Medical optics is big business. The global market for medical device technologies is expected to reach $538.7 billion in 2018, registering a compound annual growth rate (CAGR) of 5.5 percent over five years, according to market analysts at BCC Research. It’s not just patients and health-care professionals who are creating the demand — an emerging trend in wearable medical devices is set to flood the market in the coming years. Such devices are being created to track and analyze information about a person’s health, from respiration rates to glucose levels. This data can be remotely transmitted and provided to medical personnel who could then provide targeted treatment. The COMET measurement system for cellular oxygen metabolism (screen shows prototype software). The highly innovative optical device noninvasively measures oxygen availability and utilization in active mitochondria — the power houses of the cells. Measuring oxygen utilization in vivo lets researchers determine how drugs and other substances affect mitochondrial respiration. The device is currently in clinical trials, not yet commercially available. Courtesy of Photonics Healthcare BV, Utrecht, Netherlands. According to a Research and Markets report (ID: 3548489) published in January 2016, the global wearable medical devices market is poised to grow at a CAGR of more than 20 percent in the next five years to reach approximately $14.2 billion by 2020. But just how do device manufacturers gain a slice? Barriers to market for higher-risk medical devices include product trials, clinical trials and finally clearance/approval that is region-specific. All this before persuading the often overworked, time-poor health-care workers to adopt a new way of working or come to grips with a new device. For companies that may be unfamiliar with the process, it can seem daunting and too complicated to negotiate. It can be confusing at the beginning; however, regulatory agencies have created a series of tools to help guide companies to success. And success is actually more likely than one might think. In fact, the U.S. Food and Drug Administration reported a 98 percent approval rate for medical devices requiring premarket approval applications (PMAs) last year, meaning that the agency’s Center for Devices and Radiological Health (CDRH) approved 79 “novel devices,” the highest number since the advent of user fees for devices. “2015 was a very strong year for medical device innovation,” said Bakul Patel, associate director for digital health at CDRH. “While maintaining high standards for safety and effectiveness, the FDA approved record numbers of innovative devices.” Retinal image from a conventional digital fundus camera (resolution 20 µm) (left). Magnified portion of the image (center). Image of the same retina using the recently cleared retinal camera (resolution 2 µm) from Imagine Eyes (right). Courtesy of Drs. Gocho and Kameya, Nippon Medical School Hokusoh Hospital, Chiba, Japan. Although regulatory approval is a must for high-risk Class III devices (see sidebar on page 51 for a guide to what to expect), it is not the whole story. Many other aspects must be evaluated before a product can be introduced for clinical use. “As for any other development, a new medical product must be expected to provide a return on the investment required to develop and market it that is attractive in view of the risks and time scale,” said Michael Münker, CEO of Photonics Healthcare BV, Utrecht, Netherlands. Medical devices will often be complicated by extended lead times and regulatory and reimbursement uncertainty. Many factors are country-specific, regulations and their interpretations change with time, and public and political reaction to incidents or what is considered acceptable can be unpredictable. “Even a product that works as intended can fail to show a clear benefit in clinical trials, and even one that succeeds in trials can fail in clinical practice or market adoption,” Münker said. “Competition can arise not only from similar technologies but also totally different approaches to the same problem, for example, pharmaceuticals or changes in reimbursement or health policies.” A recently cleared product for ophthalmic applications based on adaptive optics from French SME, Imagine Eyes. Courtesy of Imagine Eyes. Developing a device that is successful both medically as well as economically is a three-stage approach: • Ensure the device answers an unmet need. The best way to discover if your device has a place in the market would be to speak to clinicians, surgeons and pathologists to discover what is unsatisfactory in their daily practice — probing beneath 5 mm of adipose tissues could be an example. Next comes the hard part: translating this need into photonics features — wavelength, power, brightness and so on — and sourcing the technology that fits the need best and/or to develop a technology according to the requirements of medical professionals. “Only medical staff know the specificity of their specialty and can guide the development of a technology toward a system that will answer their expectations and take into account the constraints related to working in a medical environment where time is precious, hygiene must be high, space must be optimized and resources can be low,” said Clémentine Bouyé, biophotonics technology and market analyst at Tematys, photonics market experts based in Paris. It’s those in the field who can provide the most relevant insight when it comes to adapting the technical specifications of the technology. They also offer the best vantage point to determine where the device will be best implemented in a medical workflow — in a patient’s room at the hospital, in the operating room or in the doctor’s office. “I talk to doctors. Sometimes patients, researchers, payers (insurers) and hospital administrators, too,” Münker of Photonics Healthcare said. “An unmet medical need for a significant number of patients is not enough. A product that improves care but is expected to increase cost for the health system is unfundable — even though examples of new technologies that actually reduce health-care costs are hard to come by.” • Measure the correct parameters precisely enough for a decision to be made. Given the explosion in wearable/smartphone devices, it is important to understand that there is a crucial difference in application that defines an actual medical device from one that provides some comfort information about health to the user. For example, apps on smartphones that measure heart rate using the light of the camera provides information but cannot be used for any medical decision because it lacks reliable information. Microscopic detail of living human retinas in adaptive optics. Images acquired using Imagine Eyes’ recently cleared retinal camera. Cone photoreceptor cells (top, left), pores of the lamina cribrosa (top, right), microvacuoles surrounding a macular hole (bottom, left), and wall structure of a retinal arteriole (bottom, right). Courtesy of Imagine Eyes. According to Patel, the FDA is actively working to keep up with advances in digital health and has outlined its thinking with regard to mobile medical applications in its Mobile Medical Applications guidance document (http://www.fda.gov/downloads/MedicalDevices/.../UCM263366.pdf). “The guidance, designed to address this rapidly growing sector, clarifies that a mobile app is a medical device if it is intended for use in the diagnosis, cure, treatment, mitigation or prevention of disease or other conditions,” Patel explained. While some mobile apps fit this definition, most do not. The FDA limits its focus to apps that may impact the performance of currently regulated medical devices and may pose a risk to patients if they don’t work as intended. “The agency believes consumers and health-care providers should expect the same level of assurance of safety and efficacy in devices designed to work on a mobile platform as they do from other types of medical devices,” Patel said. “In short, our approach is to regulate the functionality of the app based on risk to the patient, not the platform on which it runs.” For Tematys’ Bouyé, the market is split into two segments. One segment relates to devices for comfort, that are already on the market, and that will be fed by “cheap, simple photonics components — low-cost LEDs, photodiodes, etc.” The other segment of devices for medical information will take more time to grow, as higher performing technologies at low cost are required, Bouyé said. “These devices will address needs of targeted populations such as diabetics, people subject to allergies, cardiac patients, etc.,” she said. • Boost device adoption. Once it’s available for clinical use, the goal is to market the device. A good option is to develop the technology with medical professionals — this makes it more valuable in the eyes of the other professionals. “Moreover, working with doctors who have a great influence on the medical community might be of great help to spread the idea that the newly developed technology is reliable and provides good results,” Bouyé said. Safety First: A Guide to Gaining Device Approval As in the automobile and food industries — or any sector that deals with human lives either directly or indirectly — safety for patients/customers is the main issue at the heart of the development of every new technology. Besides safety, clinical products are also subject to concerns regarding toxicity and sterilization. Regulations vary by country or geographic area and in order to sell a medical device in a country it is necessary to have the corresponding clearance/approval/marking that is awarded by these agencies: Main regulatory agencies: • CE Medical Marking for the EEA (European Economic Area and Switzerland) • FDA (Food & Drug Administration) for the U.S. • Health Canada for Canada • JMHLW (Japanese Ministry of Health, Labour and Welfare) for Japan • CFDA (China Food and Drug Administration) in China According to agencies, the foolproof approach is to start talking to them early on in the device’s development. This means that experts can offer help in identifying the correct regulatory pathway for the device from the start. Even though a record number of medical devices were approved in the U.S. in 2015, the FDA’s associate director for digital health at the Center for Devices and Radiological Health (CDRH), Bakul Patel, is quick to point out that last year’s 98 percent approval rate was arrived at through an intensive, iterative process of FDA review and applicant refinement of premarket approval applications (PMAs). “CDRH’s initial cycle of review typically identifies major deficiencies that the applicant must correct before CDRH makes an initial decision on the approvability of an application, called a MDUFA [Medical Device User Fee Agreement] decision,” he said. In fact, the No. 1 reason for application rejection is lack of sufficient information, so by talking to them early, applicants can be guided on what to provide and time-to-market can be minimized. “Even after these corrections, only slightly more than half of the PMA applications in the fiscal year 2015 decision cohort received FDA approval at the MDUFA-decision stage of review. The remaining applications required further changes before the 98 percent approval rate was ultimately achieved,” Bakul added. While Europe is harmonized for regulatory aspects, reimbursement [government funding programs for medical devices] and the way health systems are organized vary widely. In the U.K., the Medicines and Healthcare Products Regulatory Agency (MHRA) has an Innovation Office (https://www.gov.uk/government/groups/mhra-innovation-office) to offer information and guidance to help companies, large and small, navigate scientific and regulatory requirements effectively. “As well as being a regulator, we are passionate about helping companies develop products that could benefit patients and improve public health,” said Siu Ping Lam, director of licensing, at the MHRA. “We are particularly interested in discussing technology or products that could potentially challenge the current regulatory framework, due to their novel technology, materials used or as a result of convergence of technology, whereby a technology that is established in other fields is applied to medical devices for the first time.”