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Articles from 2018 In November


REACH FAQs for Medical Device Professionals
Image source Pixabay

REACH FAQs for Medical Device Professionals

REACH stands for Registration, Evaluation, and Authorisation of Chemicals. It is European Union Regulation No 1907/2006. It has many objectives, the most pertinent of which to medical devices is to improve the protection of human health and the environment. At over 1000 pages long, it’s been described as the most complex in EU History.

Now that REACH is in full effect, I am often asked about the scope, application, and obligations for medical devices. The hard truth is that medical devices aren’t exempt from this legislation, and complying with it is no small task. Following are the most frequently asked questions posed to me by medical device developers and suppliers.

A Background on REACH

Is it like RoHS 2011/65/EU?

It’s kind of like RoHS on steroids, but it doesn’t just apply to electronic equipment, and instead of one list, there are three! There are a bunch of other small but important differences, too.

Would it be simpler to understand the differences between REACH and RoHS as opposed to learning from scratch?

Perhaps. Read this article to see a comparison.

What are the three REACH lists?

  • Substances of Very High Concern (SVHC) list. These are chemicals for which the harms to human health or the environment are thought to outweigh the benefits, but that hasn’t been fully assessed yet. Items on the SVHC list can be thought of as “in the queue” to possibly be in one of the next two lists while the European Chemicals Agency (ECHA) and the public make their cases for and against.
  • Authorization list. These are chemicals known to be harmful to human health and/or the environment, but manufacturers can apply for authorization to use them anyway. A manufacturer must show that there are no safer alternatives, and it’s better overall for the public to use that chemical for a certain application than to not be allowed to use it at all. All authorizations are application specific and are posted publicly. Medical devices need not address REACH-driven risks to human health when applying for authorization (this is presumably because risks to human health must be considered as part of the medical device regulatory process anyway).
  • Restricted list. These are chemicals known to be harmful to human health and/or the environment. Opposite of authorized, they are restricted for certain applications but are permissible for applications not addressed.

Are the lists ever updated?

Yes, usually every 6 months.

Application to Medical Devices

Does REACH apply to my medical device?

Yes, if you’re importing it to Europe.

What if it’s an exploratory medical device for a clinical trial?

Substances used for “scientific research and development” are exempt from the requirements of both Restriction (Article 61, Section 1) and Authorization (Article 56, Section 3). The legislation appears to be unclear whether this extends to SVHCs.

What if the device is being removed from the EU after a clinical trial?

Removing the device/substance after a trial appears to be mostly irrelevant, however, applications for authorization do consider the waste removal process.

But my medical device isn’t even electronic!

Unlike RoHS, REACH applies to everything – even simple medical devices like scalpels. For context, it even applies to clothes!

My medical device is a finished good, not a chemical, so isn’t this moot?

No, REACH applies to finished goods as well as to raw chemicals.

Does REACH have any exemptions for medical devices?

Not really. The only provisions for medical devices surround communications requirements and the methods the Commission takes to determine whether a substance should be authorized for certain uses. For instance, Perfluorooctanoic Acids are permitted in medical devices until 2032.

Does REACH apply to the box that my medical device is shipped in?

Yes. Everything imported into the EU is subject to REACH.

Does REACH apply if I import less than 1 ton of my medical devices per year?

Yes, the 1-ton limit is for registration of chemicals, which is not addressed in this FAQ.

Does REACH apply if I import less than 1 ton of a particular substance per year? For example, what if my medical device contains only a small amount of an SVHC?

Yes, although you aren’t required to communicate with the ECHA to the same extent as you would be if you imported more of that SVHC.

Detailed Application of REACH

Does REACH apply to my whole device or to each individual subcomponent?

Each individual subcomponent, called an “article,” must be assessed for compliance with REACH. See this guidance for details of these terms to determine how deep into your BoM you must go.

Is there a lower limit?

For SVHCs and authorized substances, nothing below 0.1% w/w would need to be considered. Restriction conditions can, however, set higher or lower limits than 0.1%.

Is the weight of the substance compared to weight of the finished device?

No, it applies to each subcomponent (or article).

So, if my device weighs 100 kg, but a subcomponent (or article) contains only 1 g of a substance on one of the lists, I am good?

No. That article must be compliant with REACH all on its own – you can’t drop a non-compliant article into a really heavy device and call it a day. Therefore, that article would have to weigh at least 1 kg to be compliant on its own should it contain 1 g of a substance on one of the lists.

Can an article contain more than one substance on one of the lists?

Yes. In the example above, if the 1-kg article contained 1 g of an SVHC, 1 g of another SVHC, and 1 g of an authorized substance (for example), it would be compliant with REACH.

Can I see some detailed examples?

Read the ECHA’s guidance on this subject here – it’s loaded with examples. 

Obligations

What do I have to do for my medical device?

REACH is a self-certification activity, so you have to assess your device on a component-to-component basis to find out whether it contains any SVHCs, authorized substances, or restricted substances, and take appropriate action if it does. Yes, this is a lot of work.

What if my device is already on the market?

Any devices already imported into the EU are not subject to REACH, but any that haven’t are. So, if you’re a North American manufacturer, REACH applies to all units not yet arrived in Europe.

What actions must I take if a component in my device does contain one or more substances on one of the lists, over the minimum weight threshold?

  • SVHC. You must inform your distributor, or, if you sell directly to European consumers, have that information available and provide it upon request. Furthermore, if you are importing more than 1 ton of that substance, then you must inform the ECHA.
  • Authorized. You must seek an authorization for your specific application or substitute the part for another option without the substance.
  • Restricted. Check to make sure that your application is what is restricted, otherwise you’re all good. If your application is restricted, you’ll have to substitute the component.

How do I find out what is in my device?

The simple answer is to ask the suppliers of your subcomponents. They should be able to send you information on the content of the component they’ve sold you. If they don’t have it handy, they may have to ask their own suppliers.

What if they can’t tell me what’s in the articles they supply?

If they can’t provide information on their products, consider an alternate supplier. If there is no alternative supplier available for that particular component, you may be painted into a corner. Physical testing is a common last resort.

Do I have to re-audit my device every 6 months when the lists are updated?

This guidance clearly states (section 3.4.2) that you be no more than 6 months out of date on your information; however, it is worth noting that timeframe applies to suppliers at the top of the supply chain, too. Therefore your suppliers would have to work more quickly than the letter of the law to allow you to keep up.

Is there anything else I should know?

Yes - lots. It would take a good chunk of a lifetime to fully understand REACH. Don’t rely on this FAQ as your only source of information.

Top Tips for Understanding and Complying with REACH

A chemical, when talking about REACH, isn’t an ethereal green liquid you’d find in a flask in a laboratory. It’s anything and everything that make up our physical world, from metal alloys to plastics to silicone in resistors. There is a much more accurate definition in the legislation, but if you’re only interested in the big picture, this is probably the best definition to remember.

Also, 99% of the battle is finding out what is in your device. After that, the process if fairly clear and predictable – replace any substances or components you need to, and inform your customers or the ECHA if so required.

Many vendors supply REACH information easily; many do not. Choose your vendors wisely and early. For some reason, electronics vendors tend to be more likely to supply REACH information, perhaps because they learned the value of getting on top of things years ago when RoHS was first implemented.

The most common problem that seems to occur with complex medical devices is designing a device around a critical component without knowing whether it is compliant with REACH. Always check your critical components before committing to a design.

Please note: these questions and answers are not endorsed by the ECHA and do not represent official responses in any way. They are a based on my understanding of the legislature and its implementation.

Auris Scores Big with $200M Raise for Robotics Platform Courtesy of Auris Health
The controller for Auris Health's Monarch platform. 

Auris Scores Big with $200M Raise for Robotics Platform

The robotics market is surging. Auris Health recent raise of $200 million to commercialize the Monarch Platform is a perfect example. The Redwood City, CA-based company has raised more than $700 million to develop and commercialize the Monarch platform - a robotic system that enables more-accurate diagnosis and treatment of small and hard-to-reach nodules in the periphery of the lung.

Monarch received FDA clearance for Monarch to perform diagnostic and therapeutic bronchoscopic procedures earlier this year. The platform uses a familiar controller interface to navigate a flexible robotic endoscope to the periphery of the lung.

“The support of this group of world-class investors will be instrumental as Auris transitions into a commercial-stage company,” Frederic Moll, M.D., founder and CEO of Auris Health said in a release. “We are pleased with our progress in launching the Monarch Platform, which was initiated earlier this year. This funding will enable us to expand our commercialization efforts for endobronchial applications, and will also support our mission to pioneer the next era of medical intervention across a broader spectrum of procedures.”

Surgical Robotics 2018 and Beyond

It probably doesn’t need to be said that 2018 has been a banner year for companies with robotic solutions in healthcare. In addition to Auris Health’s significant financing raise, Medtronic announced that its long-awaited robotics platform could debut next year and Verb gave a test run of its platform to Google’s co-founder Sergey Brin. (Did we forget to mention that Medtronic also announced it would acquire Mazor robotics for $1.6 billion.)

But where will the market be in a few years? Will there still be this much enthusiasm? And with competition mounting, will Sunnyvale, CA-based Intuitive Surgical still be the top name when discussing surgical robotics.

Roger Smith, MD, the Chief Technology Officer for the Florida Hospital Nicholson Center, spoke with MD+DI in early November about surgical robotics and its future. Smith identified 67 companies that had robotic platforms to treat various parts of the body. He noted that about 20 companies have robots in hospitals now.

“If you move forward from where we are today, I would say we’re at the top of the bubble – and the bubble still could be growing, but eventually that bubble is going to pop,” Smith said during the early November interview.

He did not rule out the potential for M&A and consolidation in the robotics market. “I think there are companies that are trying to make it on their own right now that will get acquired because they fit into a portfolio,” Smith said.

Surveying the Digital Health Device Landscape in Clinical Trials
Image source Pixabay

Surveying the Digital Health Device Landscape in Clinical Trials

From text messages to mobile apps, digital health devices are becoming increasingly important in clinical trials for their ability to streamline trials, lower site burden, and improve the patient experience. However, manufacturers must consider the safety, reliability, and convenience of these devices in order to effectively implement them into medical device trials. The digital components of these medical device trials must adhere to the same rigorous regulatory standards as the device itself, which can pose significant hurdles for some sponsors.

Digital Health Device Opportunities

In these types of clinical trials, patients interact with devices that collect data that are essentially digital biomarkers. The data are then transmitted to the investigator site, where computers analyze the information to ensure study endpoints are being met and possibly provide new insights into the safety and efficacy of the medical devices. These digital biomarkers can then be used to explain, predict, or influence health-related outcomes.

Not only are digital health devices sources for crucial information, but they provide opportunities for improvements across medical device clinical trials. For patients, they make trial participation easier while also improving adherence. For sites, the devices can facilitate recruitment, as they allow staff members to easily interact with potential patients in a timely manner. This may lead to accelerated timelines and reduced costs for sponsors, which are critical goals in a highly competitive environment.

Challenges in Adopting Digital Health Devices

Manufacturers need to be aware of the challenges that come with incorporating a digital health device into a medical device trial. If they are prepared for these challenges, they will be able to better design devices that will lead to successful trials.

Many of the challenges are regulatory. FDA Commissioner Dr. Scott Gottlieb recently announced that the agency will increase its focus on digital health devices next year. FDA is working to ensure digital biomarkers are consistent through certification of firms and developers. The goal is for platforms to be verified as responsible and safe, so future regulatory reviews of future updates can be minimized. The Clinical Trials Transformation Initiative (CTTI), a partnership co-founded by Duke University and FDA, is also working to create a framework for greater adoption of sensors and digital biomarkers in clinical trials through a collaborative effort with the pharmaceutical industry, regulatory agencies, contract research organizations, and technology providers.

It is vital that the device measures and stores data accurately and transmits those data securely and that the endpoints are appropriate. Additionally, sponsors should plan for every educational level, computer savviness, and cultural variance when utilizing these new digital devices. To reach these goals, both sponsors and digital health device developers should consider the following guidelines for incorporating digital health devices into clinical trials:

  • Usability and Accuracy. Sponsors must be able to determine that a device is providing the desired endpoint values in a trial. The metric should be accurate and presented in a usable format.
  • Safety. The manufacturer should be able to provide highly secure methods for transmitting data between the digital health device and the analysis site.
  • Convenience. The manufacturer should be able to provide logistical support to decrease the site and subject burden. They should also be able to provide full documentation of engineering verification for the devices.
  • Ease of Use. It is important to consider how the patient will interact with the device. It needs to be an appropriate size and weight, and it should allow the patient to move and behave in the same way he or she normally would.
  • Reliability. To maintain data continuity, the device should have a battery life sufficient to allow it to collect data for long periods of time with minimal glitches.

Moving forward, medical device developers and sponsors must consider the increasing regulatory requirements and be able to demonstrate technical value. Following these guidelines will improve the application of digital health devices into medical device trials, expanding opportunities for the future of research.

New Virtual Surgical Simulator Debuts in Germany
The HandsOn.surgery trainer allows surgoens to practice on virtual bones with risk structures and surgical bur (top right) and with a haptic arm for virtual milling (bottom right). Image courtesy of Fraunhofer IIS.

New Virtual Surgical Simulator Debuts in Germany

Researchers presented the latest innovation in surgical training at this year’s MEDICA 2018 conference in Düsseldorf, Germany — the HandsOn.surgery trainer. The new prototype was designed to help surgeons prepare for individual patient surgeries by enabling them to practice the surgery on a virtual simulator.

The new technology, created by Fraunhofer Institute for Integrated Circuits, offers surgeons the opportunity to extensively train for difficult procedures, such as the surgical placement of implantable hearing aids and the surgical treatment of tumor diseases. The new HandsOn.Surgery technology can help support physicians and surgeons in their education, all in an effort to minimize surgery time and reduce surgical mistakes.

“The current approach of ‘see one, do one, teach one’ is obsolete,” said Volker Bruns, group manager of medical image processing for Fraunhofer. “Especially, as for risky interventions, patients cannot be used as a practice vehicle. Thus, training on patients is risky, and training with cadavers is expensive. Training on animal cadavers becomes more and more expensive, and training on 3D printed artifacts, while feasible, only allows for printed bones to be used once. Surgeons need to train on various models that range from easy to super complicated. They also need to train on both common and rare pathologies. This is where the idea of a haptic training system for hard tissue removal was born.”

With the new virtual surgery technology, surgeons can practice individual procedures in oral and maxillofacial surgery as well as in orthopedics and other areas before ever stepping foot into an actual operating room. They can use a patient’s digital twin at any time, and as often as they want, to practice the procedure without any risk to the patient. The highly immersive technology allows the surgeon to see and feel using real CT patient data, force feedback from the surgical instrument, an intuitive touchscreen, and a 3-D monitor or virtual reality headset to allow surgeons to experience the operation as if it were live — including original operating room sounds.

“The feedback we’ve gotten from the MEDICA conference was all positive,” said Bruns. “We will now focus on implementing a scoring system and add a serious game layer to the technology. It is key that [a] surgeon is motivated to practice over a longer period of time so we can begin to track a learning curve. We’d also like to implement other scenarios into the technology for orthopedics, neurosurgery, and eventually model the interaction with soft tissue instead of just bone.”

The technology was created as part of the “HaptiVist” project funded by the German Federal Ministry of Education and Research. The aim of the project was to develop and evaluate a haptic-visual learning system for surgical procedures that can be used in both urban and rural hospitals to help address the need for more medical specialists. As the company moves forward with the technology, Bruns said that they hope to partner vendors and begin to market the technology for release sometime in the next year.

“Fraunhofer is a research organization at heart,” Bruns said. “We are currently looking for a commercialization partner and have had very good discussions both with medical simulator vendors and surgical tools vendors. We are confident that we will roll out the first units in 2019.”

Expediting 3D Analysis of Normal and Diseased Tissues
Human lung cancer images courtesy of ClearLight Biotechnologies

Expediting 3D Analysis of Normal and Diseased Tissues

The current gold standard for tissue analysis, formalin fixation paraffin embedding (FFPE) followed by 2D thin sectioning, has been around for more than a century. And like any 100-year-old technology, it has key limitations.. So, ClearLight Biotechnologies is on a mission to significantly improve the field by automating nondestructive processing of tissue in 3D as a means to initially facilitate preclinical and clinical research applications. Laurie Goodman, PhD, CEO and board manager of ClearLight Biotechnologies, explained the process in an interview with MD+DI.

ClearLight’s founder, Karl Deisseroth, MD, PhD, invented CLARITY at Stanford University, as he was trying to discover a way to understand neuronal pathways in the intact mouse brain, Goodman explained. “They needed a way to keep the brain intact and be able to study long-range neuronal projections and understand the differences between normal and diseased tissue," she said. “Prior to the invention of these 3D technologies, the researchers had to rely on trying to recapitulate a 3D structure by piecing together information from thinly sectioned brain slices.”

The essential question that Deisseroth posed, Goodman said: “How do I lock in the biology of a tissue in 3D, yet remove what impedes the ability to image deeply into the brain? In the case of the brain, it’s very lipid rich, and lipids are inherently light scattering.”

“Dr. Deisseroth created the method called CLARITY, which is pretty simple, yet quite elegant in its form and function.” Goodman said.

The process uses hydrogel monomers to create a covalent intact tissue scaffold and then employs a very simple detergent to extract the light scattering lipids, Goodman explained. “The next step is interrogating with various fluorescently labeled macromolecules that can be used to identify key analytes that can be imaged in 3D (proteins or nucleic acids).

“It allows a way to spatially observe how a variety of different biological molecules interact with each other in a 3D space,” she continued. “Additionally, it allows you to make more measurements of a particular molecule of interest over a thick volume of tissue, and chances are that your statistics are going to be a lot more accurate than if you’re just looking at a small fraction of that volume.”

CLARITY can be applied to any biological area that relies on 2D thin section analysis of tissue. A current focus of the company is oncology prognostic and predictive applications with an emphasis on predictive biomarker applications for immune-oncology T-cell-based drugs. “Common sense would say if you’re trying to predict drug response and outcome in the oncology field, if you’re only analyzing a 5-micron slice of a tumor, then you’re likely not getting the full picture of the biology of that patient’s tumor," said Goodman.

ClearLight Biotechnologies was recently nominated by StartupCity magazine as one of the 15 Most Promising BioTech Startups for 2018. In terms of future applications for the technology, Goodman said the company’s timeline includes building a beta platform, for limited use externally as well as internally to build a robust service model.

The company has key researchers who will be testing the technologies to see what improvements can be made within a three- to five-year strategy, and this will aid to inform the market and future commercialization strategy for introducing the platform into the research market.

“I am confident that next-generation tissue analysis in 3D will be the standard in the future. However, as any revolutionary technology, it will take time to get there, just as it did with next-generation sequencing. It will not be an overnight process, but the rewards will be great for patients,” said Goodman.

J&J Subsidiary Launches IDE Study for AF Biosense Webster Inc.
The Heliostar RF balloon ablation catheter has the potential to overcome the limitations of current balloon ablation catheters, result in fewer catheter exchanges and shorter procedure times, according to cardiac electrophysiologist Andrea Natale, MD, the executive medical director at the Texas Cardiac Arrhythmia Institute at St. David's Medical Center.

J&J Subsidiary Launches IDE Study for AF

A new U.S. study aims to evaluate a radiofrequency (RF) balloon ablation catheter for the treatment of symptomatic drug refractory recurrent paroxysmal (intermittent) atrial fibrillation.

Biosense Webster, a subsidiary of Johnson & Johnson, said the investigational device exemption study will enroll up to 640 patients at as many as 40 clinical sites worldwide. The STELLAR study will evaluate the company's Heliostar RF balloon ablation catheter.

"This new balloon catheter is unique because it conforms to any pulmonary vein anatomy and allows me to control electrodes individually to deliver tailored energy when ablating around pulmonary veins," said cardiac electrophysiologist Rodney Horton, MD, who treated the first patient in the study with Andrea Natale, MD, at the Texas Cardiac Arrhythmia Institute at St. David's Medical Center.

Natale, a cardiac electrophysiologist and the executive medical director at the Texas Cardiac Arrhythmia Institute at St. David's Medical Center, said the Heliostar catheter design has the potential to overcome the limitations of current balloon ablation catheters, result in fewer catheter exchanges and shorter procedure times.

The new device has 10 electrodes, which allows electrophysiologists to deliver different levels of energy depending on the tissue during lesion creation. In addition, the balloon design makes it possible to achieve pulmonary vein isolation with a single application of RF energy. The device is compatible with the Biosense Webster Carto 3 mapping system, an advanced imaging technology that enables the creation of real-time 3D maps of a patient's cardiac structures.

The potential market size of the Heliostar is significant. The company noted that about 33 million people worldwide have AF.

"The STELLAR study is an important step forward in expanding treatment options for atrial fibrillation patients in the United States," said Uri Yaron, worldwide president at Biosense Webster. "The burden of atrial fibrillation on quality of life, morbidity, and mortality is significant and we are committed to developing innovative and life-enhancing technologies that fill important clinical needs, improve care and reduce this burden."

First Device Cleared for the Prevention of Cluster Headache

First Device Cleared for the Prevention of Cluster Headache

Cluster headache is considered one of the most painful conditions known to mankind. While there are drugs and devices designed to treat these sudden and excruciating headaches, there are currently no FDA-approved pharmacologic treatments for the prevention of cluster headache. There is, however a device that just received FDA clearance to do just that.

Basking Ridge, NJ-based electroCore previously had 510(k) clearance to offer its gammaCore vagus nerve stimulator as a treatment option, but FDA just cleared an expanded label for the device. The new label makes it the first product FDA cleared for the prevention of the condition.

“The FDA clearance of gammaCore for adjunctive use for the preventive treatment of cluster headache has the potential to help the approximately 350,000 Americans impacted by this debilitating condition often referred to as a suicide headache,” said electroCore CEO Frank Amato. “We are pleased that cluster headache patients now have an FDA-cleared option and one that is both safe and effective, especially given the difficulty in treating cluster headache and the limitations of current treatments.”

The company submitted data from two studies to support the new clearance. The PREVA (PREVention and Acute treatment of chronic cluster headache) pivotal study was a prospective, open-label, controlled, randomized trial that demonstrated the safety and effectiveness of gammaCore as an adjunctive therapy for the preventive treatment of cluster headache. The second study reviewed by FDA was a real-world retrospective study examining the daily clinical use of gammaCore preventively and acutely for the treatment of cluster headache.

In the PREVA study, intention-to-treat (ITT) patients who received the standard of care and gammaCore during the randomized phase had a greater reduction from the baseline (−5.9) in the number of cluster attacks per week than those receiving standard of care (−2.1), for a mean therapeutic gain of 3.9 fewer cluster attacks per week (P=0.02). In the site-adjusted model, the mean therapeutic gain was 4.2 fewer attacks per week (P=0.02).

Also, 40% of patients who received gammaCore in addition to standard of care experienced a 50% or greater reduction in weekly cluster attacks, compared to 8.3% of patients who received standard of care alone, the company noted.

In addition, there was a 57% decrease in the frequency of abortive medication use among patients who received gammaCore plus standard of care, while patients who received standard of care alone did not experience a substantial reduction in abortive medication use.

In this study, gammaCore was found to be safe and well tolerated. The incidence of adverse events was similar between patients using gammaCore plus standard of care compared to standard of care alone. The majority of the adverse events were mild and transient. The most common adverse events reported in 5% of patients or more in the gammaCore group were headache (8%), dizziness (6%), and neck pain (6%). None of the serious adverse events were considered device-related.

To prevent cluster headaches, adult patients should self-administer two gammaCore treatments daily. Each treatment consists of three consecutive two-minute stimulations. The first treatment should be applied within one hour of waking up and the second treatment should be applied at least seven to 10 hours later.

The device is a hand-held device applied to the neck that delivers a mild electrical stimulation to the vagus nerve that passes through the skin. Designed as a portable, easy-to-use technology, gammaCore can be self-administered by patients, as needed, without the potential side effects associated with commonly prescribed drugs. When placed on a patient’s neck over the vagus nerve, gammaCore stimulates the nerve’s afferent fibers, which may lead to a reduction of pain in patients.

How Can Nanotechnologies Aid Implantable Drug-Delivery Systems?
Murty Vyakarnam, PhD, founder and principal, VYTAL Group

How Can Nanotechnologies Aid Implantable Drug-Delivery Systems?

Implantable technologies have come a long way over the years, and advancements in micro and nanotechnologies have helped device developers continue to push the envelope even further. Within the realm of drug delivery, advances in nanotechnologies have consistently improved patient outcomes by enabling sustained drug delivery to help treat chronic conditions. These scalable technologies have even offered localized drug delivery that can further improve bioavailability.

While many of these technologies offer a variety of opportunities, we’re still eagerly awaiting to see the impact of these advancements once they’re actually leveraged against implantable device technologies. Many believe that recent micro and nanotechnology advancements could pave the way for things like increased local administration of drugs, zero-order release kinetics, more efficacious use of existing drugs with great bioavailability, personalized poly-pharmacy, and even on-demand drug delivery.

To better understand some of these potential outcomes, MD+DI checked in with Murty Vyakarnam, PhD, an innovator in medical devices, drug-device combination products, and biomaterials. He previously served as head of Global R&D for medical devices and pharma solutions for the newly created Lubrizol Lifesciences business unit, a Berkshire Hathaway company. He’s also spent time as director of research and development for Advanced Technologies & Regenerative Medicine.

Vyakarnam has spent years directing research and overseeing successful product launches for several Johnson & Johnson companies, so he’s had his finger on the pulse of drug-delivery system development for quite some time. He’ll be speaking at the BIOMEDevice conference in San Jose in the December 6 talk, “Micro/Nano Technologies for Implantable Drug Delivery Systems.”

MD+DI: For starters, can you talk a little about some of the recent advancements within the realm of micro and nanotechnologies that could potentially set the stage for next-gen implantable drug delivery systems? What impact could some of these recent advancements have on these implantables?

Vyakarnam: Advances in bio-microelectromechanical systems (BioMEMS) and biosensors have led to several miniaturized medical devices and drug-delivery systems including microfluidics and lab-on-chip diagnostic devices, diagnostic wearables, miniaturized robotics, and implants with closed-loop drug delivery systems. Advances in the micro and nano particle technologies have led to numerous injectable drug delivery systems. Injectable nanoparticle-based drug delivery with tissue targeting is providing many promising solutions in tumor treatment and continues to be a very active area of research. Injectable microparticle systems or gels that can become long-acting drug-delivery depots have provided significant advances in the treatment of various conditions including pain and schizophrenia. A third underlying front involves the advances in materials science especially bioresorbable polymers and hydrogels where the properties can be tuned with new chemistries for better formulation with drugs and processed in unique ways, including 3D printing with minimal loss in potency of the small molecule or biologic therapeutics.

Increasingly the discovery of several new poorly soluble drugs and/or biologics have tremendously expanded the need for drug-delivery technologies with alternate routes of administration beyond the traditional oral and parenteral routes. Implantable drug-delivery systems deliver pharmaceutics locally, targeting the tissue/organ [and] minimizing the side effects of systemic delivery. It is the convergence of the pharmacologic need for alternate routes of administration for the new therapeutics combined with the advances in engineering solutions that is driving the development of next-generation implantable drug-delivery systems.

Implantable drug-delivery systems (IDDS) are playing a key role in the treatment and management of several chronic conditions including diabetes, oncology, ocular disorders, cardiovascular conditions, and women’s health. Managing chronic diseases with progressively debilitating outcomes can be challenging with poor compliance, and in those situations IDDS might be the only hope to slow or reverse the disease progression. Ultimately, implantable drug-delivery devices with precision-medicine approaches will improve the management of patient health, increase survival rates, and lower healthcare costs.

MD+DI: What kind of advancements are being made for sustained drug-delivery platforms that could help treat chronic conditions and potentially diseases?

Vyakarnam: Below are a few examples of advances being made in the treatment or management of chronic diseases using sustained drug-delivery platforms:

  • Osteoporosis. Osteoporosis is a disease in which bones deteriorate or become brittle and fragile due to low bone mass and bone tissue loss. This affects approximately 10 million Americans, predominantly post-menopausal women. One treatment option for patients with high risk of bone fracture is a daily injection of human parathyroid hormone fragment (marketed as Teriparatide), which can last for 2 years. However, adherence to daily injection therapy is a significant problem. MicroCHIPS (now part of Keratin Biosciences) developed a groundbreaking MEMs-based implantable drug-delivery chip to deliver Teriparatide. This implantable multi-well drug-delivery chip made of silicon is wirelessly controlled and programmable. Unlike passive drug-delivery implants, MicroCHIPS’s implants can respond to wireless signals [that] can activate, deactivate, or modify the frequency or dosing of the drug [for] up to several years. The efficacy of this microchip approach was demonstrated in a clinical trial in postmenopausal women with osteoporosis. The microchip implants delivered the same therapeutic level of drug to increase bone mass as was achieved with daily injections. This microchip technology is also being developed for several other chronic conditions including diabetes, contraception, and drug delivery to tumors.
  • Mental disorders. Less-than-optimal treatment options and inadequate resources for patient care have led to a national crisis in mental health, especially with opioid addiction. Recently, FDA approved Probuphine (Titan Pharmaceuticals), a six-month implant that delivers buprenorphine for treatment maintenance of opioid addiction. This miniaturized drug delivery implant to treat opioid addiction is a great way to address this epidemic as the very nature of this chronic condition makes patient compliance a big challenge. This implant is injected in an office setting but needs to be removed after six months. BioCorRx is developing a naltrexone implant that is bioresorbable, which will be an advantage over Probuphine, as the implant does not have to be removed. In the last decade or so, great strides have been made in treating schizophrenia using long-acting antipsychotics drugs formulated with PLGA (poly {lactic-coglycolic acid}) microparticles as an injectable depot. The prevalence of co-morbid conditions in mental health opens the doors for dual drug-delivery depots. This would be a further advancement in implantable drug-delivery systems that can potentially address more than one underlying condition, e.g. addiction and schizophrenia.
  • Cardiovascular Diseases. Another class of drug-delivery implants that were transformational in the field of interventional cardiology are the drug-device combination products. In this class of implants there is usually a physical device, like a stent, that has a mechanical function and a drug-delivery depot (usually a coating) that delivers the drug and addresses the underlying pathology. This was pioneered by JNJ’s Cypher drug-eluting stent using sirolimus to treat restenosis. Since then there have been several other drug-device combination products. More recently, drug-eluting balloons (CR Bard’s Lutonix and Medtronic’s In.Pact) using paclitaxel have proven to be efficacious in treating peripheral artery disease (PAD). Along the same lines, but a first for sinus tissue, PROPEL sinus implants (Intersect ENT) was recently introduced. These offer localized, controlled drug delivery of an advanced corticosteroid (mometasone furoate) with an anti-inflammatory directly to the sinus tissue. Here the miniaturized spring-like bioresorbable implant maintains the surgical opening, prop opens the ethmoid sinus, and gradually delivers the drug directly to the sinus lining as the implant dissolves.

MD+DI: What kinds of design and material options do you see driving innovation for implantable drug-delivery systems over the next few years?

Vyakarnam: The first thing to consider in developing implantable drug-delivery systems for sustained delivery is the route of administration. Alternate delivery routes to deliver drugs that are being increasingly considered are injectable depots, targeted delivery to tumors, surgical site, ocular, pulmonary, nasal, vaginal, transdermal, etc. These delivery routes provide the developers of the implantable drug-delivery systems with several design options.

Biomaterials, especially polymers, play a critical role in both the formulation of the drug as excipients as well as in the development of a wide variety of implantable devices for sustained drug delivery. Historically, the long-term implants were made with bio-durable polymers like silicones and ethylene vinyl acetates (EVA). Silicones have long been a material of choice for drug delivery given their extreme chemical inertness and the ability to compound various drugs within the matrix. EVA is also finding use in drug delivery application due to its ability to control drug-release kinetics by varying the vinyl acetate content. More recently, polyurethanes are also being considered for long-term drug-delivery implants as they provide greater degrees of freedom in designing the polymer to tailor the drug-release kinetics.

In many situations, it is more attractive if the long-term implant does not have to retrieved. Here the advantages of using bioresorbable polymers for the drug-delivery implant goes without saying. Bioresorbable polymers such as PLGA have the ability for control release of drugs while essentially “dissolving away” by hydrolysis to produce lactic and glycolic acid. These polymers have also been considered for numerous implantable systems including injectable microparticle and injectable depots. Other resorbable polymers that are being considered include poly caprolactone and tyrosine derived polycarbonates. The field of bio-resorbables continues to be an area of active research to tailor biodegradation rates [and] induce degradation on stimuli like pH, enzymes, or externally induced triggers.

As noted below, the advances in BioMEMS and biosensors are also driving innovation in the closed-loop injectable drug-delivery systems.

MD+DI: In a broader sense, how do you think advanced drug delivery systems could impact things like on-demand drug delivery and personalized polypharmacy?

Vyakarnam: The holy grail is an implant that can sense a condition or detect a leading biomarker that signals a need for intervention and accordingly triggers the release of a drug at the right dosage, time, and duration to intervene – essentially an on-demand drug-delivery system. The efficacy of pharmaceutical treatments can be greatly enhanced by physiological feedback from the patient using biosensors. After decades of development, great advances have been made in treating diabetes with a closed-loop insulin pump delivery. Medtronic introduced MiniMed 670G, the first hybrid closed-loop system that helps in preventing hypoglycemic and hyperglycemic conditions with better outcomes in HbA1c readings. The development of reliable continuous glucose monitoring was critical for the successful automation of insulin delivery. It was the total system of improved continuous glucose sensing technology, miniaturization of electrical devices, and development of algorithms that were key in making the closed-loop system possible. The next major advancement will be a completely implantable closed-loop system to manage diabetes.

Closed-loop drug delivery promises autonomous control of pharmacotherapy through the continuous monitoring of biomarker levels. This level of precision medicine and polypharmacy is an active area of research and offers many exciting possibilities in the future. BioMEMS offer possibilities to miniaturize biosensors, enabling them to be incorporated with drug-delivery devices with extremely small footprint that minimize both power consumption and implantation trauma. MEMS fabrication also allows mass production [that] can be easily scaled without sacrificing its high reproducibility and reliability, allowing seamless integration with control circuitry and telemetry. By integrating these systems with drug-delivery devices, which can also be MEMS-based, closed-loop drug-delivery can be achieved.

MD+DI: In your personal opinion, what are some of the more significant challenges that stand in the way of progress when it comes to advancing drug-delivery systems? How do you think we can begin to address some of these challenges?

Vyakarnam: While new technological developments are exciting, proving clinical efficacy with superior results over standard of care can be expensive and time consuming. In the case of implantable drug delivery systems, compelling evidence needs to be generated that slow or reverse disease progression as a result of localized drug-delivery compared to the standard oral and parenteral routes of administration. These issues need to be addressed at the time of clinical trial design itself. Improvement in patient compliance and convenience need to be coupled with tangible clinical endpoints to justify reimbursement from a healthcare economics standpoint – making the new development commercially attractive.

Integration of several technologies from MEMS to biosensors to drug formulations is not trivial and requires a multi-disciplinary systems approach in fabricating the implantable drug-delivery systems for reliability and quality. On top of that the medical field is risk averse in adopting new technologies as patient safety is paramount. A careful selection and integration of time-tested technologies and materials from a biostability and biocompatibility standpoint will accelerate clinical translation and bring new products in the market place sooner.

MD+DI: Finally, what does the future look like for drug-delivery systems that can deliver drugs to the eye? What are the challenges involved, and what are some of the more recent novel developments pushing this field of research further?

Vyakarnam: By 2030 nearly 20 million in the United States will have vision loss or low vision if left untreated due to age-related conditions like macular degeneration (AMD), glaucoma, and diabetic retinopathy. Despite breakthroughs in drugs to treat these chronic conditions, they do not realize their full potential as they rely on very inefficient eye drops or intravitreal injections that are highly burdensome to patients resulting in poor compliance. In many ways [the] eye is an anatomically insular organ where localized drug delivery is the preferred route of administration to be efficacious, which makes a compelling case for developing implantable drug-delivery systems.

Miniaturized sustained drug-delivery implants are very promising to treat chronic ocular conditions and several are in development. Recently, FDA approved Yutiq (EyePoint) for the treatment of chronic non-infectious uveitis using a corticosteroid affecting the posterior segment of the eye. Yutiq is a non-bioerodible intravitreal drug-delivery implant that delivers fluocinolone acetonide for 36 months. While sustained delivery of small-molecule therapeutics seems to be in the realm of possibility, sustained delivery of Anti-VEGF biologics for AMD is still very challenging. Maintaining stability of these biologic therapeutics under physiologic conditions is not trivial, and several approaches are in development. In the case of AMD treatment, the goal is to reduce the frequency of intravitreal injections from the current 6–12 times a year to 2–3 times a year to ease patient burden. Bioresorbable drug-delivery implants that can also provide zero-order sustained drug delivery will offer a big advantage in the long-term disease management of glaucoma and AMD. Combining diagnostic sensing, like intraocular pressure, with drug delivery in a closed-loop system can be very appealing in the treatment of glaucoma to slow down its progression.

Don't miss “Micro/Nano Technologies for Implantable Drug Delivery Systems” at the BIOMEDevice conference in San Jose on December 6.

Voice-Activated Kits Aid Helpers in a Bleeding Emergency Courtesy of North American Rescue

Voice-Activated Kits Aid Helpers in a Bleeding Emergency

Step-by-step audio, pictorial, and written instructions guide bystanders in emergency situations to confidently treat bleeding injuries.

“Despite the advances in trauma care and lessons learned from the military, some 80,000 lives are lost in the United States each year due to uncontrolled bleeding (https://www.ncbi.nlm.nih.gov/pubmed/16763478),” says Paul Vecchio, Vice President, North American Rescue, LLC (www.narescue.com), in an interview with MD+DI.

“There is a constant stream of emergency situations that involve major bleeding and loss of life that could be potentially preventable if bystanders were equipped with lifesaving medical equipment,” Vecchio says. “From vehicle crashes and incidents involving farming equipment or public transportation, to accidental injuries from natural disasters like tornadoes, or inflicted injuries from intentional acts of violence like shootings and bombings, uncontrolled bleeding can result in death within minutes—even before emergency medical services or other emergency responders can arrive. These first minutes following a traumatic injury are crucial to saving a life.”

The problem is so urgent that, in October 2015, the White House launched the “Stop the Bleed”  campaign, designed to provide bystanders of emergency situations with the tools and knowledge to stop life-threatening bleeding.

In response to this call to action, North American Rescue has developed an Audio Bleeding Control Kit that provides audio instructions in both English and Spanish, along with pictorial illustrations, that helps users provide immediate care to injured people. These are the only bleeding control kits on the market with built-in audio hardware, and they offer equipment and supplies to manage minor, moderate, and severe bleeding safely and effectively.

The kits contain different supply packs that are used with either severe bleeding (to an arm or leg only), moderate bleeding, or minor bleeding. These supply packs are color-coordinated to help the user determine which to use. They include a tourniquet supply pack, a hemostatic dressing supply pack, a compression dressing supply pack, and an accessories supply pack. They are easy-to open with tear notches.

The kit’s dimensions are 12.5 in. x 9.75 in. x 2.6 in., and it weighs 3.15 lb. They can be stored on a shelf, in a drawer, in the trunk of a car, and can also be wall mounted. Possible locations for the kits include schools, airports, concert venues, office buildings, cars, buses, and the company suggests that they be placed next to all automated external defibrillators.

Vecchio says the units ship with batteries installed. The batteries have a five-year shelf life and can be easily changed. A power button on the module preserves battery life until the unit is used.

“You can replay, rewind, pause, stop, or advance the audio instructions,” Vecchio says. “Since the audio is contained digitally, there is no delay after pushing your desired selection.” Volume can also be controlled, with max being the default setting for use in loud or chaotic environments.

The company also makes many other types of kits that are equipped to address the top leading causes of potentially preventable death, and can be customized to a customer’s level of training.