correctly implementing human factors methodologies, and our expertise has helped our clients submit human factors evidence that has never been rejected by a regulatory reviewer.