As discussed in the first part of this article series there are three important device development activities that are frequently overlooked or underestimated by drug manufacturers in a combination device project. From a project planning perspective, these activities should drive key project milestones, during a combination product development phase of the product lifecycle. This part of the article series covers these keys in more detail.
Key Activity 1: Manufacture of the devices for the development lifecycle:
An important integration point between the drug development timeline and device development timeline to consider is the device build milestones that are needed for each clinical trial. Multiple device builds will be intended for the assessment of safety, effectiveness and include device performance. The Phase 1 clinical requires attention to safety, but later clinical objectives require the device manufacturer to assure the devices used meet important effectiveness criteria to provide assurance in the conclusions of the clinical studies. Devices used in phase 2 and 3 clinical trials require building devices with a known configuration and a configuration management process to be in place.
A pragmatic device design process includes iterations or phases of controlled design, the evaluation and optimization of the design based on specific controlled inputs (or requirements) as well optimization of outputs to address performance as the development commences. The outputs of the design during iterations or phases should be managed and have defined configurations. If the configuration is unmanaged or unknown the design progresses and changes, and perceived improvements and optimization is not controlled or managed. Device development without configuration management would be considered an uncontrolled development. Making changes to a device in this type of an uncontrolled development is no better than ‘trial and error’ development. Confidence in the design and in the future performance of the device is more difficult to assess without some design controls. Device developers find that changes to the design based on results from an uncontrolled system result in incorrect conclusions which lead to development delays due to erroneous data or conclusions.
A configuration management process starts with identifying the items that are to be maintained under configuration control. Configuration management includes the tracking, control, baselining, storage and providing for the controlled change of defined items. Typical items that will require configuration management are: records/documents (i.e. requirements, design descriptions or specifications), material composition, software versions/builds, hardware versions, sub-systems, assemblies, and components, manufacturing test systems, calibration methods, as well as test units and units under test themselves. A procedure or plan should identify how a particular configuration item is to be managed. Within a project configuration, items will be developed and updated. These configuration items are defined by documents that are to be controlled. It should be determined which documents and items are to be controlled and when, as well as the process to keep items and documents in sync and a process for how changes are made. Typically an effort to sync configuration documentation should be made part of each iteration or phase planned for.
Key Activity 2: The planning for usability:
Another important integration point between the drug timeline and device timeline to consider is device usability. The FDA frequently states that manufacturers don’t adequately consider use errors, and this leads to clearance issues with the FDA. The FDA is particularly concerned with medical device developers addressing human factors in their design and testing their design in usability studies to address use errors. Planning the usability studies on the timeline is important to the overall planning of a combination device.
Formative usability testing can be aligned with the timing for some the phase 1 and phase 2 clinical studies done with potential patients and users. Formative testing is used to drive the determination of the design as well as help to capture requirements for the user interface, etc.. Test and evaluations with users and potential patients should be focused around device tasks were anticipated safety is involved and areas where the interaction with the user may be particularly complicated. The evaluation or testing really allows the developer to explore and understand the design options to better suit use conditions and better meet user and or potential patient needs. Drug and biologic design lifecycle is longer, but not planning for formative usability of the device will result in delays much closer to the end of the drug development.
Usability analysis does not just focus on device failure hazards; it also includes identifying and applying measures to eliminate or reduce use-related hazards. These hazards might result from aspects of the user interface design that cause the user to fail to adequately or correctly perceive, read, interpret, understand or act on information from the device.
Screens used for the human interface can be presented and prototyped, in a rapid fashion using high language tools and graphics development kits. When necessary a graphical user interface (GUI) can be generated and quickly evaluated before device function is needed in the development lifecycle for the device. These rapidly developed screens can then be integrated into the device design at a later step of the development process.
The final usability study/test is referred to as the summative usability study. Summative testing are tests with users to validate the final configuration meets the user need and provide for safe and effective use.
Key Activity 3: The coordination and application of design controls to address sources of variability:
Another important set of key activities is applying device development controls and practices to address product variability and performance. The FDA regulatory design controls are defined per the regulation part 21 CFR 820.30. When the device is defined, designed, built, analyzed for risks, verified and validated can all be plotted along the device development timeline. The device design part of the lifecycle can take many different forms, such as more of a serial set of phases or more iterative set of design builds and these can be represented in the project timeline as corresponding milestones as a device design is developed.
Much of the challenge of scheduling of the design of the device is the uncertainty associated with proofing design output solutions, identifying tasks to target project risks, factoring time to solve problems and driving out variability. Optimizing the design comes down to determining the best technical solutions to meet the needs of the users and the requirements. A good design control process provides managers and designers with clear visibility of the design process and the objectives targeting a short cadence of accomplishments. Having a short manageable time frame of tasks and good visibility of the goals for that time frame allows the team to react and effectively manage the design process. Within a timeframe, a team can specify the need/activities to be addressed, identify the problems to solve and the associated project risks than in the timeframe formulate solutions or make corrections to the current design and then evaluate or verify the intended objectives are met and characterize the performance of the solutions.
The project manager for a combinational device should look over the horizon and plan activities and milestones in a schedule to target the effort in a controlled process. To address the most significant risks in a device a controlled process should be put in place to target the sources of variability.
One approach to targeting sources a variability in the combination product
Based on experience the development lifecycle the management of project milestones and its integration points help to ensure the development team stays on target. As the project progresses and objective driven milestones are reached, project risks associated with milestones are being reduced. Similarly, setting device performance milestones can also positively impact variability in the design outputs. What is difficult is planning for what is unknown as the design evolves and iterations are measured.
In a nimble development model applying iterative cadence to define the goals, measure the outputs, analyze the resulting data, and optimize the design has the best results. Successfully driving this controlled cadence is effectively achieving a design control. One approach to driving this cadence in the development lifecycle should be the adoption of scheduling a set of milestones to address the variables that contribute to uncertainty and variability in the important product characteristics and primary mode of action.
At these milestones the evolution of the device/system should include meeting the functionality goals, characterizing and measuring operational outputs as well as optimizing them to meet the performance needed or expected by the end users. The project schedule can be developed indicating the milestones across the list of tasks used for resource management as in the case of the simplified figure below.
(milestones schedule figure)
The simplified Gantt presents a project schedule that is driven by achieving target milestones. These milestones are not going to be the same for each project. They should be determined by considering the overall timeline, the major phases of the drug and device clearance process, and identifying key activities and setting goals and quantifiable objectives to resolve these. Frequently key milestones come from a project risk evaluation that is part of the initial planning process and is consistently evolved through the project, much like the schedule is.
The next section of this article series will dive deeper into sources of variation and how software in a medical device is part of the variation challenge and solution. We would be interested in your own experiences with milestone planning and on tackling key activities in a combination medical project. Please add your comments or questions to keep a dialog going.