The Evolution of Medical Device Clinical Trials: Their Background and a Look Toward the Future

White Paper The Evolution of Medical Device Clinical Trials: Their Background and a Look Toward the Future David R. Dills, Global Regulatory Affairs & Compliance Consultant White Paper Demonstrating the effectiveness and safety of new medical products is a critical part of the medical product development process and requires significant resources to accomplish. The goal of every medical device company is to ensure that they are designing and implementing clinical trials for success while having comprehensive knowledge of coordinating, monitoring and managing a clinical trial within a framework of good clinical practices and regulatory requirements. Medical devices play a critical role in the lives and health of millions of people worldwide. From everyday household items such as oral thermometers to complex implantables such as deep-brain stimulators, patients and the general public rely on regulators to ensure that legally marketed medical devices have been shown to be safe and effective. Regulators expect the data provided by device manufacturers to reflect the risk profile of the device. A medical device is anything that is not either a drug or a biologic product. Medical devices usually work physically, while pharmaceutical products usually work chemically or biologically. Medical devices can be therapeutic, diagnostic or something else, whereas pharmaceutical products are usually therapeutic. Medical devices are invented, while drugs are usually discovered. Medical Device Development and Approval The U.S. Food and Drug Administration (FDA) approval process for medical devices is different compared to drugs from pharmaceutical industries. Medical devices are submitted for approval to the FDA’s Center for Devices and Radiologic Health (CDRH) or Center for Biologics Evaluation and Research (CBER), while drugs from pharmaceutical companies are submitted for approval to the Center for Drug Evaluation and Research (CDER) or CBER at the FDA. Not all devices need to go through controlled clinical trials to gain regulatory approval. If a device needs a confirmatory study to support a premarket approval (PMA) application, this does not rely on randomized concurrent control but on historical controls showing evidence that the device is “safe and effective.”i This confirmatory study is usually enough to support a PMA application while pharmaceutical applications generally require two adequate, well-controlled confirmatory clinical trials. When studying new drugs, a clinical trial is required. However, when studying medical devices, REQUIRMENTS FOR A CLINICAL TRIAL clinical trials may not be required, depending on the risk stratification Class I Class II Class III (or class) of the device. + Adhesive bandage + Knee prosthesis + Drug-eluting stent In the U.S., all Class III (and some Example + Surgical glove + Single-use scalpel + Insulin pen Class II) devices require a clinical trial. Source: FDA Needs a No Maybe Yes clinical trial? The Evolution of Medical Device Clinical Trials 1 White Paper The development of a medical device follows a different route than that of a drug. While clinical trials on drugs focus on dose response study, medical device clinical trials give attention to prototype development. Drug development follows an extensive Phase I, II, III and IV clinical trialing process to test for safety, efficacy and toxicity, whereas medical devices have feasibility, pilot and pivotal study models. Some medical device research involves substantial bench and animal testing for reliability and biocompatibility (like in implants), but there are no studies for toxicity on devices like the Phase I or animal studies required for pharmaceutical research. Pilot and feasibility studies on medical devices are considered first-in-man studies. For drug studies, post-marketing CLINICAL TRIAL CLASSIFICATION studies are typically considered Phase IV studies. For device studies, Device Studies Drug Studies the requirement for long-term data Pilot: Phase I: is generally satisfied with a post- Small study (10-30 patients with the condition) Small study (20-100 healthy volunteers or people approval study. Source: FDA to determine preliminary safety and performance with condition) to determine preliminary safety and dosage Pivotal: Phase II: Larger study (150-300 patients with the condition) to Larger study (up to several hundred people with the determine efficacy and adverse effects condition) to determine efficacy and adverse effects Post-approval: Phase III: Post-approval study to collect long-term data (sometimes known as pivotal study) Even larger study (up to thousands of people with the condition) to determine efficacy and monitor adverse effects Phase IV: Post-marketing study to collect long-term data Device development is iterative, and designs may be refined or improved as device development progresses. While user feedback, adverse events or difficulties in deploying or delivering a device can all lead to changes to the device, second- or third-generation designs do not always require a new clinical trial. Bridging the new to the old design may require additional bench studies or small confirmatory post-market studies. A medical device can be changed during clinical development and once it’s on the market a newer, improved version may already be in development. Thus, the life cycle of a medical device may only be as short as a couple of years. In contrast, drugs are usually on the market for many years. Medical devices are approved through the PMA application process and a single confirmatory study is often sufficient for approval. In contrast, drugs are approved through the New Drug Application (NDA) process and drug development is characterized by Phases I through IV clinical trials. There are numerous medical device companies registered with the FDA. The Evolution of Medical Device Clinical Trials 2 White Paper The medical device manufacturing industry is becoming a major player in health-care delivery. Physicians treat many illnesses and conditions, such as cardiovascular and neurological diseases, with medical devices as often as with medicine. Medical device manufacturers can conduct clinical trials more easily in Europe where currently regulatory barriers to clinical testing have less constraints. Consequently, new innovative medical devices typically come to market in Europe first. Approval for marketing these devices in the U.S. follows in five to 10 years, then an additional five to 10 years for Japan, which has the longest regulatory pathway. A medical device clinical trial can cost between $5 and $10 million USDii, and this varies for obvious reasons, in the U.S. or Western Europe and more in Japan. The cost of the same trial conducted in Eastern Europe will be considerably lower, and in India, China, or Korea, it may be one-tenth as expensive.iii Manufacturers are turning to Asian countries for their high-risk, first-in-human studies and even for their pivotal studies because these countries contain a huge available human population with limited alternatives for healthcare. Also, the regulatory barrier to starting a device clinical trial in India, China or Korea is sometimes easier but this can vary due to a multitude of factors. Regulations and Good Clinical Practices Regulations for conducting medical device clinical trials around the world have varied widely. Complications that arise between trials conducted under different protocols make bringing a device to market difficult in a stricter country. Data may be considered questionable given different requirements. The time required to determine acceptability and perhaps repeat trials may delay the device’s approval, frustrating patients as well as manufacturers. In addition, the safety of human subjects participating in the clinical trial – and ultimately patients – is in question in countries with lax regulations and resultant uncontrolled clinical settings. Less rigorous studies cannot ensure consistent performance quality, thus potentially jeopardizing the health the devices are meant to protect. In 2011, the International Organization for Standardization (ISO) adopted and published a revised version of ISO14155, essentially a clinical practice roadmap for taking a medical device through the clinical trial life cycle. This amendment to the 2003 standard, known as ISO 14155:2011, provides guidance for conducting medical device clinical investigations, in which sponsors are responsible for implementing a risk management program, classification of adverse events and monitoring the ongoing safety evaluation of the clinical investigation for their medical devices.iv Perhaps the most obvious change is the title of the standard itself: ISO 14155:2011 Clinical Investigation of Medical Devices for Human Subjects – Good Clinical Practice (GCP). The addition of GCP to the title indicates the alignment of medical device investigations to the International Conference on Harmonization Good Clinical Practices (ICH GCP) E6 guidelines.v The Evolution of Medical Device Clinical Trials 3 White Paper For medical devices, frequent innovations in the design and use (for example, minor modifications that enhance safety, reliability, patient comfort, or ease of use) are common and often do not require prior regulatory approval. Bench and/or animal testing is often sufficient to validate the suitability of a design change. In cases when a clinical trial is required (for example, for high-risk or some medium-risk devices), evidence can come from sources other than well-controlled clinical

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