Studies Often a Trial
As sponsoring companies face cost and timing challenges, the role of CROs in clinical studies continues to expand.
Clinical trials are the lifeblood of most medical device companies’ existence, but they’re also the bane of that existence, as they take vast amounts of both time and money.
Many OEMs—at least those who fall into the small or midsized category—are mitigating the time aspect of that formula by outsourcing some or all of their clinical trial activities. Even the so-called “big guys” in the device space are spinning more and more of those activities to contract research organizations (CROs) and others who provide a variety of services in the clinical trials space.
Medical Product Outsourcing asked several people involved with different aspects of work on such trials to reflect on trends in the trials business, particularly including how the U.S. Food and Drug Administration (FDA) is addressing clinical trials activity.
Evan Rosenfeld, M.D., J.D., vice president of medical and scientific affairs, medical devices, at King of Prussia, Pa.-based Theorem Clinical Research, said the FDA has shown “a devotion to encouraging promotion of study initiatives for medical devices” over the past few years. He cited a 2011 FDA guidance document in which the agency referred to its efforts to promote the timely start of studies while still protecting trial participants.
“One of the ways it proposed doing that was to allow studies to begin, under certain circumstances, even if there were still outstanding issues in Investigational Device Exemption [IDE] submissions,” he said. “Depending on the nature of the device and the study, you either have to go through FDA and an Investigational Device Exemption in order to get approved or you can go direct to an IRB [Institutional Review Board] if it’s a less risky type of device. The FDA has basically allowed the sponsors of the more risky types of products to move forward with their IDE submissions and their studies under several scenarios.”
Jennifer Buell, Ph.D., senior director of clinical program management at Harvard Clinical Research Institute (HCRI), a Boston, Mass.-based, Harvard Medical School-affiliated academic research organization, said that with respect to general trends in trials in the device space, “we’re seeing changes in manufacturing innovation in terms of what products are becoming available and that drives trends in clinical trials. In addition to the innovation in interventional products, we’re seeing growth in the area of prevention-oriented devices, and consumer-available products in terms of ‘What can we use at home?’ ”
In that realm, she said, “the FDA is really emphasizing human risk management: How do you best describe how hazards related to medical device use are addressed during development of clinical trials. How do you demonstrate that there is no hazard for these devices?”
Buell added: “One of the more significant changes that we’re seeing from the regulatory side is that we have to demonstrate the ability of not only clinical use safety, but now also consumer use safety.”
Linda Alexander, a vice president at NAMSA, a Northwood, Ohio-based CRO, said many companies now are looking for high-quality clinical trials to be conducted outside the United States. “The reasons include time and cost—or perhaps just cost. For a clinical trial, more time means more money. Worse than that, more time means the start to revenue is delayed; for one spinal company we worked with, every day of delay meant a million dollars in lost revenue.”
Alexander, the founder and CEO of Alquest LLC before that company’s acquisition by NAMSA in the latter part of 2009, said the most significant recent change “is FDA’s shift to expecting much more from post-market clinical trials. They’ve heard the criticism of the device industry that it just takes too long to get approved in the U.S. but they’re also seeing hints of longer-term complications from devices they need to evaluate. The result is an increased focus on getting longer-term, broad-based, real-world device experience.”
She said that while the new emphasis on post-market studies “might seem like ‘kicking the can down the road’ in terms of understanding product safety, it seems like the only realistic approach that could both encourage innovation and ensure the long-term outcome is understood. However, costs are going to go up for manufacturers and, combined with the device tax, the pressure will be difficult.”
Rosenfeld also cited the trend toward expanded requirements for post-market surveillance, saying that has become another area in which companies such as Theorem become heavily involved.
Michael Winegar, head of regulatory affairs, medical devices, in the Minneapolis, Minn., office of the Cincinnati, Ohio-based Medpace Inc. contract research organization, said that “offshoring of trials still is a major focus,” but added that another big trend is the FDA asking for more clinical trials on 510(k) devices, “which is certainly a change. The big change is the need for clinical data in 510(k) products, and having statistical rigor to it. You’re not going out there and running a 30- or 40-patient trial; you’re actually doing a 100- or 200-patient study, possibly even more. They’re usually non-randomized, but still, they’re clinical trials.”
He acknowledged that the agency is showing much more flexibility when it comes to conditional approvals. “It’s not overly difficult to get an IDE conditional approval as long as you’ve proven that your device is safe and is not going to do any harm.”
Encouragement From FDA
Theorem’s Rosenfeld said one of the four scenarios being followed by the FDA is approval with conditions, “which is saying that a study can start on the condition that its sponsor agrees to submit the information to address the identified issues the FDA has found, usually within 45 days of that conditional approval. Then there’s something called ‘staged approvals,’ which means that there are still outstanding issues, but they have approved the IDE and the sponsor must address those issues that will be gathered in parallel with the enrollment of some portion of the study subjects. There’s another aspect of this called ‘staged approval with conditions,’ which is a combination of the two prior approaches. And then there is a fourth approach called ‘communication of outstanding IDE issues through future considerations.’ ”
For the latter, he said the FDA may inform the sponsor of one or more issues to be considered in the later market application or future clinical studies that might be done. “For example, if there are known limitations for the IDE study itself that is under consideration, let’s say in regard to certain claims or considerations that might be addressed later—for example, specific exclusion criteria in the current IDE—those might be things that FDA says, ‘Well, you need to address that later, but in the meantime you can go on with your study as it is.’ Another example is potential IDE limitations that depend on variables that are currently unknown and that may become known over the course of the study or after the course of the study,” Rosenfeld noted. “That’s one very general trend in device studies.”
To MPO’s observation that the FDA seems to be much more willing to have trials move forward, even if all the Ts aren’t crossed and I’s dotted, Harvard Clinical Research Institute’s Buell said, “I would agree with that assessment of increased FDA support for trial activation. Once there has been a demonstration of no harm, there does seem to be strong FDA support for expediting a trial.”
Medpace’s Winegar also cited the initiatives that FDA is trying to put in place to encourage first-in-man studies and feasibility trials in the United States, which he said “are being talked about with regularity as an alternative to going offshore and doing those kinds of studies, including the release of draft guidance relating to feasibility and first-in-man trials late last year.”
Rosenfeld said another trend with the FDA is more emphasis on reporting adverse events promptly and accurately to both the IRB and/or FDA. “There has been a very large emphasis on the application of human factors—something called human factors analysis, in which the FDA is interested in having the sponsor show whether or not the investigational device can actually be used properly in a real clinical setting. So, for example, in real use, is it simple enough or straightforward enough so that it will be used without too high a risk of error, or is it too complicated, which increases the risk of potential error while using that device?
“There also has been much more stress on quality system compliance for quality and accuracy of study results, and there also has been a move to risk-based monitoring strategies and plans,” Rosenfeld said. “The primary goal of that is to protect the rights and welfare and safety of the study subjects while also preserving and improving the quality of the data that’s going to be going to FDA.”
He also cited the issue of requirements of pediatric studies. “In the past, pediatric populations have been very much ignored or left out of studies, but now, unless you can show that a condition is primarily limited to an adult population versus a pediatric population, there is often a requirement that you include those pediatric populations in your studies.”
Buell said that what HCRI is seeing from the agency side “is they’ve been going out and doing quite a bit of independent monitoring, determining whether the risk-based approach to monitoring is working, and they continue to support it. We’re seeing a reduction in trial costs of 30 percent to 60 percent overall, driven largely by U.S. regulatory initiatives. We are likely to see similar adaptations in Europe. I think that’s a significant advantage to U.S. trials right now.”
Harder in America? Maybe Not
Asked by MPO why it seems harder to start a clinical trial in the U.S. compared to almost every other advanced country, Rosenfeld said, “That is not necessarily true. I think it’s a very widely held misperception that starting a trial in the U.S. is necessarily more difficult or more expensive than doing so elsewhere in the developed world.”
For example, he said that for devices, “studies are split into two general categories. One is a ‘significant risk’ category and the other is a ‘non-significant risk’ category. Those two categories are based on the nature of the product being studied. For non-significant risk types of devices, let’s say ones that are not implanted, that do not impose risks to health or are life-sustaining types of devices, those trials only need IRB approval—they don’t have to go to FDA or get IDE approval from the agency. So it’s very similar for getting approval for trials of such devices as it is to getting approval in the EU for studies outside the United States. From that standpoint, there’s really no difference.”
Buell agreed with Rosenfeld’s view on trial approvals for non-critical devices. “That’s exactly right,” she said. “It’s true for devices and diagnostics as well. It’s easier to conduct trials in the U.S. The regulatory initiatives in some of the BRIC (Brazil, Russia, India and China) countries, with clinical trial registration requirements and the implementation of increased regulations without the formal infrastructure, has resulted in delays in initiations.”
She said that while the United States remains a high-cost place to conduct trials, some of that impact is mitigated by other positive factors such as not spending money to send staff overseas, being a lot more certain about trial enrollment, and other similar factors.
Furthermore, Buell said, “the FDA is strongly adopting risk-based monitoring, which has supported a significant reduction in overall trial costs while maintaining data integrity.”
Given the ease of gaining approval for trials of non-significant risk products, Winegar said, “If you gain an IRB approval for a study that meets the NSR [non-significant risk] definition, it really makes no sense to go outside of the U.S. In addition, FDA is amenable to granting conditional IDE approvals if safety is proven. The U.S. IDE process is 30 days and there are very few countries outside the U.S. that have a 30-day review cycle for clinical trials, it’s usually going to be 60 days or more.”
On the other hand, he said, “If you want to get a 10-patient study approved to show feasibility and you do it in Europe, you’re going to need less development data than you will in the U.S. so there’s a chance you can start earlier OUS [outside United States].”
Alexander cited what she termed “FDA’s changing expectations for what’s needed to gain approval to start. What used to work, sometimes even last year, might not get you approval now.”
Trial Management a Key Need
Asked which activities most lend themselves to being outsourced, Winegar said, “If you consider a foreign clinical trial and you look at the folks who might be running that, small and midsized companies likely are not going to have the local knowledge and resources to manage a trial OUS, so certainly trial management is an important part.”
CROs are valuable on the back end as well, he said, “particularly in having local monitors who are familiar with the language and the requirements of a specific site within a specific country. The front end and the back end are really where outsourcing to people with knowledge of the product and the region is a great asset, and from a continuity standpoint, you want to involve an outsourcing partner if they’re also involved with your overall regulatory plan.”
Rosenfeld said sponsoring companies can look for everything from singular services that are part of the overall trial program, or want to hand off the entire project to an outsourcing partner. “There can be one service outsourced to CROs or 20 services outsourced,” he said. “It often depends on the site or sites where the sponsors are conducting their studies.” Many companies, he continued, “are looking for a one-stop shop for their clinical trials and for development of their product, so that includes not only running their clinical trial but also up front strategically figuring out what the regulatory pathway is going to be, what are the clinical strategies that are going to best optimize getting the product into clinical studies and to market, and then covered by reimbursement, whether it be Medicare or private payers. So companies often are looking to outsource that entire effort.”
For her part, Buell said, “In this era of risk-based monitoring, having outsourced the setup of the trial at the beginning and the analysis piece of it at the back end, in the middle are all of those components of the trial where you’re actually looking at the risk—where are patients falling out, where are there going to be data concerns? Outsourcing the activation piece is important, but there are definite advantages to having an integrated, outsourced data management team with a statistical interface to enhance data monitoring and evaluation.”
Winegar said that “Big Pharma” for some time has followed a pattern of contracting out all of the management of a massive trial, beginning to end, “and now we’re seeing large device companies starting to do that also. At first it was in post-market studies, where they wouldn’t want to staff up for such studies and would contract that out to a CRO. But we’re starting to see requests for premarket trials as well.”
NAMSA’s Alexander cited trial monitoring and data management, “with complete trial management right on the heels of that.” She said that for outsourcing partners, integrity and a system that ensures data quality are “table stakes.” The partner should be responsive, she said, “excellent at communicating and have the right plan to speed the trial to completion. Experience in the therapeutic area is a plus—especially for ensuring access to the best physicians and for protocol design.”
Safer in the United States? ‘Maybe’
Is the United States “safer” than other countries when it comes to clinical trials? Maybe. Rosenfield claims that many studies conducted outside the United States “have some inadequacies and different standards than we have here in the U.S. They have different standards of subject selection criteria, subject safety, how much informed consent needs to be taken and how data is collected and managed.”
Outside the U.S., “there sometimes is greater emphasis just on basic safety of a device rather than efficacy as well. In the U.S., you have to show substantial equivalence to a device that is safe and effective in order to get approval or clearance. For the CE mark, you only have to show the product is safe; the efficaciousness of the product comes later in post-marketing studies. For that reason, U.S. trials likely are safer.”
HCRI’s Buell said, “I think there are some very rigorous safety requirements and regulations regarding oversight of patients in U.S. trials, but that said, there also are the same rigorous patient protections in Europe as well. Now, data has revealed that some countries new to clinical trials may not have those same protections—they don’t yet have such rigorous requirements in place.”
Winegar opined: “I don’t know if it’s any safer, really. Many industrialized nations have fairly rigorous premarket clinical trial approval processes.”
But, he said, “there are companies out there who say, ‘We want to see if it works before we spend any more money on it, so let’s go to Venezuela or some other country with a less-developed regulatory system and try it on a few people.’ Obviously that’s not going to happen in the U.S., but that’s not going to happen in Europe either. It’s going to be those Tier 2 countries where they may have a Ministry of Health but they don’t necessarily have a developed regulatory structure and likely don’t have an enforcement arm to that ministry.
Alexander said, “The Informed Consent process is typically more robust, but that’s about it. Working with the right partner, one familiar with U.S. ethics and regulatory expectations, can optimize the trial for both patient safety and regulatory success.”
Pros and Cons of OUS Trials
Tackling a question on the advantages and disadvantages of conducting clinical trials in India, China and elsewhere, Alexander said: “On the plus side—speed of enrollment and cost savings for per patient remuneration. On the down side—your data may not be accepted or you could lose control of your trial completely (investigators enrolling patients outside those you intended or not documenting information, significant protocol deviations or adverse events), risking your company’s reputation as well as the clinical trial data.”
She said that small and medium-sized medical device companies “often try to conduct a trial with just one clinical manager/monitor sent overseas. While this seems like a good, low-cost solution, it often results in significant trial delays. Navigating a foreign culture and trying to execute the study with too few people have led more than one company to failure.”
Rosenfeld weighed in: “Let’s take India as an example. Our company is not currently conducting any trials in India. About two years ago there were some very high liability constraints that were imposed by the authorities in India, so while we do have an office in India and do provide services through that office, we don’t run clinical trials there. That’s one of the disadvantages of India—very high standards of liability that many sponsors are not willing to take a risk of the process.
“On the other hand, there are multiple advantages to conducting trials in China. One is access to patients; you have a billion people there, and the approval process often is less time-consuming than the E.U. [European Union] countries or in the U.S., and enrollment is often quicker than in the U.S. or E.U. On the flip side, the quality of data may differ. To ensure the data, a CRO like Theorem has to spend a lot more time at the sites in China and provide more support than at sites in the U.S. So that costs more, but the average cost may still be less than in the U.S. and E.U.”
Buell said a big disadvantage in doing trials outside the United States is whether the FDA will accept such data. “That’s always a big risk that sponsors take on when they initiate trials OUS.”
She said that one thing sponsors “often have not done particularly well in OUS trials is characterizing the patient population, because there often are differences culturally, behaviorally, and in physicality that may impact use of the product.”
Winegar said that based on where FDA “still is today in practice, those early trials, those first-in-man studies and non-randomized feasibility studies of 10 to 20 patients, I still think those are best done offshore. First, it’s hard to get that kind of a study approved in the U.S. You need to provide a lot of data in an IDE to get that approved. Secondly, if you’re running a study in a major market like Germany, say, you keep it off the competitive and scientific radars a little bit more than if you were running it in the U.S., in case things don’t go as well as you anticipate.”
However, he said, “I’m not a big fan of going into what FDA would categorize as a Tier 2 country. The standards of clinical trials in India or Venezuela or even China, and therefore the credibility of that data, are something that people have to be aware of and concerned about.”
Jim Stommen, retired editor of industry publication Medical Device Daily, is a freelance writer focusing on the medical product sector.
As sponsoring companies face cost and timing challenges, the role of CROs in clinical studies continues to expand.
Clinical trials are the lifeblood of most medical device companies’ existence, but they’re also the bane of that existence, as they take vast amounts of both time and money.
Many OEMs—at least those who fall into the small or midsized category—are mitigating the time aspect of that formula by outsourcing some or all of their clinical trial activities. Even the so-called “big guys” in the device space are spinning more and more of those activities to contract research organizations (CROs) and others who provide a variety of services in the clinical trials space.
Medical Product Outsourcing asked several people involved with different aspects of work on such trials to reflect on trends in the trials business, particularly including how the U.S. Food and Drug Administration (FDA) is addressing clinical trials activity.
Evan Rosenfeld, M.D., J.D., vice president of medical and scientific affairs, medical devices, at King of Prussia, Pa.-based Theorem Clinical Research, said the FDA has shown “a devotion to encouraging promotion of study initiatives for medical devices” over the past few years. He cited a 2011 FDA guidance document in which the agency referred to its efforts to promote the timely start of studies while still protecting trial participants.
“One of the ways it proposed doing that was to allow studies to begin, under certain circumstances, even if there were still outstanding issues in Investigational Device Exemption [IDE] submissions,” he said. “Depending on the nature of the device and the study, you either have to go through FDA and an Investigational Device Exemption in order to get approved or you can go direct to an IRB [Institutional Review Board] if it’s a less risky type of device. The FDA has basically allowed the sponsors of the more risky types of products to move forward with their IDE submissions and their studies under several scenarios.”
Jennifer Buell, Ph.D., senior director of clinical program management at Harvard Clinical Research Institute (HCRI), a Boston, Mass.-based, Harvard Medical School-affiliated academic research organization, said that with respect to general trends in trials in the device space, “we’re seeing changes in manufacturing innovation in terms of what products are becoming available and that drives trends in clinical trials. In addition to the innovation in interventional products, we’re seeing growth in the area of prevention-oriented devices, and consumer-available products in terms of ‘What can we use at home?’ ”
In that realm, she said, “the FDA is really emphasizing human risk management: How do you best describe how hazards related to medical device use are addressed during development of clinical trials. How do you demonstrate that there is no hazard for these devices?”
Buell added: “One of the more significant changes that we’re seeing from the regulatory side is that we have to demonstrate the ability of not only clinical use safety, but now also consumer use safety.”
Linda Alexander, a vice president at NAMSA, a Northwood, Ohio-based CRO, said many companies now are looking for high-quality clinical trials to be conducted outside the United States. “The reasons include time and cost—or perhaps just cost. For a clinical trial, more time means more money. Worse than that, more time means the start to revenue is delayed; for one spinal company we worked with, every day of delay meant a million dollars in lost revenue.”
Alexander, the founder and CEO of Alquest LLC before that company’s acquisition by NAMSA in the latter part of 2009, said the most significant recent change “is FDA’s shift to expecting much more from post-market clinical trials. They’ve heard the criticism of the device industry that it just takes too long to get approved in the U.S. but they’re also seeing hints of longer-term complications from devices they need to evaluate. The result is an increased focus on getting longer-term, broad-based, real-world device experience.”
She said that while the new emphasis on post-market studies “might seem like ‘kicking the can down the road’ in terms of understanding product safety, it seems like the only realistic approach that could both encourage innovation and ensure the long-term outcome is understood. However, costs are going to go up for manufacturers and, combined with the device tax, the pressure will be difficult.”
Rosenfeld also cited the trend toward expanded requirements for post-market surveillance, saying that has become another area in which companies such as Theorem become heavily involved.
Michael Winegar, head of regulatory affairs, medical devices, in the Minneapolis, Minn., office of the Cincinnati, Ohio-based Medpace Inc. contract research organization, said that “offshoring of trials still is a major focus,” but added that another big trend is the FDA asking for more clinical trials on 510(k) devices, “which is certainly a change. The big change is the need for clinical data in 510(k) products, and having statistical rigor to it. You’re not going out there and running a 30- or 40-patient trial; you’re actually doing a 100- or 200-patient study, possibly even more. They’re usually non-randomized, but still, they’re clinical trials.”
He acknowledged that the agency is showing much more flexibility when it comes to conditional approvals. “It’s not overly difficult to get an IDE conditional approval as long as you’ve proven that your device is safe and is not going to do any harm.”
Encouragement From FDA
Theorem’s Rosenfeld said one of the four scenarios being followed by the FDA is approval with conditions, “which is saying that a study can start on the condition that its sponsor agrees to submit the information to address the identified issues the FDA has found, usually within 45 days of that conditional approval. Then there’s something called ‘staged approvals,’ which means that there are still outstanding issues, but they have approved the IDE and the sponsor must address those issues that will be gathered in parallel with the enrollment of some portion of the study subjects. There’s another aspect of this called ‘staged approval with conditions,’ which is a combination of the two prior approaches. And then there is a fourth approach called ‘communication of outstanding IDE issues through future considerations.’ ”
For the latter, he said the FDA may inform the sponsor of one or more issues to be considered in the later market application or future clinical studies that might be done. “For example, if there are known limitations for the IDE study itself that is under consideration, let’s say in regard to certain claims or considerations that might be addressed later—for example, specific exclusion criteria in the current IDE—those might be things that FDA says, ‘Well, you need to address that later, but in the meantime you can go on with your study as it is.’ Another example is potential IDE limitations that depend on variables that are currently unknown and that may become known over the course of the study or after the course of the study,” Rosenfeld noted. “That’s one very general trend in device studies.”
To MPO’s observation that the FDA seems to be much more willing to have trials move forward, even if all the Ts aren’t crossed and I’s dotted, Harvard Clinical Research Institute’s Buell said, “I would agree with that assessment of increased FDA support for trial activation. Once there has been a demonstration of no harm, there does seem to be strong FDA support for expediting a trial.”
Medpace’s Winegar also cited the initiatives that FDA is trying to put in place to encourage first-in-man studies and feasibility trials in the United States, which he said “are being talked about with regularity as an alternative to going offshore and doing those kinds of studies, including the release of draft guidance relating to feasibility and first-in-man trials late last year.”
Rosenfeld said another trend with the FDA is more emphasis on reporting adverse events promptly and accurately to both the IRB and/or FDA. “There has been a very large emphasis on the application of human factors—something called human factors analysis, in which the FDA is interested in having the sponsor show whether or not the investigational device can actually be used properly in a real clinical setting. So, for example, in real use, is it simple enough or straightforward enough so that it will be used without too high a risk of error, or is it too complicated, which increases the risk of potential error while using that device?
“There also has been much more stress on quality system compliance for quality and accuracy of study results, and there also has been a move to risk-based monitoring strategies and plans,” Rosenfeld said. “The primary goal of that is to protect the rights and welfare and safety of the study subjects while also preserving and improving the quality of the data that’s going to be going to FDA.”
He also cited the issue of requirements of pediatric studies. “In the past, pediatric populations have been very much ignored or left out of studies, but now, unless you can show that a condition is primarily limited to an adult population versus a pediatric population, there is often a requirement that you include those pediatric populations in your studies.”
Buell said that what HCRI is seeing from the agency side “is they’ve been going out and doing quite a bit of independent monitoring, determining whether the risk-based approach to monitoring is working, and they continue to support it. We’re seeing a reduction in trial costs of 30 percent to 60 percent overall, driven largely by U.S. regulatory initiatives. We are likely to see similar adaptations in Europe. I think that’s a significant advantage to U.S. trials right now.”
Harder in America? Maybe Not
Asked by MPO why it seems harder to start a clinical trial in the U.S. compared to almost every other advanced country, Rosenfeld said, “That is not necessarily true. I think it’s a very widely held misperception that starting a trial in the U.S. is necessarily more difficult or more expensive than doing so elsewhere in the developed world.”
For example, he said that for devices, “studies are split into two general categories. One is a ‘significant risk’ category and the other is a ‘non-significant risk’ category. Those two categories are based on the nature of the product being studied. For non-significant risk types of devices, let’s say ones that are not implanted, that do not impose risks to health or are life-sustaining types of devices, those trials only need IRB approval—they don’t have to go to FDA or get IDE approval from the agency. So it’s very similar for getting approval for trials of such devices as it is to getting approval in the EU for studies outside the United States. From that standpoint, there’s really no difference.”
Buell agreed with Rosenfeld’s view on trial approvals for non-critical devices. “That’s exactly right,” she said. “It’s true for devices and diagnostics as well. It’s easier to conduct trials in the U.S. The regulatory initiatives in some of the BRIC (Brazil, Russia, India and China) countries, with clinical trial registration requirements and the implementation of increased regulations without the formal infrastructure, has resulted in delays in initiations.”
She said that while the United States remains a high-cost place to conduct trials, some of that impact is mitigated by other positive factors such as not spending money to send staff overseas, being a lot more certain about trial enrollment, and other similar factors.
Furthermore, Buell said, “the FDA is strongly adopting risk-based monitoring, which has supported a significant reduction in overall trial costs while maintaining data integrity.”
Given the ease of gaining approval for trials of non-significant risk products, Winegar said, “If you gain an IRB approval for a study that meets the NSR [non-significant risk] definition, it really makes no sense to go outside of the U.S. In addition, FDA is amenable to granting conditional IDE approvals if safety is proven. The U.S. IDE process is 30 days and there are very few countries outside the U.S. that have a 30-day review cycle for clinical trials, it’s usually going to be 60 days or more.”
On the other hand, he said, “If you want to get a 10-patient study approved to show feasibility and you do it in Europe, you’re going to need less development data than you will in the U.S. so there’s a chance you can start earlier OUS [outside United States].”
Alexander cited what she termed “FDA’s changing expectations for what’s needed to gain approval to start. What used to work, sometimes even last year, might not get you approval now.”
Trial Management a Key Need
Asked which activities most lend themselves to being outsourced, Winegar said, “If you consider a foreign clinical trial and you look at the folks who might be running that, small and midsized companies likely are not going to have the local knowledge and resources to manage a trial OUS, so certainly trial management is an important part.”
CROs are valuable on the back end as well, he said, “particularly in having local monitors who are familiar with the language and the requirements of a specific site within a specific country. The front end and the back end are really where outsourcing to people with knowledge of the product and the region is a great asset, and from a continuity standpoint, you want to involve an outsourcing partner if they’re also involved with your overall regulatory plan.”
Rosenfeld said sponsoring companies can look for everything from singular services that are part of the overall trial program, or want to hand off the entire project to an outsourcing partner. “There can be one service outsourced to CROs or 20 services outsourced,” he said. “It often depends on the site or sites where the sponsors are conducting their studies.” Many companies, he continued, “are looking for a one-stop shop for their clinical trials and for development of their product, so that includes not only running their clinical trial but also up front strategically figuring out what the regulatory pathway is going to be, what are the clinical strategies that are going to best optimize getting the product into clinical studies and to market, and then covered by reimbursement, whether it be Medicare or private payers. So companies often are looking to outsource that entire effort.”
For her part, Buell said, “In this era of risk-based monitoring, having outsourced the setup of the trial at the beginning and the analysis piece of it at the back end, in the middle are all of those components of the trial where you’re actually looking at the risk—where are patients falling out, where are there going to be data concerns? Outsourcing the activation piece is important, but there are definite advantages to having an integrated, outsourced data management team with a statistical interface to enhance data monitoring and evaluation.”
Winegar said that “Big Pharma” for some time has followed a pattern of contracting out all of the management of a massive trial, beginning to end, “and now we’re seeing large device companies starting to do that also. At first it was in post-market studies, where they wouldn’t want to staff up for such studies and would contract that out to a CRO. But we’re starting to see requests for premarket trials as well.”
NAMSA’s Alexander cited trial monitoring and data management, “with complete trial management right on the heels of that.” She said that for outsourcing partners, integrity and a system that ensures data quality are “table stakes.” The partner should be responsive, she said, “excellent at communicating and have the right plan to speed the trial to completion. Experience in the therapeutic area is a plus—especially for ensuring access to the best physicians and for protocol design.”
Safer in the United States? ‘Maybe’
Is the United States “safer” than other countries when it comes to clinical trials? Maybe. Rosenfield claims that many studies conducted outside the United States “have some inadequacies and different standards than we have here in the U.S. They have different standards of subject selection criteria, subject safety, how much informed consent needs to be taken and how data is collected and managed.”
Outside the U.S., “there sometimes is greater emphasis just on basic safety of a device rather than efficacy as well. In the U.S., you have to show substantial equivalence to a device that is safe and effective in order to get approval or clearance. For the CE mark, you only have to show the product is safe; the efficaciousness of the product comes later in post-marketing studies. For that reason, U.S. trials likely are safer.”
HCRI’s Buell said, “I think there are some very rigorous safety requirements and regulations regarding oversight of patients in U.S. trials, but that said, there also are the same rigorous patient protections in Europe as well. Now, data has revealed that some countries new to clinical trials may not have those same protections—they don’t yet have such rigorous requirements in place.”
Winegar opined: “I don’t know if it’s any safer, really. Many industrialized nations have fairly rigorous premarket clinical trial approval processes.”
But, he said, “there are companies out there who say, ‘We want to see if it works before we spend any more money on it, so let’s go to Venezuela or some other country with a less-developed regulatory system and try it on a few people.’ Obviously that’s not going to happen in the U.S., but that’s not going to happen in Europe either. It’s going to be those Tier 2 countries where they may have a Ministry of Health but they don’t necessarily have a developed regulatory structure and likely don’t have an enforcement arm to that ministry.
Alexander said, “The Informed Consent process is typically more robust, but that’s about it. Working with the right partner, one familiar with U.S. ethics and regulatory expectations, can optimize the trial for both patient safety and regulatory success.”
Pros and Cons of OUS Trials
Tackling a question on the advantages and disadvantages of conducting clinical trials in India, China and elsewhere, Alexander said: “On the plus side—speed of enrollment and cost savings for per patient remuneration. On the down side—your data may not be accepted or you could lose control of your trial completely (investigators enrolling patients outside those you intended or not documenting information, significant protocol deviations or adverse events), risking your company’s reputation as well as the clinical trial data.”
She said that small and medium-sized medical device companies “often try to conduct a trial with just one clinical manager/monitor sent overseas. While this seems like a good, low-cost solution, it often results in significant trial delays. Navigating a foreign culture and trying to execute the study with too few people have led more than one company to failure.”
Rosenfeld weighed in: “Let’s take India as an example. Our company is not currently conducting any trials in India. About two years ago there were some very high liability constraints that were imposed by the authorities in India, so while we do have an office in India and do provide services through that office, we don’t run clinical trials there. That’s one of the disadvantages of India—very high standards of liability that many sponsors are not willing to take a risk of the process.
“On the other hand, there are multiple advantages to conducting trials in China. One is access to patients; you have a billion people there, and the approval process often is less time-consuming than the E.U. [European Union] countries or in the U.S., and enrollment is often quicker than in the U.S. or E.U. On the flip side, the quality of data may differ. To ensure the data, a CRO like Theorem has to spend a lot more time at the sites in China and provide more support than at sites in the U.S. So that costs more, but the average cost may still be less than in the U.S. and E.U.”
Buell said a big disadvantage in doing trials outside the United States is whether the FDA will accept such data. “That’s always a big risk that sponsors take on when they initiate trials OUS.”
She said that one thing sponsors “often have not done particularly well in OUS trials is characterizing the patient population, because there often are differences culturally, behaviorally, and in physicality that may impact use of the product.”
Winegar said that based on where FDA “still is today in practice, those early trials, those first-in-man studies and non-randomized feasibility studies of 10 to 20 patients, I still think those are best done offshore. First, it’s hard to get that kind of a study approved in the U.S. You need to provide a lot of data in an IDE to get that approved. Secondly, if you’re running a study in a major market like Germany, say, you keep it off the competitive and scientific radars a little bit more than if you were running it in the U.S., in case things don’t go as well as you anticipate.”
However, he said, “I’m not a big fan of going into what FDA would categorize as a Tier 2 country. The standards of clinical trials in India or Venezuela or even China, and therefore the credibility of that data, are something that people have to be aware of and concerned about.”
Jim Stommen, retired editor of industry publication Medical Device Daily, is a freelance writer focusing on the medical product sector.
