Clinical data is required for all submissions of premarket approval (PMA) and for more than ten percent of 510(k) premarket notifications to FDA. Clinical data is also expected in Europe as part of the CE marketing approval process of most Class III devices, and many Class IIb devices. One of the essential requirements for CE Markings is that, “Any undesirable side-effect must constitute an acceptable risk when weighed against the performances intended.” In addition, under the Medical Device Directive (MDD) and the Active Implantable Medical Device (AIMD), CE Marking requires a clinical evaluation for all devices as part of the submission for CE Marking and thereafter.
Often, companies applying for a CE Mark will rely upon a literature review to meet the requirement for the clinical evaluation of low- and medium-risk devices or for high-risk devices where substantial equivalence is claimed. In the case of high-risk medical devices claiming substantial equivalence to an existing CE Marked product, the manufacturer is also expected to conduct postmarket clinical follow-up (PMCF) studies.
The Need for Clinical Data
A simultaneous confluence of factors is impacting the impetus for change in the medical device industry:
- The cost of healthcare is skyrocketing and all constituents are price-sensitive. The Affordable Care Act incentivizes value-based approaches. Medical device manufacturers are compelled to demonstrate the value of their products in terms of a comprehensive value to patients, payers and healthcare providers. Value may be derived from one of all of the following drivers: innovation, pricing, reduction of procedural/surgical cost, reduction of human capital and other resources per patient, improving post-procedure care including re-admissions, reducing hospital stay time and increasing throughput, and
- Payers (i.e., Center for Medicare and Medicaid Services (CMS) and private insurance providers) are demanding clinical evidence showing that new products are as effective and cheaper or are significantly more effective than existing products, and
- Healthcare providers’ margins are being squeezed as a result of the provisions of the Affordable Care Act. This new reality has been driving purchasing decisions, pressuring the manufacturers of medical devices to drive down the selling price of medical devices and asking for clinical data derived from evidence-based clinical trials to demonstrate safety and effectiveness of their products as well as their economic value to the healthcare providers’ bottom line.
The collision of these factors has exponentially increased the value and importance of clinical, health economic and outcome data generated from well-thought-out and well-designed clinical trials.
As companies evaluate new products and new indications for marketed products in their pipelines, the cost of generating clinical data weighs heavily in the decision making process. Historically, clinical data was gathered as part of a premarket design validation process and as part of postmarket phase IV clinical trials. Premarket clinical trials are expensive and patient enrollment timelines are notoriously underestimated, resulting in product launch delays. These delays are due to two factors: 1) screening and recruiting patients who meet the carefully chosen clinical trial inclusion and exclusion criteria, and 2) the safety and effectiveness of permanently implantable devices require long-term follow up of five to eight years. Regulatory agencies require a minimum of six to 12 months’ worth of follow-up data as part of the premarket submission of a new device. Only the largest and most well-funded manufacturers can afford adding two to five years to generate, summarize and submit clinical data to support a PMA application or a CE Marking dossier.
Premarket Clinical Data
Premarket Clinical Studies are designed to demonstrate safety and effectiveness in the U.S. In Europe, the primary focus is on safety. Clinical trials are designed to gather data in support of safety and to confirm that the device performs as intended.
A prospective randomized, double-blinded clinical trial design provides the highest scientific evidence-based approach to generating meaningful clinical data and the least room for bias. The purpose of the clinical data is to support or refute the study hypothesis by comparing the tested article to a control arm. The control may be another marketed device with similar indications or a sham procedure with the test article not being used.
A statistical analysis plan is designed to ensure that the proper sample size of patient data is available for the analyses of trial endpoints. Patients invited to participate in a clinical trial have to meet stringent patient selection criteria that increase the odds of the endpoints being met; i.e., they do not necessarily represent the broader population of patients suffering from the disease or condition that is being treated. In other words, patients participating in clinical trials, in many cases, do not represent the “real world” patient population.
Meeting the above criteria typically requires a sample size as low as tens of patients and as large as thousands of patients, a matching number of clinical sites and a representative cadre of investigators with clinical and clinical research qualifications.
European premarket clinical studies for devices are typically smaller than studies in the U.S., because these studies are designed primarily to demonstrate safety. Instead of using clinical data to demonstrate efficacy, most CE Marking submissions utilize pre-clinical studies involving animals, cadavers and simulations studies in order to demonstrate performance of the device. Simulations include bench-top studies, Sawbones models and finite element analysis (FEA). None of these design validation methods are 100 percent effective at predicting long-term health effects and durability of permanent implants.