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Orthopaedic device manufacturers continue to outsource clinical research projects, as the importance of data collection grows and the complexity and cost of studies increases. BONEZONE asked three experts to share their insights on best practices and strategies for conducting clinical trials inside and outside of the U.S., as well as ways to manage outsourcing of the process to a partner.
Participants included:
Marcy Rogers, President and CEO, SpineMark
John Lehmann, Director of Business Development, IMARC Research
Hallett Mathews, M.D., Executive Vice President and Chief Medical Officer at Paradigm Spine and Former President, Musculoskeletal Clinical Regulatory Advisers (MCRA)
BONEZONE: What challenges do OEMs report with clinical trials?
Marcy Rogers: Traditionally, the biggest challenges have always been patient recruitment, managing the budgets (whether they are choosing an insurance model for payment for clinical services versus cash) and meeting the enrollment criteria of FDA without incurring a long list of post-market studies.
John Lehmann: The biggest challenges that we see lie in the areas of trial recruitment and protocol compliance.
Hallett Mathews: First of all, the barrier for clinical trial approval has changed so much with regard to whether it’s a 510(k) approval or a Premarket Approval (PMA). The trial itself is under challenge, specifically, not necessarily if it’s a 510(k) of just being substantially equivalent, but could it show equivalence with clinical data to support outcomes? Outcomes are being injected into 510(k) approval status, so a lot of 510(k)s actually have to produce clinical evidence as well as substantial equivalence to get their 510(k) approval. For the PMA, it’s a whole different game. It’s usually a level one perspective randomized control study that really challenges methodology and challenges the highest level of evidence, because it’s difficult to have blindedness in medical device insertion or device trials. It’s difficult to have sham procedures, so we are always challenged to get the highest level of evidence in order to get the best labeling or approval for a PMA study.
BONEZONE: What clinical trial strategies or best practices do you recommend, presently? Do these recommendations differ greatly from those of five years ago? Ten? How so?
Rogers: There are a number of trials going on right now. Some are smaller registry type trials, looking at collection of data on patients; others are new technologies. Orthopaedics currently has more innovation than spine in terms of trials. Spine is not very active in conducting the large number of studies that they had in the past. In 2008, there were ten, 12 or 15 clinical trials going on at the same time. Orthopaedics seems to be more active in that area and the trends are addressing biologics, new devices from our generation one, two or three, innovative ways for access and various bone substitute materials.
Lehmann: There has been an increased emphasis on risk-based monitoring (RBM) and increasing awareness on value of auditing. RBM has been a hot topic of late. Many see this as a way to control monitoring costs, which isn’t always the case. IMARC sees this as “intelligent” monitoring, making decisions based on site performance. As to auditing, more sponsors are making this investment earlier in studies as a way to prepare and take corrective action in case of an FDA audit.
Mathews: Obviously, evidence rules, and the better the level of evidence, the better your marketing claims and your ability to receive approvals for new technologies. I really think that it’s important that people understand the game that they’re in, whether they’re in the 510(k) world and want to be substantially equivalent and get quick to market, or if they want to be able to make marketing substantiations through evidence. With evidence, then comes the ability to look at clinical outcomes and performance, safety and efficacy of a device. Then, that can be translated into marketing claims and differentiation for their products.
BONEZONE: Have you seen a greater emphasis on conducting clinical trials outside of the U.S.? If yes, in what global regions are orthopaedic device companies focusing their research?
Rogers: I’ve seen a much greater interest outside the U.S. in Spain and the United Kingdom. You’re seeing a lot of companies go outside the U.S., because in some cases the locations offer lower rates for the whole study and that makes it easier for manufacturers to get their data. You’re seeing Croatia as a market; India is also a market. The E.U. and the U.K. have also revamped their systems so that everything is electronic, and in many cases you can file for your trial and be up and running and ready to roll in patients in about 30 days. When you’re looking at markets, it really comes down to your budget. The data and cost of the trial is going to be more expensive than in places like Poland, Romania, Croatia, India or Mexico.
Lehmann: Yes, we definitely see a trend for more ex-U.S. studies. Many sponsors view this as an easier regulatory path, thus a way to begin generating revenue. Many are going to Europe and the Pacific Rim.
Mathews: Yes, it’s difficult and expensive in the U.S. to get good, high-quality clinical trials done because of the cost of services and the reluctance of a lot of people to enroll patients in clinical trials. It’s hard to do research in the U.S.; it’s under a lot of scrutiny. There’s always risk of audit from FDA, and it’s difficult to do the highest level of research unless you’re a totally dedicated research institution, of which there are not that many. So, it’s just a difficult and expensive process in the U.S. versus ex-U.S. and different regions, such as the EU, which is France, Germany, Italy, Amsterdam, Netherlands, England, countries that can do good quality research and can basically adhere to the same standards at a much lower price point. There is an emphasis on going outside the U.S. for at least pilot studies for PMA approval products and maybe even pilot to pivotal studies for PMA products.
BONEZONE: What services are orthopaedic device manufacturers most interested in when seeking an outside vendor, such as a clinical research organization (CRO)? How has this changed over the years?
Rogers: As I see it, there’s a huge need for a vertically-integrated approach to clinical trials, which is what we’ve put together and what we’re trying to accomplish. Managing all the arms of this can be very time intensive, labor intensive and costly. Right now, what I’ve seen in the industry is a move toward working on pricing and accelerated enrollment.
Lehmann: As a medical device CRO that services the orthopaedic market, we have provided monitoring, auditing, good clinical practice (GCP) training and consulting services. This happens to be our core service offering and has not changed over the years that we have serviced this therapeutic area.
Mathews: They’re looking for the complete service line. It’s very expensive for medical device manufacturers to house a clinical department that can really do it all. Over the last ten years, it’s been a growing trend that a lot of this is outsourced. Even more of it’s outsourced to the point of doing the entire clinical study outside of a manufacturing company and totally outsourcing everything, from monitoring, to collecting the data, to the analysis and then to submission. I think the trend is to get more and more outside of the country support for an advanced clinical study.
BONEZONE: What one question should orthopaedic device manufacturer customers ask when seeking the services of a CRO?
Rogers: What differentiates you from anyone else in the market?
Lehmann: Assistance with site qualification and selection, involvement with site initiation visits and investigator meetings.
Mathews: Defining the overall intent of what the study is supposed to do, and also defining the goals. Is it to get a product approval without market substantiation of claims and to get the least amount of labeling possible? Or, is to get the most amount of labeling with the most market substantiation, and the most safety and effectiveness of clinical data? Defining the intent of the study at the beginning is as important as the outcome of the study. You must understand the original intent and what the goals are, and then execute the study—those are the keys. It’s that synchrony that really gets a good process going and provides a lot of value for the company sponsoring the study.
