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An FDA Viewpoint on Unique Considerations for Medical-Device Clinical Trials

Friday, April 7, 2017   (0 Comments)
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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 data that are provided by device manufacturers to reflect the risk profile of the device. For example, a device that most consumers can use without instruction, such as reading glasses or elastic bandages, will require a very different evidence profile than a device, such a portable ventilator, on which a patient’s life could depend.

Although devices are manufactured and marketed worldwide, this review focuses on the strategy used by the U.S. Food and Drug Administration (FDA); special attention is paid to the ways in which the evaluation of devices is distinct from that of drugs. The entry of the FDA into the device arena was largely prompted by several deaths and claims by an estimated 200,000 women that they were harmed by the use of the Dalkon Shield, an intrauterine device (IUD) intended for contraception. Women who used this device had five times the risk of pelvic inflammatory disease as those using other IUD types, and several had uterine rupture or septic pregnancies. Congress responded by passing the Medical Device Amendments to the Food, Drug, and Cosmetic Act.1,2 These 1976 amendments established a risk-based regulatory framework for evaluating medical devices in the United States. Under this framework, the requirements that a device must meet to be lawfully marketed depend on the risk classification of the product, with risk being assessed as the potential for the device to present harm to the patient, including in circumstances in which the device could malfunction or be used improperly.
Most low-risk devices, which present a minimal potential for harm to the user (e.g., prescription eyeglasses, elastic bandages, and dental floss), are exempt from FDA review before marketing, although manufacturers are still subject to certain requirements. Manufacturers of most moderate-risk devices, such as condoms, nebulizers, and blood glucose meters, generally need to show that their device is substantially equivalent to another device already cleared by the FDA; in most cases, this is achieved through bench (nonclinical laboratory) testing and without clinical data.3 Higher-risk and innovative moderate-risk devices (approximately 4% of all medical devices), which are the primary focus of this article, generally require clinical evidence to show that the benefits of a technology outweigh its risks. Such information is often critical not only for showing the safety and effectiveness of the device but also for informing clinicians and patients about the preferred use of the device in the marketed clinical setting. This article seeks to illustrate the broad array of trial designs and clinical data sources that may be used to support the safety and effectiveness of these critical products.

In clinical studies of pharmaceuticals, we might see double-blind, randomized, phase 3 trials assessing outcomes, sometimes in thousands of participants followed over a period of many months or years. There are many notable exceptions for situations in which a drug treatment has great clinical need that counterbalances its risks; in these contexts, we often accept smaller studies or less certainty because risk tolerance is higher in serious diseases for which current treatment options are inadequate. For some device studies, a similar approach is feasible. For example, the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy, sponsored by Boston Scientific, randomly assigned 1820 participants with mild-to-moderate heart failure and a long QRS complex to receive either a standard implantable cardioverter–defibrillator (ICD) or cardiac-resynchronization therapy with a defibrillator (CRT-D) and followed them for an average of 2.4 years.4 The addition of cardiac resynchronization therapy was intended to increase the efficiency and effectiveness of cardiac contractions in a patient population with decreased exercise tolerance, increased left ventricular chamber size, and elevated risks of hospitalization and death. The trial showed a lower risk of heart-failure–related events with CRT-D than with ICD alone, resulting in an expansion of the approved label for Boston Scientific CRT-D devices,5 which had previously been restricted to patients with severe heart failure, and contributing to a subsequent expansion of the medical guidelines for CRT-D to include less-sick patients.6

For many devices, however, practical limitations related to the device or disease condition require alternative approaches to conducting large, randomized, controlled, double-blind studies and increased flexibility in trial design and statistical analysis. For example, it may be infeasible to conduct a blinded trial of an implantable device because it is impractical or unethical to use a sham control for the target patient population owing to the risk of the implantation or procedure itself. For some devices, opportunities exist for leveraging alternative data sources, such as existing registries or modeling techniques, to allow regulators to have a good idea of the risks and benefits of the device without the need for conducting detailed trials. For the majority of devices, the benefits and risks are expected to be manifest through registries and evolve as clinical techniques are refined and the technologies themselves are rapidly modified and improved. Such a continuous improvement cycle would be impossible if every device iteration required a full trial to test its safety and efficacy. The FDA has in many cases accepted a somewhat greater degree of uncertainty regarding those benefits and risks early in the life cycle of a device, while allowing patients access to potentially important technologies and supporting the iterative refinement of the technologies.


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