In our previous blog “Using Technology Readiness Levels to Manage Risk” we introduced the concept of Technology Readiness Levels (TRLs). In that article, the basic descriptions for TRLs as used by NASA and the Department of Defense (DOD) were presented. We also mentioned that TRLs descriptions have have been developed for all types of products: spacecraft, weapon systems, software, pharmaceuticals (drugs, biologics, vaccines), medical devices, etc. While the wording in the definitions may differ for different types of products being developed, the concept is the same.
In a 1999 report, the United States General Accounting Office (GAO) stated that the level of maturity of a new technology being incorporated into a product development program is related to the success of the program; that is, the higher the level of readiness of critical technologies when incorporated into a product, the greater the probability for a successful outcome.
The US Army Medical Research and Materiel Command (MRMC) used the basic TRL descriptions (shown in the previous blog) to develop TRL descriptions for the development of medical devices based on consideration of the applicable Federal Drug Administration (FDA) regulatory process along with industry practices and experience with their research and development (R&D) processes (discovery through manufacturing, production, and marketing). In developing these descriptions, the MRMC used external anchors such as “FDA events” wherever practical to define each TRL level. The MRMC intent was to describe activities as occurring between successive TRLs to exemplify the kinds of activities that routinely take place when maturation is sequential and stepwise in the development of medical devices.
Note: THE MRMC cautioned that the medical device TRLs they developed are not to be considered absolutes, and characterization of activities associated with the TRLs may vary. Project managers need to work together with the regulatory agency in exercising discretion in the selection, progression, and timing of specific activities to be accomplished in attainment of the various TRLs. This flexibility and tailoring are needed to appropriately align the TRL level with the maturation and risk characteristics of a particular technology, including consideration of the associated investment strategy and transition procedures that may vary among project managers.
The key point is that the lower a critical technology’s TRL when transitioning from technology development to product development, the greater the risks. For medical technologies, risk reduction is not linear across TRLs. The rate of risk reduction remains very low until very late. The MRMC stated that historically, FDA-regulated products do not achieve significant risk reduction (i.e., >50%) until completion of clinical trials. They also made the point that, although technology maturation is commonly perceived as a sequential continuum of activities from basic research, through development to production and deployment, evolution of the TRL for a critical technology may not be sequential — the change in TRL may be greater than a single TRL.
Medical Device TRL Definitions
The nine TRL descriptions developed by the MRMC as they apply to medical devices are shown below. The TRL definitions pertain predominately to Class II and Class III medical devices (see 21CFR860.3 for device class definitions) that are subject to approval via the Premarket Approval (PMA) process. Devices that are subject to approval via the 510(k) process (Market clearance; generally limited to certain Class I and Class II devices) may not require all of the studies described, and only require an Investigational Device Exemption if human studies are necessary.
These definitions are provided only as an example. If you choose to incorporate the concept of TRLs to product development approach, you need to tailor these descriptions to reflect your organization’s system engineering processes, culture, product line, and current regulations and standards.
- Lowest level of technology readiness. Maintenance of scientific awareness and generation of scientific and bioengineering knowledge base. Scientific findings are reviewed and assessed as a foundation for characterizing new technologies. TRL 1 DECISION CRITERION: Scientific literature reviews and initial Market Surveys are initiated and assessed. Potential scientific application to defined problems is articulated.
- Intense intellectual focus on the problem with generation of scientific “paper studies” that review and generate research ideas, hypothesis, and experimental designs for addressing the related scientific issues. TRL 2 DECISION CRITERION: Hypothesis(es) is generated. Research plans and/or protocols are developed, peer reviewed, and approved.
- Basic research, data collection, and analysis begin in order to test hypothesis, explore alternative concepts, and identify and evaluate component technologies. Initial tests of design concept, and evaluation of candidate(s). Study endpoints defined. Animal models (if any) are proposed. Design verification, critical component specifications, and tests (if a system component, or necessary for device Test and Evaluation) developed. TRL 3 DECISION CRITERION: Initial proof-of-concept for device candidates is demonstrated in a limited number of laboratory models (may include animal studies).
- Non-Good Laboratory Practice (GLP) laboratory research to refine hypothesis and identify relevant parametric data required for technological assessment in a rigorous (worst case) experimental design. Exploratory study of candidate device(s)/systems (e.g., initial specification of device, system, and subsystems). Candidate devices/systems are evaluated in laboratory and/or animal models to identify and assess potential safety problems, adverse events, and side effects. Procedures and methods to be used during nonclinical and clinical studies in evaluating candidate devices/systems are identified. The design history file, design review, and when required a master device record, are initiated to support either a Premarket Notification (510(k)) or PMA for Medical Devices. TRL 4 DECISION CRITERION Proof-of-concept and safety of candidate devices/systems demonstrated in defined laboratory/animal models.
- Further development of selected candidate(s). Devices compared to existing modalities and indications for use and equivalency demonstrated in model systems. Examples include devices tested through simulation, in tissue or organ models, or animal models if required. All component suppliers/vendors are identified and qualified; vendors for critical components audited for Current Good Manufacturing Practices (cGMP)/ Quality System Inspection Technique (QSR) compliance. Component tests, component drawings, design history file, design review, and any master device record verified. Product Development Plan drafted. Pre-Investigational Device Exemption (IDE) meeting held with Center for Devices and Radiologic Health (CDRH) for proposed Class III devices, and the IDE is prepared and submitted to CDRH. For a 510(k), determine substantially equivalent devices and their classification, validate functioning model, ensure initial testing is complete, and validate data and readiness for cGMP inspection. TRL 5 DECISION CRITERION: IDE review by CDRH results in determination that the investigation may begin. For a 510(k), preliminary findings suggest the device will be substantially equivalent to a predicate device.
- Clinical trials conducted to demonstrate safety of candidate Class III medical device in a small number of humans under carefully controlled and intensely monitored clinical conditions. Component tests, component drawings, design history file, design review, and any master device record updated and verified. Production technology demonstrated through production-scale cGMP plant qualification. For 510(k), component tests, component drawings, design history file, design review, and any master device record updated and verified. Manufacturing facility ready for cGMP inspection. TRL 6 DECISION CRITERION Data from the initial clinical investigation demonstrate that the Class III device meets safety requirements and supports proceeding to clinical safety and effectiveness trials. For a 510(k), information and data demonstrate substantial equivalency to predicate device and support production of the final prototype and final testing in an operational environment.
- Clinical safety and effectiveness trials conducted with a fully integrated Class III medical device prototype in an operational environment. Continuation of closely controlled studies of effectiveness, and determination of short-term adverse events and risks associated with the candidate product. Functional testing of candidate devices completed and confirmed, resulting in final down-selection of prototype device. Clinical safety and effectiveness trials completed. Final product design validated, and final prototype and/or initial commercial scale device are produced. Data collected, presented, and discussed with CDRH in support of continued device development. For a 510(k), final prototype and/or initial commercial-scale device are produced and tested in an operational environment. TRL 7 DECISION CRITERION: Clinical endpoints and test plans agreed to by CDRH. For a 510(k), information and data demonstrate substantial equivalency to predicate device and use in an operational environment, and support preparation of 510(k).
- Implementation of clinical trials to gather information relative to the safety and effectiveness of the device. Trials are conducted to evaluate the overall risk-benefit of using the device and to provide an adequate basis for product labeling. Confirmation of QSR compliance, the design history file, design review, and any master device record, are completed and validated, and device production followed through lot consistency and/or reproducibility studies. Pre-PMA meeting held with CDRH. PMA prepared and submitted to CDRH. Facility PAI (cGMP/QSR/Quality System Regulation (QSIT)) completed. For 510(k), prepare and submit application. TRL 8 DECISION CRITERION: Approval of the PMA [or, as applicable, 510(k)] for device by the CDRH.
- The medical device may be distributed/marketed. Post marketing studies (nonclinical or clinical) may be required and are designed after agreement with the FDA. Post marketing surveillance. TRL 9 DECISION CRITERION: None – continue surveillance
In my experience, the existence of these TRL descriptions for medical devices is not widely known to exist in the commercial medical device industry. Given the highly regulated nature of the medical device industry, these TRL descriptions are can be very valuable in that they provide a systematic way for medical device developers to assess and communicate to the federal regulators the level of maturity of a particular technology or combination of technologies as it relates to the particular category and the maturity necessary for successful product development.
Comments to this blog are welcome.
If you have any other topics you would like addressed in our blog, feel free to let us know via our “Ask the Experts” page and we will do our best to provide a timely response.