by Eric Distad, Senior Director, Medical Device & Diagnostics, Novella Clinical
The market for drug device combination products is expected to grow at a compound annual growth rate of 11.95 percent by 2019, according to a new report from Technavio. The report, which segments the market by the following product types: drug-eluting stents, prefilled syringes, wearable injectors and insulin delivery systems, also found bioabsorbable stents to be a key trend to follow during the next five years. We are already seeing great progress made in this area with the U.S. Food & Drug Administration’s (FDA) October approval of Boston Scientific’s Synergy Bioabsorbable Polymer Drug-Eluting Stent System making it the first and only commercially available drug-eluting stent with a bioabsorbable polymer in the U.S.
While advancements in drug/device combination products will continue to make headlines, it’s the product review process that has recently come under scrutiny. According to the Office of Combination Products (OCP) fiscal year 2014 Performance Report to Congress, the OCP responded to 650 requests for assistance from Centers and sponsors – a 67 percent increase from the 390 requests received in 2013 – while intercenter consulting reviews increased 22 percent to 1,013 in 2014 compared to 828 in 2013. Despite this, the pace and process used by the FDA became the subject of considerable concern by many device companies this year. As a result, the FDA’s Office of Planning Issues published a report summarizing a study of the intercenter consultation process for the agency’s review of combination products. The report served to identify the challenges reviewers currently face and recommendations for addressing these issues.
Combination products are notably more complex than single component products, particularly when it comes to designing clinical trials and readying companies for regulatory review. While the FDA looks to improve its processes, there are proactive steps sponsors can implement now to help them best work through the challenges of conducting clinical trials involving combination products. Here, we discuss our recommended three-step approach.
- Begin with bio availability (BA) and bio equivalence (BE) studies. The FDA wants BA/BE studies completed before embarking on a pilot trial. Start with small feasibility trials of about 20 patients to establish safety, begin to define the expected adverse effects and validate the performance of the product in the field. BA/BE studies typically must be randomized, placebo-controlled and parallel in design and require comparative clinical endpoints in patients with a clinical diagnosis for the condition of interest. In such trials, investigators randomize patients to receive the proposed combination product, reference product alone (standard of care) or the device alone.
Typical randomization is 2:2:1, with equal numbers randomized to each active treatment arm and half as many to the device alone arm. If ethical issues are a concern for use of the device alone, the FDA may allow a crossover design for the study, so that patients who received the device alone but did not resolve their condition within a specified time could be later randomized to one of the two treatment groups.
While these BA/BE studies are typically double-blinded, this design may not always be possible. The FDA will usually accept an unblinded design if a single, blinded core laboratory can be used for all of the trial evaluations. To demonstrate BE, both active treatments should also be superior to device alone, which also shows the study design is adequately sensitive to document a difference between products.
The FDA does not specify the size of the required BA/BE studies, but does specify that it is the sponsor’s responsibility to enroll sufficient patients for the study to demonstrate bioequivalence between the products. Study requirements for combination products can be defined only from the pre-investigational new drug discussions with the Center for Drug Evaluation and Research (CDER) or the pre-biologics license application discussions with the Center for Biologics Evaluation & Research (CBER). Of note, FDA guidance documents for clinical evaluation of such products specify that each study should contain a minimum of 100 subjects, yet Novella finds FDA approval typically was granted after studies including three or more sites have tallied a total of at least 500 patients.
- Move to a smaller, pilot-controlled trial. Changing established clinical practice is difficult. Typically, pivotal trials require a prospective, two-arm, controlled study that is at least partially blinded to directly compare both the safety and efficacy of the combination product with a previously cleared product or to standard of care. Novella recommends a staged process in which a smaller, pilot-controlled trial, generally involving about 50 to 60 patients, verifies safety, and confirms patient inclusion/exclusion criteria before moving to the larger pivotal trial.
- Prove with larger pivotal studies. The size of the full pivotal trial depends on the primary mode of action (PMOA), intended use and claims for the combination product, the adverse event types and rates observed in previous studies, and the product effectiveness compared with standard of care. Generally, patient numbers are smaller for trials to establish equivalence, as trials powered to show superiority of the new combination product to standard care will be much larger. For example, a randomized, double blind two-arm study of a new drug or biologic-coated device against a non-coated device would be used to show non-inferiority in effectiveness with an increase in safety, such as fewer adverse events, or decreased infection rates. Such a trial typically requires about 1,500 patients, equally randomized to the two arms. In contrast, a two or three-arm superiority trial against the competitor ‘predicate’ product increases trial size significantly, typically to 3,000 to 5,000 patients, while also increasing trial complexity, number of sites required and duration.
The FDA generally only requires combination product trials to show ‘substantial equivalence’ to a predicate device or standard of care, so the patient numbers are generally smaller in these trials. In contrast, Centers for Medicare & Medicaid Services (CMS) may require a new combination product be superior in terms of safety, efficacy or both, with a decrease in the overall cost of care, before a new reimbursement code can be issued. As a result, such superiority trials are much more expensive to undertake because of the larger number of required patients, the additional data required for healthcare cost comparison and the longer timelines required to show differentials between the new treatment and current standard of care.
Conducting combination product trials is no easy task but following this three-step process can help improve the regulatory journey from classification to market clearance. Additionally, a CRO with medical device and pharmaceutical experience can assist in providing accurate and current direction and best practices to companies that will have immediate and long-term impact on the success and use of the pivotal trial and the subsequent data.
For more information, view our white paper at http://novellaclinical.com/resource/clarifying-regulatory-road-combination-products/.
Eric Distad, Senior Director, Medical Device and Diagnostics Division at Novella Clinical. Mr. Distad has over 17 years’ experience in all facets of clinical research including 13 years in medical device clinical research, ranging from one of the top three medical device companies to startup companies. Geographically, he has significant experience managing trials in the United States, Canada, Europe, and Hong Kong/China. He can be reached at email@example.com.
The opinions expressed in this blog post are the author’s only and do not necessarily reflect those of MassDevice.com or its employees.