Introduction

An increasing number of medical device companies are going overseas to trial their technologies. As of July 2012, the U.S. National Institutes of Health’s ClinicalTrials.gov registry contained 129,291 clinical trials in 179 countries with 10,618 trials currently being conducted in East Asia and 2281 in South Asia.¹ Many in the industry believe this trend will continue in the coming years. During a 2012 survey of leading U.S. medical devices companies conducted by research and consulting firm Best Practices LLC, 86% of respondents expressed their belief that the number of trials run in emerging markets will increase in the years ahead as companies look for efficient and cost-effective ways to bring new technologies to market.

This article explores the challenges and opportunities of conducting clinical trials overseas based on GlySure’s experience conducting human use trials for its continuous blood glucose monitoring system in India. It presents the realities of conducting trials abroad, tips for the contract research organization (CRO) and site selection processes, and suggestions on how to successfully position technology for future clinical regulatory trials in the United States and Europe.

Prior to conducting our trials in India, the GlySure management team had experience running clinical trials in the United States and the United Kingdom for both Fortune 500 and venture start-up organizations. This was, however, the first experience that any of us had in conducting trials in the developing world. The outcomes far exceeded our expectations, with direct trial costs savings of 50–70% compared to U.S. or EU study costs and, more importantly, savings of 9–12 months in development time due to faster regulatory approval processes. At the same time, there were multiple challenges and learning opportunities throughout the course of the study.

Getting Started: Trial Preparation

Any medical device trial requires extensive planning but trials conducted outside of the United States and Europe, particularly those in emerging markets, add a new layer of complexity because of the unique challenges of distance, basic logistics, foreign regulatory paths, and cultural differences that come with the territory. 

CRO and Site Selection. Being hundreds or even thousands of miles away from your trial site, as we were in the case of GlySure’s Intensive Care Unit (ICU) Pilot Trial in India, a medical device company does not have the ability to provide daily hands-on support. It must thus lean heavily on its Contract Research Organization (CRO) and primary investigator (PI). Therefore, the success of a company’s trial often hinges on choosing the right CRO and PI to meet its specific needs.

The good news is that a growing number of CROs have the ability to conduct medical device trials overseas. To choose a CRO for our trials in India, we partnered with Technomark Life Sciences in the United States. With corporate offices in the United States and the United Kingdom and a regional office in India, Technomark was able to bridge the gap between East and West, helping us overcome challenges and capitalize on the opportunity.

Technomark took a broad approach when working with us to select a site and PI for our Indian trials. They first examined 100 potential sites and then narrowed down the list to three, selecting those best suited to our technology and trial type. Technomark then arranged for us to interview the final three PIs and visit the sites to make our selection.

No One Size Fits All Solution. It’s important to note that a medical device company should select a CRO that has experience with medical technologies and not just pharmaceuticals because the trial process and requirements are vastly different. The CRO should also have experience in successfully managing your specific trial type. There’s a big difference between conducting a regulatory approval trial where the core product design has been finalized compared with a development trial where there are fewer patients but investigators and sites must have the flexibility to work with prototype devices.

An Experienced and Enthusiastic Leader. In regards to site selection, regardless of the trial type and where it is conducted, it is universally true that the ultimate success of the trial depends on the PI and his or her ability to drive patient enrollment and conduct the trial in accordance with study protocols. Therefore, it is critical that a company work with its CRO to find a PI who has a genuine interest in the trial and the right background and experience. During the PI/site selection process, the company should gather information on how many studies the PI has managed, the types of studies, technologies trialed, and his/her patient throughput.

According to Allen Hakimi, managing director of Technomark, the “softer” PI attributes are important as well.

“Personality is key,” Hakimi says. “While it’s important to select a PI with all of the necessary quantitative attributes, such as education and past clinical trial experience, qualitative characteristics are essential as well, including friendliness, enthusiasm for the technology and trial, and flexibility. Because we took all of these factors into consideration when selecting a PI for GlySure’s Indian trials, the PI is now an ambassador for the product and someone who continues to serve as an invaluable asset to the company.”

On our first day in India, we met with the PI and were greeted with a list of half a dozen suggestions for improving the product before we had even run our first case. One of these was to change the location of our sensor from the radial artery (RA) to the internal jugular (IJ). After spending four years and plenty of market research getting the product to the point of being ready for the first ICU test, our response was perhaps a bit subdued. We wanted an eager PI, but had expected to get some data in hand before the suggestions started flowing. It is a bit embarrassing to admit, but six months later, with data in hand, we found ourselves incorporating half of the suggestions the PI made on day one, including the switch from the RA to IJ placement.

This brings up one of the additional challenges of doing emerging market studies, “How do you determine which feedback is geographically specific and which will apply globally?” In our case we benefited from the strong historical British–Indian ties. Our PI had trained and worked in the United Kingdom for a decade before returning to found an anesthesia practice in India. He was quite effective at pointing out where ICU practices were the same or different. In addition, we used our existing U.S. and UK clinical advisory board to confirm the feedback coming out of the trial.

Regulatory Path

Because every country has its own regulatory path for clinical trials, it can be difficult to navigate the waters when conducting a trial overseas. The regulatory bodies are different, the timelines for submitting and receiving approval to conduct a trial vary widely and oftentimes, regulations in emerging markets are not as clear cut as they are in the United States or Europe.

“In the U.S., you submit your trial application to the FDA and, if you do not hear anything back within 30 days, you know you are good to go. The onus falls on the regulatory body to be timely and diligent,” Hakimi says. “This is not the case in other countries. There have been times when we’ve had a four-week trial approval and others where it has taken 14 months. The accountability infrastructure is not always there, which can be frustrating for a U.S. or European company that is used to standard timelines and deadlines.”

A good CRO and PI can help a medical device manufacturer navigate foreign regulatory paths and provide direction on what exactly it needs to do in order to secure the necessary approvals. During GlySure’s trials, every approval came on or ahead of the target date. In the case of local ethics boards, choosing a PI who is experienced and well respected played a critical role in paving the way for an efficient and successful program.

Time is Money

We chose India knowing that conducting trials overseas doesn’t mean that a company has to do less—the product must still be safe for use in humans, patient interests must be protected, and the data must be both accurate and credible. The main benefit for us came in the form of quicker turn around times—timing for both the official regulatory approvals and ethics board approvals were faster, which shaved months off of the time required to get the data we needed.

At first glance, two-to-three months time savings might not sound like a big deal, but this time adds up for a company in the development stage. During GlySure’s clinical program in India, we would conduct patient testing, collect the results, modify the product and then repeat the cycle again. Each time we went through that cycle, we needed to go back through the regulatory approval path. Having gone through that cycle four times, we saved anywhere between nine and 12 months of regulatory submission time.

A company must take into consideration not only the time saved, but also the cost savings to which it equates. A development stage company could be burning through $100,000 to $200,000 a month while it awaits regulatory approvals. We just completed our 100^th subject in India last month and the direct trial savings are between $500,000 and $750,000. The savings in burn rate, by being able to collect that data nine months faster, is two-to-three times the direct cost savings.

Patient Enrollment: A Question of Ethics

Companies conducting clinical trials abroad are often asked if they are taking advantage of third-world patients in order to save time and money. One way to assess this is to look at patient consent rates: how often do patients decline to consent to participate? In our case, the answer is most definitely the same or more frequently than I have seen in U.S. trials.

For our clinical trials in India, we took pains to ensure that we selected only well-qualified trials sites that comply with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. During the trials, there were plenty of days when our PI told us that we didn’t have any patients because they all refused consent. As frustrating as it was to miss an enrollment, it was always a good reality check that patients were not being coerced to participate in the trials or taken advantage of in some way. If a company is conducting a trial abroad where every patient consents to participate, it must ask itself if its trial is being run in an ethical manner.

Companies are also asked if they are using third-world populations as test subjects for unsafe or unproven devices. One of the reasons that we chose India for GlySure’s initial clinical trials was that its Central Drugs Standard Control Organization (DGCI) enforces ICH GCP guidelines, so products must be proven safe for human use before initiating a trial. Not only does this protect patients from potential harm, it lends credibility to the trial and the results.

At GlySure, we had the upmost confidence in the safety of our technology, to the point where the company’s founder, one of our chief scientists and I served as the first human subjects. Before we started any trials abroad, we had already tested it on ourselves. This isn’t uncommon in the medical diagnostics/monitoring world, particularly among early stage companies with minimally invasive products.

Challenges

While there are clear advantages in terms of time and cost savings when conducting trials in emerging markets, there are countless logistical and cultural challenges as well. My advice to other medical device manufacturers is not to expect a trial abroad to run like a trial in the United States or Europe. This expectation will only leave you extremely upset and frustrated. Be prepared to take the good with the bad and focus on the long-term benefits.

Time and Distance. We were fortunate with our technology that we were able to go to India at the start of a trial, train for a couple of weeks with the PI and site staff and then go back home knowing they could conduct the study on their own. Issues inevitably arose during the trials but because we couldn’t hop on a plane every time something went wrong, we leaned heavily on our CRO to resolve matters on our behalf.

“Conducting a trial abroad requires a leap of faith,” Hakimi says. “We don’t tell clients not to go abroad. We tell them just don’t go abroad without us.”

Even with a strong team on the ground in India, it was still critical that we hold regular conference calls with the PI and the CRO every two-to-three days in order to track enrollment, discuss progress and answer questions. The time difference was definitely an issue. We had the advantage of being in the United Kingdom where there is a four-to-five hour time change to India, which is half a working day. U.S. companies face an even greater challenge, particularly those based on the West Coast where it is a 12-hour time difference. When managing a trial in Asia from the U.S. or Europe, be prepared to work at odd hours. Somebody is always up early and somebody is working late.

Customs. One of the greatest challenges that we faced during our trials in India was importing and exporting our equipment. Some parts of our technology, such as the sensors, are small, lightweight and relatively inexpensive to insure, making them relatively easy to navigate through the customs channels. Where we ran into issues was with our hardware. Computers, circuit boards and other equipment that are large, heavy, and expensive can trigger multiple red flags in customs, raising questions and resulting in significant delays.

The first time we brought our equipment over from the United Kingdom to India, we encountered a number of unexpected challenges. We arrived in India one week after our equipment arrived but one week before it made it through customs and to the trial site. As a result, we had a one-week unintended holiday stuck in our hotel rooms where the air conditioning cranked on high brought the 115° Fahrenheit temperatures down to a balmy 80°.

Cultural Differences and Language Barriers. One of the advantages of conducting trials in India is that English is a common language for business. As an emerging country for medical trials, India sees its high English literacy rates as a competitive advantage compared with countries such as China.

Cultural differences are always present. A company must be prepared to work with its CRO to ensure that all parties participating in its trials understand what is being asked of them, agree to the protocols and come up with realistic timelines so that there are no surprises and minimal misunderstandings.

“When a problem arises it’s sometimes hard to find the reality of a situation because different cultures communicate in different ways,” Hakimi says. “That’s why it’s important for a trial sponsor to have people on the ground who live and breathe the local customs and are able to communicate effectively across geographical and cultural boundaries to resolve issues.”

Effectively Positioning Technology for U.S. and European Trials

While the U.S. Food and Drug Administration (FDA) and the European Union (EU) ultimately require data on patients within their borders before issuing FDA clearance or a CE mark respectively, a trial conducted abroad in a credible manner can give a company a running start to securing regulatory approvals these markets.

Broad Patient Scope. When conducting trials abroad, there is always the question of whether medicine is practiced in the same way as it is in the ultimate launch markets. Are patients exposed to the same drugs, are they in the same care situations? To address this concern a company must ensure that its trials cover a broad scope of patients—different patient types, conditions and co-morbidities. The broader the patient scope, the more applicable the data.

A Hands-Off Approach. Regulatory bodies take with a grain of salt data from trials where the manufacturer of the product was frequently on-site making modifications. While leaving a device in the hands of site staff thousands of miles away for months at a time can be challenging, it certainly lends credibility to not only device usability but to the trial data itself.

Established Relationships. Now that GlySure has completed its pilot trials in India, we are now preparing for larger, international, multi-center regulatory trials in the United States, Europe, and India. It is extremely beneficial to have an established site up and running in India so that we can put our time and effort into establishing our new sites in the United States and Europe.

Conclusion

While we would have liked to have conducted a trial in our own backyard as opposed to somewhere that was a 10-hour plane ride away, the reality is that conducting clinical trials in India allowed GlySure to secure the data it needed in a relatively short time period. This in turn enabled us to secure further funding and successfully position ourselves for trials in the United States and Europe.

Beyond the strength of our technology platform, the key to our success was having a strong capable team on the ground in India, including the PI, site personnel and CRO representatives, who could drive patient enrollment, follow study protocols and help resolve issues. We knew that GlySure staff could not be on-site micromanaging every aspect of the trials. In the end, this ability to place our trust in this local team added to the strength and integrity of our technology and has enabled us to gather accurate and credible data to fuel the next stage of our development.

Christopher Jones is the chief executive at GlySure Ltd. He has more than 20 years of experience in the medical device and diagnostic industry. Prior to joining GlySure in 2008 he was CEO of Tensys Medical and led the development of the first clinically acceptable, continuous, non-invasive blood pressure monitor. Jones also spent nine years with Nellcor Inc., a division of Tyco, serving most recently as VP of Marketing responsible for the pulse oximetry and critical care businesses. Prior to that, he spent six years in sales and marketing management positions at BioGenex Laboratories. Jones is a graduate of Yale University with a bachelor of science in molecular biophysics and biochemistry. 

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