Trials and Tribulations
Partnering With a CRO Can Make All the Difference in Saving Time and Money in the R&D Process
By Jennifer Whitney, Editor
The advent of clinical trials goes back as far as 1020, according to Wikipedia, but it’s not been until the past 50 or so years that rigorous testing of medical products has been employed. Clinical trials are a routine part of the development process for pharmaceutical products, since the FDA dictates specific phases of study that must be completed prior to submission for approval. However, not all medical devices (depending on class) have such stringent requirements that need to be satisfied prior to approval.
In the past few years, though, some of the latest innovations have necessitated more safety data given the novel technologies they employ. Adding to this is the growing number of watchdogs—regulators, politicians, advocacy groups and the media, not to mention the end-users themselves—seeking to ensure that products today are proven safe and effective for use.
“In the early years, many companies were quick to jump into pivotal studies without fully understanding their own device design and how the product should be studied,” said David West, PhD, vice president, medical device development for Quintiles Consulting, a division of Research Triangle Park, NC-based Quintiles Transnational Corp. “In more recent years, companies recognize the value and critical role of pilot studies and feasibility studies to help guide product development and the design of the pivotal study.”
The proliferation of clinical trials being held today isn’t just about new products, though. Many manufacturers desiring expanded indications for their products will perform new clinical trials to gain approval.
Another factor giving rise to the number of clinical trials is that the opportunity to be granted reimbursement for a new product is strengthened by irrefutable evidence about the product’s attributes. “Sometimes you can just argue your reimbursement codes without any clinical data on a device per se, but it’s getting more common to demonstrate something specific to your device to gain reimbursement in the first place,” said Helen Colquhoun, CEO of Pleiad Devices, a clinical research organization (CRO) with US headquarters in Cambridge, MA (European headquarters are in Scotland). “Cost capping is going on everywhere in the world, and everyone is trying to get better value for the dollars spent. If you have no clinical information about how your device works, it’s increasingly difficult to argue for reimbursement.”
Finally, many companies are taking heed of recent large-scale recalls and ensuing legal debacles associated with Merck’s painkiller drug Vioxx and Guidant’s implantable cardiovascular products, which gained widespread attention in the media and cost the manufacturers hundreds of millions of dollars in legal fees and payouts to patients who received the drugs or devices. A recent analysis by Consumer Reports shows deaths linked to medical devices are at an all-time high, with 2,716 fatalities (as well as increased hospitalizations related to the devices) reported in 2006, more than double the number in 1997.
“Manufacturers today need to consider both their responsibilities to the public and the agency’s expectations with respect to post-market surveillance data, as well as their own requirements for data to defend against potential liability suits. Companies need to view themselves as the stewards of their products, and the public is expecting them to take on bigger responsibility for the product,” West said.
And with good reason. The FDA’s Division of Bioresearch Monitoring, responsible for ensuring data quality, among other quality initiatives, has brought forth increased allegations of research misconduct among device companies in the past year or two, according to a recent presentation given by Susan Rockwell, manager, clinical trials and clinical development for Medical Device Consultants, Inc. (North Attleboro, MA), at the recent MPO Symposium held in November. In 2006, she noted, 82 inspections of clinical trial sites led to 154 allegations of misconduct. The more common study-sponsor deficiencies cited were inadequate monitoring practices (23%), failure to secure investigator compliance (13%), inadequate device accountability (15%) and failure to obtain FDA/Institutional Review Board approval (5%).
Given the challenges facing device professionals in terms of their clinical research programs, it’s not surprising that many OEMs are opting to partner with a CRO to manage these types of projects.
A Growing Phenomenon
The CRO market, comprised of an estimated 100,000 professionals globally, currently is estimated at $10 billion, with growth increasing at rates of 14%-16% annually, according to the Association of Clinical Research Organizations. Outsourcing to CROs can present a variety of benefits to medical device manufacturers, the most notable being the ability to mange product development processes more efficiently and cost effectively. In fact, independent research by KMR Group, Inc. found that clinical trials conducted by CROs can be completed an average of 30% faster than those performed in-house.
Indeed, today’s CROs and other providers of R&D programs can help with everything from helping companies scout locations for clinical trials to identifying qualified investigators to oversee trial sites, employing the correct statistical methodologies, using the right sample size in studies and other planning.
“A general problem is to accurately define the objectives of a clinical trial and to set up the necessary and/or sufficient criteria, patients and endpoints to document these objectives,” noted Dr. Rosy Eloy, medical director for Europe at Biomatech, a Chasse-sur-Rhone, France-based division of NAMSA (with US headquarters in Northwood, OH). “The CRO [can] be involved in the leadership of all steps of the clinical evaluation: design, regulatory, protocol, investigation plan and CRFs discussion with the investigators; investigator evaluation and follow-up; monitoring; database setup; evaluation of data; statistics; preparation of investigator meetings and preparation of intermediate/final reports; compliance to regulations; preparation of adverse events reports…The adequate selection of the CRO will also provide all support around the clinical trial, including, for example, the submission of the data to potential investors. In this case, the CRO will act as an independent but competent third party who is able to efficiently assist the [device manufacturer] in the process of product/technology selling.”
One of the biggest benefits an outsourcing provider can offer is assistance with investigator selection and patient enrollment, said Susan Atkinson, PhD, senior vice president of biostatistics and data management for PPD, a global CRO based in Wilmington, NC with offices in 30 countries. “Studies that have slow enrollment will have a big impact on how long it will take to get a product to market. We can influence those factors to help avoid missteps and efficiently use our resources to get to market sooner without cutting corners on quality and product safety evaluation,” she said. “We customize our delivery approach based on our client’s operational and financial objectives. Understanding our client’s corporate objectives and milestones and providing input into trial design are keys to a successful communication and operational plan. We can help them with their study start-up activities and ongoing trial timelines to ensure success.”
Global Outreach Made Easier
As more companies look to market their products in regions such as Latin America, Europe and Asia, those that are based in the United States and unfamiliar with these geographies often need help complying with a new set of regulatory requirements. Many CROs are well versed in overseas regulations that can present language and jurisdiction challenges and have devised robust internal systems for performing trials with ease in multiple time zones.
“If I am working with a client on how a process is regulated in Germany or Australia, I can collaborate with one of my colleagues in that particular country to tap their expertise and current opinions. The global access is something that smaller and medium companies may lack, which they can gain by working with a consultancy that has that capability,” explained Barry Sall, a principal consultant for PAREXEL Consulting, a division of PAREXEL International in Waltham, MA.
For example, Sall recently had a client who was looking to perform clinical research on a device used to diagnose a seasonal disease. Since the United States didn’t have a climate that was conducive to studying the device at the time of the year the company wanted to start its research immediately, PAREXEL leveraged its ability to identify alternate locations to carry out the project. “They might have had to wait a year before they could be able to start the work otherwise,” Sall explained. “But we were able to leverage out global capabilities and locally based experts to help our client start its study sooner.”
Jean-Pierre Boutrand, general manager and scientific director of NAMSA’s Biomatech division, has found that a growing number of US- or European-based device manufacturers are using European clinical data for 510(k)/PMA approval in an attempt to shorten the process. However, while US data usually are acceptable for CE marking, data from Europe may be acceptable only under certain conditions in the United States. Therefore, CROs with quality systems that are capable of complying with both ISO 14155 (parts 1 and 2) and the FDA’s 21 CRF (parts 50, 56 and 812) can be of great benefit to companies lacking these systems, he said.
“In addition to these basic requirements, during an informal [investigational device exemption] meeting at the FDA, one must consider discussing the following elements: study designs and objectives; how to overcome any difference between the state-of-the-art or current evaluation methods in both continents; volume of foreign data that the FDA will accept; and what is the right combination between the early endpoints providing performance data (CE marking and European Notify Bodies) versus latter efficacy data (as expected by the FDA),” Boutrand explained. “The goal for combining studies in the US and in Europe is not just to avoid repeating studies over both continents, but also to accelerate the time to market, as it is generally faster to initiate a pilot study in Europe than in the US, and use the EU pilot data to define the pivotal study.”
Even if a company doesn’t plan to market its product abroad, Colquhoun has found that many companies, particularly those that are small in size, are saving money by conducting trials in low-cost regions such as South America. Although money can be saved, she has found that this is only possible if a company truly knows how to structure the study and manage the process. “We’ve been involved in two situations in which data were gathered in countries such as these, and the studies weren’t properly monitored,” she said. “In the end, I’m quite sure the total cost of the study is going to be just as expensive as if they’d done it in the United States. They came to us after the fact, and we had to clean up the situation for them.”
Since CROs manage many studies simultaneously in various regions of the world, many have invested in information systems that give their medical device clients an opportunity to review emerging data in real time. With PPD’s electronic data collection systems, for example, “Companies we work with will know how their study is progressing as soon as investigative sites capture and enter the data,” said Atkinson. “We’re looking for trends, assessing data queries, making sure we’re collecting data in a way that will stand up to regulatory scrutiny and evaluating if we need to improve any training or processes. Data quality and time to market are improved with ongoing evaluation of study progress.” The other benefit, she added, is that if any particular site isn’t fully compliant with standards or regulatory requirements, PPD can intervene more quickly and address any concerns.
How to Select a CRO for Your Outsourcing Needs
Although numerous CROs are in operation today to serve myriad healthcare needs, they’re still relatively new partners for medical device companies. As such, experts advise device manufacturers to be sure that a prospective partner truly understands the device market as opposed to simply being well versed in generalized regulatory affairs and statistics. In addition, specific therapeutic expertise is highly desirable. If you are considering turning to outside help, the experts offer the following advice in selecting a CRO.
A good first step is to talk to colleagues and seek referrals, West said. “It’s amazing how collegial and cooperative competitors can be. CEOs and senior managers can be sources of the best referrals. Almost all of our new work comes to us through direct referrals from other clients,” he noted.
Along with referrals from colleagues, it’s helpful to identify potential partners by scouring the Web. Colquhoun suggests targeting up to eight CROs and interviewing them about their capabilities. Once you have identified a number of candidates, narrow down the list to three providers that appear to be a good fit for the company’s needs. Next, solicit written proposals from each of the top three candidates.
Don’t base your decision solely on cost, experts cautioned—a better determination of the optimal fit is to select a provider that will offer the best value for the money. “Because running a clinical investigation is a teamwork, the team process and effectiveness matters,” Boutrand said. “Obviously, a long-term relationship will facilitate the overall performances and the selection of the partner.”
Furthermore, examine the CRO’s corporate culture and figure out if it jives with that of your company. “It’s all about the culture. Many people throw their hands up when I say that, because it doesn’t sound very concrete, but culturally the companies should be similar. If you are a go-getter and marry that with a CRO that is very regimented [for example], that’s a match made in hell, not in heaven,” Colquhoun said. “But if you have a small, flexible CRO that is used to projects with changes in scope, culturally that will probably be a good fit.”
Several of the largest CROs believe the best partner is one that offers a wide range of services under one roof. Since unexpected events can crop up while a device company is devising its R&D strategy, the expertise of a CRO that additionally manages non-clinical research initiatives (as a complement to its clinical trial skills) can make a difference in accelerating timelines.
Above all, be realistic about what to expect from your partnership. “I spent half of yesterday with a client where we plotted things out with more than one product that will be going through the pipeline. No matter where the funding is coming from, even established companies, everyone is looking at working as fast as possible. We needed to bring our scientific, regulatory and business expertise to the table and build a strategy that will work for the client,” Salls of PAREXEL said. For this customer, he said, much of the work involved devising a strategic roadmap and accompanying timeline. “In sitting down with the CEO and chief scientific officer, they’d love to be able to say, ‘In two months we’ll be to market.’ That’s not going to happen in this case, though. They needed to come up with a realistic estimate and work their business strategy around that.”
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With the device industry seeking to strengthen its pre-clinical and long-term safety and efficacy data—thanks to stricter FDA regulatory enforcement, a tougher reimbursement climate and the need for more proactive risk management—companies most likely will see even more attention paid to their R&D programs in coming years. This bodes well for the growth of outsourcing relationships with CROs.
As Atkinson noted, “In 2003, PPD established a unit dedicated just to devices and diagnostics, which indicates we believe the market will continue to grow. As the FDA enforces strict regulations to oversee the safety of devices, the device industry will need to proactively align regulatory expectations with corporate goals to have successful programs. As they’re doing that, they’re turning more to us for our device and therapeutic experience and our proven track record to resource trials globally.”
Sidebar: CRO Consultants: Going Beyond Clinical Trials for Research Programs
Maybe you’ve got a great idea for a new product and are ready to capitalize on it but don’t know enough about regulatory processes to proceed with the tasks that will be needed to eventually gain approval. Or perhaps you are a regulatory professional working for an OEM that has some terrific design engineers with some great inventions in mind, but you’ve got too much on your plate to help get these concepts into your company’s R&D pipeline.
So many ideas but too few resources can leave a product idea languishing when it could be reaping profits. But with the help of a consultant, new products often can get through the R&D stage more quickly and less expensively.
For example, Quintiles Consulting, a division of Research Triangle Park, NC-based Quintiles Transnational Corp., works with companies of all sizes looking for guidance in navigating regulatory requirements to gain approval for their products. “In our group, we have among our staff individuals who have worked inside the agency and bring the perspectives and sensitivities to FDA’s thinking,“ noted David West, PhD, vice president, medical devices for Quintiles Consulting.
Large companies often look to consultants, he said, when second opinions are needed or an internal R&D staff is too overloaded to handle new projects. Smaller companies, on the other hand, can turn to one source of expertise to help them gain the fundamental knowledge needed to proceed with developing strategies and design controls, identifying the essential preclinical tests needed, managing FDA interactions, and narrowing target indications for use.
“Younger companies sometimes don’t have the experience to anticipate the regulatory and clinical communities’ expectations of their product or data,” West said. “They often are focused on what they see as the attributes of their device, and that focus sometimes is too narrow and they have difficulty seeing the broader issues—either regulatory issues or public health issues. We can help them articulate the benefit of their product and put it in broader perspectives.”
A growing market for CRO consultancies is the cluster of start-up ventures that aren’t looking to actually get involved with manufacturing a new technology but, instead, prefer to prime themselves as an attractive takeover target. In these cases, consultants can use their industry experience to help these “virtual” companies formulate exit strategies (ie, sell their technology to a larger player).
And sometimes, a client simply may need help in keeping up with the ever-changing regulatory landscape. For example, several years ago, a manufacturer of kidney dialysis membranes approached Quintiles for help after the FDA announced that manufacturers of dialysis membranes being reused in dialysis centers would soon have to gain special labeling and get validated for re-use of the product. Before the guidelines officially were released to manufacturers, the client approached West’s division for help in obtaining the new labeling and validation required.
“We helped them undertake the preclinical testing as well as the studies required, and we provided insights into how to design the experiments,” West recalled. “All of these companies were on the starting line at the same time, because they had to wait for the guidance document to come out. In the end, we submitted a 510(k) three months before any of the company’s competitors. They were the first on the market with this reuse labeling. To me, it’s a dramatic example of how we can help companies.”