Postmarket Studies in Lieu of Clinical Trials

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:

  1. 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
  2. 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
  3. 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.

In an attempt to balance the need to demonstrate safety and effectiveness and using a least burdensome scientific approach, FDA has required that patients participating in pre-marketing clinical trials involving investigational devices will be followed for a minimum of six months and more often for 12 months. FDA relies on mandatory postmarket clinical trial’s long-term data and the participation of real-world patients and a broader range of physicians as a way to assess the long-term safety, mostly, and effectiveness of newly-marketed devices and combination products.

Postmarket Clinical Data
The requirement to conduct PMCF trials is not new. Release of MEDDEV 2.12/2 rev 2 in 2012 has increased the orthopaedic industry’s awareness of this tool’s purpose and importance. In Europe, Notified Bodies are required to verify that manufacturers have included a PMCF protocol as part of the postmarket surveillance (PMS) plan. The requirement for PMCF studies is found in Annex X, 1.1c of the Medical Device Directive (93/42/EEC as modified by 2007/47/EC). Most orthopaedic manufacturers attempt to provide a justification for not conducting PMCF studies, yet implant recalls and the prevalence of revision surgery have increased the scrutiny around these justifications.

FDA has been addressing postmarket surveillance by requiring mandatory post-approval clinical trials of recently-approved products. PMS are required as a condition of device approval, and this may include a requirement for creating a patient registry, collecting additional real world clinical data, from a broader patient population treated by a broader range of physicians. Manufacturers are required to monitor the adverse event rates, expected to perform trend analysis of specific clinical endpoints and constantly assess the benefit/risk profile of the product based on new information collected from real world clinical data.

Strategic Combination of Premarket Clinicals and PMCF Studies
Orthopaedic implant manufacturers are positioned to gain the most value from PMCF studies designed to address the etiology and prevention of revision surgery, this being the biggest concern for regulators, surgeons and patients. Therefore, if your company is planning to develop a novel orthopaedic implant (e.g., vertebral disc replacement using novel materials), you may want to consider the following approach to gathering clinical data:

  1. Perform a literature search to partially meet the requirement for a clinical evaluation report; Please refer to the MDDE 2.7.1, Rev.3 (2009)
  2. Create a patient registry for your new product
  3. Perform a small clinical study in Europe and the U.S. to gather safety data
  4. Write a PMCF study protocol to monitor long-term patient outcomes
  5. Write a PMCF study protocol to include health economic and outcome and quality of life data. This data will serve your company’s reimbursement discussions with Health Technology Assessment (HTA) groups in Europe, CMS and other private payers in the U.S.
  6. Submit a CE Marking Application to your Notified Body
  7. Request a Pre-IDE meeting with FDA in order to gain agreement for the scope of a bridge study to meet the requirements for a PMA submission
  8. Perform a clinical study in the U.S. to bridge the gap between the available clinical data and what FDA wants for a PMA submission
  9. Submit a PMA Application

Throughout the process described above, your company will continue to gather PMCF data through your patient registry. Your Notified Body will review this data, and it will also serve as supporting evidence for your PMA submission to FDA, for CMS reimbursement and for convincing orthopaedic surgeons to adopt your new implant. Often PMCF study data is used to generate white papers and peer-reviewed journal articles about the clinical results of new devices. The combined approach enables device companies to commercialize their novel device in Europe early, and generate revenues sooner. This approach also proactively establishes a systematic process to identify any hidden problems with the design of a device, problems with patient selection criteria in the Instructions For Use and any surgical techniques that result in less favorable patient outcomes.

Robert Packard of Packard Consulting is a regulatory consultant with 20 years of experience developing products and managing projects in the medical device, biotechnology and pharmaceutical industries. His experience includes research, product development, operations management, manufacturing engineering, equipment design, regulatory affairs, quality assurance and fund-raising. Rob’s passion is training others. Specific questions about ISO 13485 Certification or Quality System training can be directed to Mr. Packard by This email address is being protected from spambots. You need JavaScript enabled to view it..

Medical Device Academy

Dov Gal, DVM, MBA is a clinical and medical affairs consultant. He holds a BSc., an MBA and a doctorate in veterinary medicine. He also completed a research fellowship in human interventional cardiology. Dov is an expert in preparing Clinical Evaluations for CE Marking and Canadian Device License Applications, and he specializes in developing strategic plans for the design of clinical studies involving high-risk medical devices. You can contact Dr. Gal directly by This email address is being protected from spambots. You need JavaScript enabled to view it..