Sensor Issues pubs.acs.org/acssensors
Medical Sensors − Defining a Pathway to Commercialization Rudy A. Mazzocchi* ELENZA, Inc., Roanoke, Virginia, United States ABSTRACT: Novel sensor technologies are under development in a variety of medical industries, to detect specific biological, chemical, or physical processes that transmit or report valuable patient data. In parallel, there is also a growing global regulatory requirement to improve the external identification of implantable medical devices, e.g., manufacturer, device, and procedure-related information. Sensor developers and manufacturers need to define a concise regulatory and commercialization plan that identifies the challenges, risks, costs, and timelines of bringing such technologies to the market, well in advance of finalizing initial design requirements. KEYWORDS: sensors, biosensors, regulatory, risk assessment, implantable device
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ew innovations in materials, manufacturing processes, and nanotechnology have allowed for advancements in biosensor design and development. As with any new medical technology, innovation creates a variety of challenges in establishing new criteria for “clinical validation” and regulatory requirements to demonstrate “safety and efficacy”. For the sake of this discussion, “biosensors” shall be segmented into two classifications: (1) activethose sensors requiring a power source to function and transmit data, and (2) passivethose that detect and respond to some environmental input without requiring a power source. We can further break down these classifications into five categories: (i) Identificationtracking through distribution and use, (ii) Monitoringyielding other mechanical, electrical, and/or physiological data, (iii) Safety providing information indicating a failure or potential adverse event, (iv) Diagnosticchanges in physiological conditions relating to specific clinical symptoms, and (v) Triggering sensing a physiologic event that actuates or regulates an associated implantable device or one in which the sensor is integrated. As with any medical device, when designing to address a specific requirement to meet the needs of the above-mentioned categories, there are a variety of other elements that need to be considered before determining the most effective regulatory pathway for commercial availability. These include the following:
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DETERMINING THE REGULATORY PATHWAY The US Food and Drug Administration (FDA) has classified and differentiated over 1700 distinct types of devices and segmented them into 16 medical specialty “panels”. Based on the clinical data provided by an implantable sensor, intended use, and/or the integration or association of the sensor to another implantable device, the Code of Federal Regulations can be used to not only determine the class to which the device belongs (i.e., Class I, II, or III), but also define which panel shall review the regulatory submission for approval of Class III devices. As an example, in May of 2014, the FDA approved the CardioMEMS HF System, the first permanently implantable wireless system intended to provide pulmonary arterial pressure measurements, including systolic, diastolic, and mean pulmonary arterial pressures. This Class III sensor provides valuable data to physicians in the treatment of patients suffering from congestive heart failure and implanted through a trans-venous catheter delivery system into the distal pulmonary artery. The manufacturer submitted data from their pivotal clinical study in December of 2011 and underwent a stringent Pre-Market
• Is the sensor integrated or independent of another implantable device? • Exposure and selection of materials to ensure biocompatibility? • Power requirements: self-powered, rechargeable, or passive? • Cycle life and/or rechargeability of the power cell? • Overall failure analysis as integrated with other implants? © XXXX American Chemical Society
• Methods of sterilization to ensure integrity of sensor componentry? • Methods and means of delivery and/or implantation? • MRI safety and potential image artifacts due to materials used? • Desired labeling indications and claims? • Programmability or ability to upgrade the residing software/firmware?
Received: September 1, 2016 Accepted: September 23, 2016
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DOI: 10.1021/acssensors.6b00553 ACS Sens. XXXX, XXX, XXX−XXX
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ACS Sensors Approval review by the Circulatory System Devices Panel of the FDA’s Center for Devices and Radiological Health. Upon submission of additional follow-up data in October 2013, the company finally received pre-market approval from the FDA nearly 30 months following submission of their pivotal clinical data. During the design phase of the sensor, it is imperative to properly assess the FDA Guidance documents relating to the device, the intent of how its data will be utilized, and the physiological and clinical environment in which it will reside. These guidance documents are provided to advise manufacturers with regard to labeling, preclinical testing requirements, study design, submission processes, clinical considerations, and even inspection and enforcement policies: http://www.fda.gov/MedicalDevices/ DeviceRegulationandGuidance/default.htm.
manufacturer wishes to pursue. A sensor that counts the number of cycles of a moving implant (e.g., the clicks of a heart valve or the range and number of rotations of an artificial knee or hip) or a pressure sensor (e.g., biomechanical load transducer implanted into an artificial vertebral disc) is intended to provide data to assess longevity or performance features of the related implant. Output data that is not critical to the safety or efficiency of the associated implant may still be of benefit for product warranty purposes or to provide valuable research data. Safety. Safety sensors are those designed to notify the patient, caregiver, and/or the clinician of a failure of the integrated medical device or related clinical sequela that may place the patient in jeopardy. Such sensors require stringent durability tests and failure mode analysis to prove longevity, reliability, and analysis of performance errors that may be viewed as false positives or negatives. Regulatory agencies require such preclinical test data prior to granting approvals to begin a Phase I safety study. Take, for example, a sensor that has been designed to assess the electrophysiological onset of arrhythmia, a variety of irregular heartbeats. In the event the sensor fails or provides incorrect data, the patient will not receive the appropriate clinical care to correct the anomaly and may suffer serious injury as a result. Company management should be required to assess the potential “return on investment” to determine the value of pursuing a development and commercialization effort that will require mitigation of risk of sensor failure at an early stage of development. The costs associated with clinical risks (e.g., serious risks and even mortality), the direct costs of product liability insurance to cover such worst case adverse events, as well as the development, clinical, and regulatory expenses associated with design, development, and testing of a fault-tolerant sensor, all must be taken into consideration to calculate the potential return on such an investment over the expected life cycle of the product. Diagnostic. Independent implantable sensors that provide clinicians with a patient’s physiological data for the purpose of determining or altering therapy is the next most challenging of sensors to commercialize. Here the regulatory requirements are the most stringent, and clinical validation comparing outcomes to existing, well-established diagnostic measures can be difficult to achieve. Often referred to as a “lab-on-a-chip”, these sensors are often initially assessed and approved as a screening indicator to inform the caregiving physician whether or not a physiological, chemical, or even cellular change has occurred. This binary data (change or no change) is then considered by the clinician in order to assess the underlying cause of the change, including the potential use of other conventional diagnostic methods. Several companies may seek initial labeling
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RISK ASSESSMENT In the development of all medical devices, and most imperative to those implantable devices, it is essential to assess the balance of the product’s benefits-to-risk profile. Initial design review assessment needs to determine how best to minimize risks while preserving the technological benefits. While ISO standards and FDA guidelines require the application of risk management and mitigation practices that incorporate clinical factors such as risks associated with implantation and explantation of the device, it is management’s responsibility to create a rational plan that coincides with and enables the clinical application and commercialization plans of the company’s products. These plans need to begin and end with the safety profile, functionality, and intended use of the device. An analysis of hazards should critically identify those elements of the device that cause risk of a catastrophic event, e.g., an event caused by device failure that can have serious adverse health consequences, including sudden death. In consideration of the five sensor categories identified above (Identification, Monitoring, Safety, Diagnostic, and Triggering), each has both a specific device and clinical risk profile. Identification. The most basic sensors are those designed for identifying the devices through distribution and their clinical use, known as a Unique Device Identification system. These features provide substantial internal benefits to the manufacturer for inventory control purposes, and become essential in the event of a product recall. Identification sensors (such as a radiofrequency microtransponder) can also provide valuable device, implant, and procedural data that can be entered into the patient’s electronic records. Most recently, an implantable radiofrequency identification sensor has been developed by JAMM Technologies, previously VeriTeQ Corporation (Bloomington, MN), that is being utilized as an imbedded identification chip within silicone breast implants manufactured and distributed by Establishment Laboratories, SA (Costa Rica). This microtransponder provides access to valuable device information including the name of the manufacturer, date of implantation, and specific model and lot number. The FDA has recently established a guidance document for Unique Device Identification Systems for both the industry and FDA staffers that defines the requirements for device manufacturers to consider such product identifiers for automatic identification and data capture. Monitoring. Second to identification, sensors designed for monitoring purposes are most likely the least challenging to bring to market contingent upon the labeling claims that the B
DOI: 10.1021/acssensors.6b00553 ACS Sens. XXXX, XXX, XXX−XXX
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in sensor technology. Experience has proven that it is wise to consider seeking professional guidance since meeting regulatory and clinical requirements prior to commercialization is most likely to be one of the highest expense items in any medical company. Meeting with the regulatory agencies (and specifically with the FDA) in advance of defining your final regulatory pathway and freezing product design is essential. Preparation for a presubmission meeting with the FDA will require the manufacturer to develop a preliminary design, flush out all the risk factors through computer simulation of device performance using realistic models of relevant human clinical environments, as well as preliminary bench testing of critical components, and define preclinical and clinical testing requirements for regulatory submission. At this point, an open dialogue with regulatory examiners will help identify areas of concerns the agency may have in anticipating review of your final data submission. Depending on the complexity of the “systems”, as described earlier, it is also wise to consider expanding the regulatory team to include legal counsel, clinical trial manager(s), biostatisticians, and possibly even other regulatory personnel from key vendors and suppliers. Despite having access to all of these professionals, it remains the responsibility of management to properly define a concise, rational, and well-communicated overview of the product specifications, design, and intended use. Failure to be well prepared will result in exorbitant delays and cost overruns.
claims for screening purposes while continuing to capture clinical data to support future diagnostic claims. Triggering. The most challenging biosensors are those that are fully integrated into another Class III active implantable medical device. These sensors are used to detect a physiological signal for the purpose of actuating a response of the implant causing a chemical, mechanical, or electrical change in the body. These sensors are usually associated with an application-specific integrated circuit or a microcontroller that includes sophisticated firmware as well as embedded software designed to enhance signal-to-noise ratio of the raw data captured by the sensor in order to provide a clean signal required by the embedded software to reach a decision to actuate the device. Examples include sensors that read a physiological condition in surrounding tissue or fluids for the purpose of actuating the release of a controlled substance (i.e., drug delivery), or a pressure sensor that measures threshold increases in intraocular pressure to stimulate a gating mechanism to open or close an intraocular shunt inside the eye of a glaucoma patient. Such complex systems will require careful risk assessment and validation of the sensor, the active componentry, firmware/ software, and the fully integrated system. Here the sensor is scrutinized as a critical component in conjunction with the overall device. This author has specifically been involved in the design and development of an implantable electro-active intraocular lens, specific for the replacement of a patient’s natural cataractous lens. This implantable lens includes an integrated physiological sensor to trigger an autofocusing feature of a liquid-crystal optical component of the device (ELENZA, Inc.; Roanoke, Virginia). During the initial design phase, a great deal of consideration was given to a variety of physiological triggers associated with visual accommodation: the neuro-ophthalmic mechanism that causes the eye to focus under every possible distance and light conditions. Applications for patent protection were filed for a variety of potential sensors associated with all known physiological triggers. However, the company elected to pursue a final sensor design that would yield the most reliable signal, utilize the least amount of power, provide for the easiest integration into the lens (including material, size, and assembly processes), and overall cost. Validation studies have been designed to assess the sensor−device interface, the soundness of the firmware/software, and overall reliability of the entire system. All such factors weigh heavily into the regulatory and clinical strategies necessary for commercial approval.
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CONCLUSION Balancing the introduction of new technology innovations with desired regulatory approvals, without undue delays and design iterations, is complex and challenging. The more innovation and novelty, the more preclinical information is required, and most likely, the larger the patient study population required to provide clinical validation. Therefore, it is imperative that the initial risk assessment process be supported by extensive modeling of device performance under extreme conditions (e.g., using out-of-range values of input parameters) and that preclinical testing requirements be determined during the initial design process. Preliminary discussions with regulatory agencies and advisors will help drive an outline and budget. However, up-front considerations should also be made regarding other market-driven factors such as time to commercial release, market adoption, reimbursement, patent life, and even competitive activities. By definition, “regulatory process” is a set of reviews conducted according to established rules or principles and/or best practices. In order to fully navigate the regulatory pathway, it is essential that the manufacturer first fully understand these rules and constraints before designing and testing the device. Some of these requirements will affect the design specifications (and imposing possible limitations) of the operating range of the final product simply because the most optimal design requires testing and validation parameters that drive the cost of the device well beyond what the market will bear. Implantable sensor technology adds another layer of complexity when associated or integrated with other implantable devices. Failure mode analysis and risk assessment of this integrated system now includes a larger set of variables and parameters that impact safety and reliability. The incorporation of new materials, or combination of materials, also requires a deeper analysis of the tissue−device interface to evaluate biocompatibility. Safety analysis also will now need to consider
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REGULATORY PROCESS There are many regulatory management consulting firms and clinical research organizations that are highly qualified to assist with determining the most optimal regulatory pathway based on the functionality and intended use of these new innovations C
DOI: 10.1021/acssensors.6b00553 ACS Sens. XXXX, XXX, XXX−XXX
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ACS Sensors changes in physiological conditions and potential “external” interference. Regulatory agencies will look for assurance that the manufacturer has considered and evaluated all these varying scenarios. In totality, these additional requirements translate into additional costs. It is standard practice to include an assessment of the overall cost of conceptualization to commercialization when considering the market needs and size of the opportunity in the product design process. Therefore, it is essential to establish a well-defined regulatory pathway prior to the finalization of the sensor design in order to minimize costs and time to market. Bringing new innovation to the market requires a combination of solid engineering principles, robust regulatory strategies, clinical validation with definitive end points, and artful market deployment. Manufacturers need to consider compromises in product design (as defined by the market needs), regulatory requirements and timelines, and the cost−risk benefits of the applied technology.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The author declares the following competing financial interest(s): Rudy Mazzocchi is the Co-Founder/Chief Executive Officer of ELENZA, Inc. and Executive Chairman of Establishment Labs, SA. Biography Rudy A. Mazzocchi has over 25 years of senior executive management, technology and intellectual property development and financing experience in the med-tech/biotech industries. He currently serves as Co-Founder/Chief Executive Officer of ELENZA, Inc., an ophthalmology company that has developed an electro-active Autofocusing implantable lens, Executive Chairman of Establishment Laboratories, Executive Chairman of LAFORGE Optical, and Executive Chairman of OptiSTENT, Inc. He previously served as Managing Director of Accuitive Medical Ventures and The Innovation Factory, Co-Founder/C.E.O. of Image-Guided NEUROLOGICS, acquired by Medtronic in 2005, and was also Founding C.E.O. of MICROVENA Corporation, which became “eV3″, acquired by Covidien. He was formerly Co-founder/Director of Vascular Science, acquired by St. Jude Medical in 1996, and Co-founder/Chairman of CytoGenesis, one of the first U.S. stem cell companies that was merged with BresaGen, Ltd. and listed on the Australian public exchange. He is the recipient of the Technology Leadership Award, the Businessman of the Year Award, the Ernst & Young Entrepreneur of the Year Award in Healthcare, and Global Entrepreneur of the Year Award. He has also authored more than 70 patents, two published award-winning novels (medical thrillers), and a top-selling business book on Art of Entrepreneurism.
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DOI: 10.1021/acssensors.6b00553 ACS Sens. XXXX, XXX, XXX−XXX
