Ranica Arrowsmith , Associate Editor04.06.16
Ypsilanti, Michigan, 1942: Dr. Jonas Salk (inventor of the polio vaccine) injects male patients in a mental hospital with an experimental flu vaccine, and then exposes them to the flu virus several months later. Some of the patients were not able to describe their symptoms, which raised questions about whether they fully understood the experiment they were being subjected to. One newspaper account mentioned the test subjects were “senile and debilitated,” but quickly moved on to the promising results.
Middletown and Norwich, Connecticut, 1940s: Once again, men in a mental hospital were exposed by Researcher Dr. W. Paul Havens Jr. to hepatitis in a series of experiments. Havens, a World Health Organization expert on viral diseases, was one of the first scientists to differentiate types of hepatitis and their causes.
West Coxsackie, New York, 1940s: Researchers studied the transmission of a deadly stomach bug by having young men swallow unfiltered stool suspensions. The study was conducted at the New York State Vocational Institution, a reformatory prison in West Coxsackie. The goal was to identify how well the disease spread by ingestion rather than airborne. The research concluded that swallowing it was a more effective way to spread the disease, but the study did not make clear if the men were either informed of the risks or paid for their participation.
Minneapolis, Minnesota, 1940s: A University of Minnesota study in the latter part of the decade injected 11 public service employee volunteers with malaria, then starved them for five days. Some were also subjected to hard labor, and those men lost an average of 14 pounds. They were treated for malarial fevers with quinine sulfate. One of the authors was Ancel Keys, a noted dietary scientist who developed K-rations for the military and the Mediterranean diet for the public.
Jessup, Maryland, 1957: When the Asian flu pandemic was spreading, federal researchers sprayed the virus in the noses of 23 inmates at Patuxent prison in Jessup to compare their reactions to those of 32 virus-exposed inmates who had been given a new vaccine.
And these are just the incidents on U.S. soil. The United States also has an ugly history of experimentation abroad, including syphilis experiments in Guatemala between 1946 and 1948. In this instance, the United States finally apologized formally in 2010 for the human rights breaches it carried out during these years when federally funded physicians infected soldiers, prostitutes, prisoners, and mental patients with syphilis and other sexually transmitted diseases without the informed consent of the subjects. This resulted in at least 83 deaths.
Notably, all of these experiments took place during and after the horrors of World War II shook the world. Among the atrocities that came to light after the war was over were the experiments Nazi scientists and doctors carried out on concentration camp prisoners. When the United States and its allies entered the camps in the days following liberation, the discoveries were overwhelming and sobering—to put it in the mildest terms. Those days were the impetus for a large part of America’s foreign policy today, in which the United States gives much aid to nations in dire need. The guilt of late action during Hitler’s reign has spurred this nation into action today, finding a place in the federal budget year after year to give aid to nations affected by natural disasters, conflict, and more.
In similar fashion, the U.S. Food and Drug Administration (FDA), which was founded in 1906 when President Theodore Roosevelt signed the Food and Drug Act into law, today takes its job as gatekeeper between for-profit enterprises that make food, drugs, and medical products, and users (either consumers or patients) very seriously. Those in the medical device industry know quite well the criticism the agency hears most: that it lags in review times when compared to regulatory bodies around the world. Experts disagree whether this is actually true or not; but more to the point is that the FDA is acting on behalf of public health, despite pressures it faces from industry, government, and patients alike. Review times are what they are because the agency does not want unsafe medical devices getting to market—and really, who does want that?
FDA Review Times
A brief history of the FDA in the past decade (as it concerns medical devices) may be summed up as follows: review times for devices were too high, industry called for change, the agency responded, and now review times are at an all-time low.
Except that may not be true. Much has been said (and written) about the FDA making major gains on its sluggish review times for pre-market approvals (PMAs), which averaged 464 days in 2009 but dropped to 252 days in 2013 after MDUFA III (Medical Device User Fee Amendments to the FDA Amendments Act) was instated.1 However, experts outside the agency have started to point out that the various data being tracked and charted both by the FDA and watchdog groups may not be entirely representative of the time it truly takes to review a medical device, either through the PMA process or the less stringent 510(k) clearance process.
In the time since MDUFA III, the FDA has released three key requirements for companies seeking device approvals or clearances. First is the Q-Sub, a catch-all term for any pre-submission requirements a company must meet. These include pre-submissions, informational meetings, study risk determinations, formal early collaboration meetings (i.e., agreement and determination meetings), submission issue meetings, and PMA day 100 meetings. Since these are pre-submission, the time taken to complete such requirements do not factor into the tracked review times from the FDA.
Secondly are Refuse to Accept Checklists (RTA). These checklists provide submitting medical device companies a checklist they can use to make sure their submissions meet a minimum threshold of acceptability and should be accepted for substantive review. However, the agency can refuse to accept a submission within 15 days, adding a significant amount of time to a company’s submission efforts (pre actual submission).
“There’s no limit of the number of RTA cycles, and that to me, I think, is one of the most dangerous things,” said Jorge Ochoa, Ph.D., principal engineer at engineering and scientific consulting company Exponent Inc., at the 2014 10x Medical Device Conference. “…Fifteen days at a time plus the time in between to react can add up pretty quickly. If you are on a very short timeframe as far as your product development cycle—if you are in hips, knees, spine, where new products, really significant products get launched every five to 10 years, it’s not as big a deal. If you’re doing stents; if you’re doing pacemakers where the technology changes every six months, two or three cycles, it’s 20 percent of your product development cycle. So it is significant.”
In the same session, senior managing scientist for Exponent Carrie M. Kuehn, MPH said, “The RTA checklist … is enormous. It has multipart questions, there are separate sections for different pieces, and it is anything but administrative. If you look through it, there is definitely a blurred line between that administrative or substantive review.”
Thirdly, the FDA introduced a requirement for electronic copies (e-copies) of a submission in 2013. An e-copy is defined as an exact duplicate of the paper submission, created and submitted on a CD, DVD, or a flash drive. An e-copy is accompanied by a paper copy of the signed cover letter and the complete paper submission.
“Each process has both positive and negative consequences,” Maria Griffin and Daniel Aisen, senior compliance specialists for Great Neck, N.Y.-based MDI Consultants Inc., told MPO. “For example, the RTA is meant to assure that the submission arrives at the agency pre-reviewed by the sponsor for completeness and then reviewed by the FDA prior to a substantive review. The FDA has 15 days to perform this review, which does not count towards the 90-day review time, and just like that, the FDA added 15 days to their ‘clock’ without it actually counting.”
Jim Dunning, CEO of Mesa, Ariz.-based FDA regulation consulting services company QPC Services LLC, agreed, saying, “I believe the FDA is managing their time metrics, but I do not believe the FDA is truly providing 510(k) reviews faster. I actually believe that the true time for a 510(k) review is increasing. I think a major component of the reason for this is that the FDA reviewers often attempt to make up for weaknesses; and the 510(k) review process itself.”
This is not to say the FDA is duplicitous in its operations. The agency has undoubtedly tried to address the major concerns of the medical device industry, if not all of them; whether it’s doing it effectively or not is the question.
“The FDA is working toward a more consistent and predictable process for 510(k)s and PMAs, and we have seen considerably more consistency in our submission communications over the last few years,” Meredith May, MS, RAC, CQA, vice president of King of Prussia, Pa.-based Empirical Consulting LLC, noted to MPO. “While the review times for Empirical Consulting’s submissions have not shortened dramatically over the last two years, the review time and deficiency content has become more consistent and predictable. While the industry average for review time is approximately 185 calendar days, we have seen ours staying consistently around the 105-110 day mark, which helps with project planning and product launch schedules.”
“The bright spot today with the FDA is actually the programs that are focusing on decreasing time to investigational device exemption (IDE) approval—approximately 400 days in 2011 and down to 30 days in 2015, according to the FDA annual report,” Seth J. Goldenberg, Ph.D., director of product development and strategy at Northwood, Ohio-based NAMSA (North American Science Associates Inc.) told MPO. “They also have initiatives such as Early Feasibility Studies (EFS) that gives more attention and support from the agency to medical device companies that are bringing innovative products to market.”
Indeed, for 2015, the FDA reported far fewer RTA rejections as well as substantial reduction times for IDE and de novo reviews. The agency reported that RTA rates fell from 57 percent in the first quarter of 2014 to 37 percent in the second quarter of 2015. The FDA attributes this decrease to more training as well as greater RTA policy transparency for industry, which in turn may have led to fewer mistakes and omissions in 510(k) submissions to the regulator. Since the RTA policy’s introduction in early 2013, rates of rejection have steadily decreased, suggesting greater awareness on the part of 510(k) applicants of what must be included in a premarket notification submission to warrant substantive FDA review. The most dramatic reductions were reported for IDE and de novo reviews; IDE review times fell by more than a year, according to the FDA, while de novo reviews decreased from more than three years in 2010 to 10 months in 2014.2
A New World: Mobile Apps
The FDA has found itself scrambling in recent years to keep up with burgeoning health technologies in the mobile health space (including mobile apps), wearables, and other wireless technologies. May of Empirical Consulting found the agency’s pre-submission meetings were particularly helpful to companies seeking to launch new and innovative technologies, giving them a chance to pre-empt any unforeseen issues and challenges that may arise during the submission process.
“We have found that the pre-submission process has been wildly successful with these types of devices and would recommend a pre-submission meeting to anyone looking to launch an innovative device,” she said. “This pre-submission meeting serves as an agreement between the company and the FDA about what the indications will be and what testing would be needed. After the successful conclusion of the pre-submission process, the FDA won’t ask for additional testing unless something in the test results causes concerns that would require testing to alleviate. This takes so much of the guessing out of the submission process.”
For mobile apps, the FDA is moving with a welcome symbiotic attitude with industry. Instead of issuing strict regulations that are difficult to navigate, the agency is regulating apps on a case by case basis and only, according to draft guidance issued last year, applying its regulatory oversight “to those mobile apps that are medical devices and whose functionality could pose a risk to a patient’s safety if the mobile app were to not function as intended.”
NAMSA’s Goldenberg told MPO that the agency is exercising regulatory discretion “appropriately,” saying, “This technology is going to continue to evolve and by not issuing regulations, the FDA is supporting its growth. Companies do need to be aware of regulations and not impact industry by overstepping their claims. They also need to be aware of other regulatory agencies (such as the Federal Trade Commission) that are enforcing aggressive claims as well.”
The Federal Trade Commission (FTC) has jurisdiction over false advertising, so “lax” or generous oversight from the FDA should not tempt app developers to “plump” their claims. Let Theranos Inc., the much-maligned maker of a new blood-testing technology, be a lesson. The Palo Alto, Calif.-based company launched to much fanfare (its technology shrouded in much secrecy) in 2003, and gained a lot of media attention as much for its young, promising CEO Elizabeth Holmes as its supposedly ground-breaking blood testing technology. Today, many news outlets have reported that most of the claims made by Holmes and Theranos were exaggerated and perhaps even false. New, exciting technologies in the consumer space often follow a path of media-aided hype fueled by an air of mystery around the technology itself; there is no room for that in medical technology, where the device or software is created to help patients manage diseases or physicians perform life-saving tasks.
The FDA is operating in a somewhat deregulatory climate due to pressures to lower review times and not stifle innovation in the United States, pushing device makers to bring their devices to market overseas first. However, just because the FDA is giving mobile developers some latitude does not mean the FTC is not paying strict attention. In 2011, the commission settled with marketers of the AcneApp and Acne Pwner, mobile apps that were marketed for treating acne by emitting colored lights from smartphones. The settlements forbid the marketers from making acne-treatment claims about their mobile apps, or any other devices, in the absence of substantiating scientific evidence. Then in 2015, the FTC barred marketers of the MelApp and Mole Detective mobile apps from making any representation that the apps could detect or diagnose melanoma, identify risk factors of melanoma, or increase users’ chances of detecting melanoma in its early stages, in the absence of substantiating scientific evidence. Later that year, the FTC settled with the developer of the UltimEyes app, which was marketed as “scientifically shown” to improve vision. The company agreed to pay a $150,000 fine and to stop making the vision improvement claims.
The most legally conservative approach, according to recent FDA guidance and FTC activity, is to avoid any claim that an app is designed to diagnose, cure, prevent, or mitigate a specific disease. Low-risk apps that promote general health and wellness will likely avoid regulation, but as always, consulting with the FDA will help ensure a device is on the right track—because, as befits the space, mobile health regulation moves fast and changes regularly.
A Global Perspective
In February this year, the European Commission (EC) issued a draft that seeks to revoke the medical device status of proanthocyanidin (PAC)-based cranberry products for the treatment of cystitis, or urinary tract infections. The request for revocation came from France, which stripped company Arkopharma of its medical devices status in 2014 for lack of data in relation to cranberry products. French regulators now want all 28 nations in the European Union to follow its example, and the EC is taking steps to do so.
Traditionally, American device makers have looked to Europe as a market in which they can get devices approved much faster than they can in the United States. However, EU medical device legislation has been undergoing an upheaval in recent years. In 2012, the EC released two proposed new regulations, one for medical devices and one for in-vitro diagnostics (IVDs). According to the commission, the goals of the new regulations are to deliver greater consistency and safety to patients, and to bring medical device and IVD legislation up to speed with technological and scientific advancements that took place in the 20 years since the current legislation was adopted. The European Council’s approach is to have notified bodies—which are the individual entities that evaluate medical devices for CE mark approval—undergo a stricter designation process and increased monitoring by competent authorities.
Notified bodies are proposed to be given the authority to carry out unannounced factory inspections. Manufacturers will also face increased postmarket surveillance requirements compared to the commission text. Now, they will be required to form a postmarket surveillance system proportionate to the risk class and appropriate for the type of device. Companies will be required to submit periodic safety update reports similar to pharmaceutical reporting requirements, on an annual basis. They will also be required to act faster in response to serious public health threats or deaths caused by devices.
Finally, the council has amended the commission’s proposed texts to include greater protections for patients participating in clinical investigations for medical devices. To demonstrate conformity, companies must demonstrate their products have an acceptable benefit-to-risk ratio. For high-risk devices, companies must conduct clinical investigations to demonstrate their product’s safety and performance. The council proposal includes a provision to allow manufacturers of Class III (highest risk) devices to consult with an expert panel to provide feedback on the company’s clinical investigation strategy. The regulation also provides criteria for, and restrictions on, clinical investigations, and allows for individual member states to further restrict certain practices within the scope of a clinical investigation.
“Today the global regulatory burden is increasing around the world,” Goldenberg told MPO. “Countries that used to only require approval in a high regulatory burden market are now issuing their own regulations and requiring independent review. You also have a consolidation and changing regulations in the EU that is slowing down the historically ‘get to market fast’ location for medtech.”
“The regulatory environment both in the United States and abroad have created an uncertain environment for the medical device industries,” said Griffin and Aisen of MDI Consultants. “Several factors contribute to this, including inconsistent regulations, inconsistent level of inspection expertise, graft and corruption in a few of the regulatory agencies, and constant posturing of countries that believe that their system is the best and, as such, do not want to collaborate with other regulators. The end result for business is trying to comply with a burdensome and inconsistent regulatory regime while simultaneously meeting customer demands for new and improved technologies.”
It is indeed frustrating for medical device companies to keep up with regulatory changes year to year, when the lifetime of a medical device from conception to market can sometimes span decades. Brazil, for instance, once a key player in the emerging medtech markets (part of the BRIC bloc—Brazil, Russia, India, and China), has recently experienced an unprecedented economic burnout, leaving medical device hopefuls questioning whether their efforts there have now been rendered useless.
According to a recent CNN report, five years ago, Brazil’s economy was growing three times faster than the United States’. In 2011, its economic size surpassed Great Britain’s. Millions of Brazilians moved from poverty to the middle class, and the president at the time, Luiz Inácio Lula da Silva, had an 83 percent approval rating. But massive political scandal brought the economy down with it. The country suffered from the European debt crisis, as well as slowed economic growth in China.
Nonetheless, a TforG Healthcare Market review report for Brazil released in February reported that a growing middle class and aging population left room for healthcare industry growth. Although unemployment rates are dismal and rising, the report predicts an uptick in the economy to the tune of 3 to 5 percent per year. If timing is everything, the timing might be right for medtech companies seeking to jump in while others might be ignoring what seems to be an unpromising market.
References
Middletown and Norwich, Connecticut, 1940s: Once again, men in a mental hospital were exposed by Researcher Dr. W. Paul Havens Jr. to hepatitis in a series of experiments. Havens, a World Health Organization expert on viral diseases, was one of the first scientists to differentiate types of hepatitis and their causes.
West Coxsackie, New York, 1940s: Researchers studied the transmission of a deadly stomach bug by having young men swallow unfiltered stool suspensions. The study was conducted at the New York State Vocational Institution, a reformatory prison in West Coxsackie. The goal was to identify how well the disease spread by ingestion rather than airborne. The research concluded that swallowing it was a more effective way to spread the disease, but the study did not make clear if the men were either informed of the risks or paid for their participation.
Minneapolis, Minnesota, 1940s: A University of Minnesota study in the latter part of the decade injected 11 public service employee volunteers with malaria, then starved them for five days. Some were also subjected to hard labor, and those men lost an average of 14 pounds. They were treated for malarial fevers with quinine sulfate. One of the authors was Ancel Keys, a noted dietary scientist who developed K-rations for the military and the Mediterranean diet for the public.
Jessup, Maryland, 1957: When the Asian flu pandemic was spreading, federal researchers sprayed the virus in the noses of 23 inmates at Patuxent prison in Jessup to compare their reactions to those of 32 virus-exposed inmates who had been given a new vaccine.
And these are just the incidents on U.S. soil. The United States also has an ugly history of experimentation abroad, including syphilis experiments in Guatemala between 1946 and 1948. In this instance, the United States finally apologized formally in 2010 for the human rights breaches it carried out during these years when federally funded physicians infected soldiers, prostitutes, prisoners, and mental patients with syphilis and other sexually transmitted diseases without the informed consent of the subjects. This resulted in at least 83 deaths.
Notably, all of these experiments took place during and after the horrors of World War II shook the world. Among the atrocities that came to light after the war was over were the experiments Nazi scientists and doctors carried out on concentration camp prisoners. When the United States and its allies entered the camps in the days following liberation, the discoveries were overwhelming and sobering—to put it in the mildest terms. Those days were the impetus for a large part of America’s foreign policy today, in which the United States gives much aid to nations in dire need. The guilt of late action during Hitler’s reign has spurred this nation into action today, finding a place in the federal budget year after year to give aid to nations affected by natural disasters, conflict, and more.
In similar fashion, the U.S. Food and Drug Administration (FDA), which was founded in 1906 when President Theodore Roosevelt signed the Food and Drug Act into law, today takes its job as gatekeeper between for-profit enterprises that make food, drugs, and medical products, and users (either consumers or patients) very seriously. Those in the medical device industry know quite well the criticism the agency hears most: that it lags in review times when compared to regulatory bodies around the world. Experts disagree whether this is actually true or not; but more to the point is that the FDA is acting on behalf of public health, despite pressures it faces from industry, government, and patients alike. Review times are what they are because the agency does not want unsafe medical devices getting to market—and really, who does want that?
FDA Review Times
A brief history of the FDA in the past decade (as it concerns medical devices) may be summed up as follows: review times for devices were too high, industry called for change, the agency responded, and now review times are at an all-time low.
Except that may not be true. Much has been said (and written) about the FDA making major gains on its sluggish review times for pre-market approvals (PMAs), which averaged 464 days in 2009 but dropped to 252 days in 2013 after MDUFA III (Medical Device User Fee Amendments to the FDA Amendments Act) was instated.1 However, experts outside the agency have started to point out that the various data being tracked and charted both by the FDA and watchdog groups may not be entirely representative of the time it truly takes to review a medical device, either through the PMA process or the less stringent 510(k) clearance process.
In the time since MDUFA III, the FDA has released three key requirements for companies seeking device approvals or clearances. First is the Q-Sub, a catch-all term for any pre-submission requirements a company must meet. These include pre-submissions, informational meetings, study risk determinations, formal early collaboration meetings (i.e., agreement and determination meetings), submission issue meetings, and PMA day 100 meetings. Since these are pre-submission, the time taken to complete such requirements do not factor into the tracked review times from the FDA.
Secondly are Refuse to Accept Checklists (RTA). These checklists provide submitting medical device companies a checklist they can use to make sure their submissions meet a minimum threshold of acceptability and should be accepted for substantive review. However, the agency can refuse to accept a submission within 15 days, adding a significant amount of time to a company’s submission efforts (pre actual submission).
“There’s no limit of the number of RTA cycles, and that to me, I think, is one of the most dangerous things,” said Jorge Ochoa, Ph.D., principal engineer at engineering and scientific consulting company Exponent Inc., at the 2014 10x Medical Device Conference. “…Fifteen days at a time plus the time in between to react can add up pretty quickly. If you are on a very short timeframe as far as your product development cycle—if you are in hips, knees, spine, where new products, really significant products get launched every five to 10 years, it’s not as big a deal. If you’re doing stents; if you’re doing pacemakers where the technology changes every six months, two or three cycles, it’s 20 percent of your product development cycle. So it is significant.”
In the same session, senior managing scientist for Exponent Carrie M. Kuehn, MPH said, “The RTA checklist … is enormous. It has multipart questions, there are separate sections for different pieces, and it is anything but administrative. If you look through it, there is definitely a blurred line between that administrative or substantive review.”
Thirdly, the FDA introduced a requirement for electronic copies (e-copies) of a submission in 2013. An e-copy is defined as an exact duplicate of the paper submission, created and submitted on a CD, DVD, or a flash drive. An e-copy is accompanied by a paper copy of the signed cover letter and the complete paper submission.
“Each process has both positive and negative consequences,” Maria Griffin and Daniel Aisen, senior compliance specialists for Great Neck, N.Y.-based MDI Consultants Inc., told MPO. “For example, the RTA is meant to assure that the submission arrives at the agency pre-reviewed by the sponsor for completeness and then reviewed by the FDA prior to a substantive review. The FDA has 15 days to perform this review, which does not count towards the 90-day review time, and just like that, the FDA added 15 days to their ‘clock’ without it actually counting.”
Jim Dunning, CEO of Mesa, Ariz.-based FDA regulation consulting services company QPC Services LLC, agreed, saying, “I believe the FDA is managing their time metrics, but I do not believe the FDA is truly providing 510(k) reviews faster. I actually believe that the true time for a 510(k) review is increasing. I think a major component of the reason for this is that the FDA reviewers often attempt to make up for weaknesses; and the 510(k) review process itself.”
This is not to say the FDA is duplicitous in its operations. The agency has undoubtedly tried to address the major concerns of the medical device industry, if not all of them; whether it’s doing it effectively or not is the question.
“The FDA is working toward a more consistent and predictable process for 510(k)s and PMAs, and we have seen considerably more consistency in our submission communications over the last few years,” Meredith May, MS, RAC, CQA, vice president of King of Prussia, Pa.-based Empirical Consulting LLC, noted to MPO. “While the review times for Empirical Consulting’s submissions have not shortened dramatically over the last two years, the review time and deficiency content has become more consistent and predictable. While the industry average for review time is approximately 185 calendar days, we have seen ours staying consistently around the 105-110 day mark, which helps with project planning and product launch schedules.”
“The bright spot today with the FDA is actually the programs that are focusing on decreasing time to investigational device exemption (IDE) approval—approximately 400 days in 2011 and down to 30 days in 2015, according to the FDA annual report,” Seth J. Goldenberg, Ph.D., director of product development and strategy at Northwood, Ohio-based NAMSA (North American Science Associates Inc.) told MPO. “They also have initiatives such as Early Feasibility Studies (EFS) that gives more attention and support from the agency to medical device companies that are bringing innovative products to market.”
Indeed, for 2015, the FDA reported far fewer RTA rejections as well as substantial reduction times for IDE and de novo reviews. The agency reported that RTA rates fell from 57 percent in the first quarter of 2014 to 37 percent in the second quarter of 2015. The FDA attributes this decrease to more training as well as greater RTA policy transparency for industry, which in turn may have led to fewer mistakes and omissions in 510(k) submissions to the regulator. Since the RTA policy’s introduction in early 2013, rates of rejection have steadily decreased, suggesting greater awareness on the part of 510(k) applicants of what must be included in a premarket notification submission to warrant substantive FDA review. The most dramatic reductions were reported for IDE and de novo reviews; IDE review times fell by more than a year, according to the FDA, while de novo reviews decreased from more than three years in 2010 to 10 months in 2014.2
A New World: Mobile Apps
The FDA has found itself scrambling in recent years to keep up with burgeoning health technologies in the mobile health space (including mobile apps), wearables, and other wireless technologies. May of Empirical Consulting found the agency’s pre-submission meetings were particularly helpful to companies seeking to launch new and innovative technologies, giving them a chance to pre-empt any unforeseen issues and challenges that may arise during the submission process.
“We have found that the pre-submission process has been wildly successful with these types of devices and would recommend a pre-submission meeting to anyone looking to launch an innovative device,” she said. “This pre-submission meeting serves as an agreement between the company and the FDA about what the indications will be and what testing would be needed. After the successful conclusion of the pre-submission process, the FDA won’t ask for additional testing unless something in the test results causes concerns that would require testing to alleviate. This takes so much of the guessing out of the submission process.”
For mobile apps, the FDA is moving with a welcome symbiotic attitude with industry. Instead of issuing strict regulations that are difficult to navigate, the agency is regulating apps on a case by case basis and only, according to draft guidance issued last year, applying its regulatory oversight “to those mobile apps that are medical devices and whose functionality could pose a risk to a patient’s safety if the mobile app were to not function as intended.”
NAMSA’s Goldenberg told MPO that the agency is exercising regulatory discretion “appropriately,” saying, “This technology is going to continue to evolve and by not issuing regulations, the FDA is supporting its growth. Companies do need to be aware of regulations and not impact industry by overstepping their claims. They also need to be aware of other regulatory agencies (such as the Federal Trade Commission) that are enforcing aggressive claims as well.”
The Federal Trade Commission (FTC) has jurisdiction over false advertising, so “lax” or generous oversight from the FDA should not tempt app developers to “plump” their claims. Let Theranos Inc., the much-maligned maker of a new blood-testing technology, be a lesson. The Palo Alto, Calif.-based company launched to much fanfare (its technology shrouded in much secrecy) in 2003, and gained a lot of media attention as much for its young, promising CEO Elizabeth Holmes as its supposedly ground-breaking blood testing technology. Today, many news outlets have reported that most of the claims made by Holmes and Theranos were exaggerated and perhaps even false. New, exciting technologies in the consumer space often follow a path of media-aided hype fueled by an air of mystery around the technology itself; there is no room for that in medical technology, where the device or software is created to help patients manage diseases or physicians perform life-saving tasks.
The FDA is operating in a somewhat deregulatory climate due to pressures to lower review times and not stifle innovation in the United States, pushing device makers to bring their devices to market overseas first. However, just because the FDA is giving mobile developers some latitude does not mean the FTC is not paying strict attention. In 2011, the commission settled with marketers of the AcneApp and Acne Pwner, mobile apps that were marketed for treating acne by emitting colored lights from smartphones. The settlements forbid the marketers from making acne-treatment claims about their mobile apps, or any other devices, in the absence of substantiating scientific evidence. Then in 2015, the FTC barred marketers of the MelApp and Mole Detective mobile apps from making any representation that the apps could detect or diagnose melanoma, identify risk factors of melanoma, or increase users’ chances of detecting melanoma in its early stages, in the absence of substantiating scientific evidence. Later that year, the FTC settled with the developer of the UltimEyes app, which was marketed as “scientifically shown” to improve vision. The company agreed to pay a $150,000 fine and to stop making the vision improvement claims.
The most legally conservative approach, according to recent FDA guidance and FTC activity, is to avoid any claim that an app is designed to diagnose, cure, prevent, or mitigate a specific disease. Low-risk apps that promote general health and wellness will likely avoid regulation, but as always, consulting with the FDA will help ensure a device is on the right track—because, as befits the space, mobile health regulation moves fast and changes regularly.
A Global Perspective
In February this year, the European Commission (EC) issued a draft that seeks to revoke the medical device status of proanthocyanidin (PAC)-based cranberry products for the treatment of cystitis, or urinary tract infections. The request for revocation came from France, which stripped company Arkopharma of its medical devices status in 2014 for lack of data in relation to cranberry products. French regulators now want all 28 nations in the European Union to follow its example, and the EC is taking steps to do so.
Traditionally, American device makers have looked to Europe as a market in which they can get devices approved much faster than they can in the United States. However, EU medical device legislation has been undergoing an upheaval in recent years. In 2012, the EC released two proposed new regulations, one for medical devices and one for in-vitro diagnostics (IVDs). According to the commission, the goals of the new regulations are to deliver greater consistency and safety to patients, and to bring medical device and IVD legislation up to speed with technological and scientific advancements that took place in the 20 years since the current legislation was adopted. The European Council’s approach is to have notified bodies—which are the individual entities that evaluate medical devices for CE mark approval—undergo a stricter designation process and increased monitoring by competent authorities.
Notified bodies are proposed to be given the authority to carry out unannounced factory inspections. Manufacturers will also face increased postmarket surveillance requirements compared to the commission text. Now, they will be required to form a postmarket surveillance system proportionate to the risk class and appropriate for the type of device. Companies will be required to submit periodic safety update reports similar to pharmaceutical reporting requirements, on an annual basis. They will also be required to act faster in response to serious public health threats or deaths caused by devices.
Finally, the council has amended the commission’s proposed texts to include greater protections for patients participating in clinical investigations for medical devices. To demonstrate conformity, companies must demonstrate their products have an acceptable benefit-to-risk ratio. For high-risk devices, companies must conduct clinical investigations to demonstrate their product’s safety and performance. The council proposal includes a provision to allow manufacturers of Class III (highest risk) devices to consult with an expert panel to provide feedback on the company’s clinical investigation strategy. The regulation also provides criteria for, and restrictions on, clinical investigations, and allows for individual member states to further restrict certain practices within the scope of a clinical investigation.
“Today the global regulatory burden is increasing around the world,” Goldenberg told MPO. “Countries that used to only require approval in a high regulatory burden market are now issuing their own regulations and requiring independent review. You also have a consolidation and changing regulations in the EU that is slowing down the historically ‘get to market fast’ location for medtech.”
“The regulatory environment both in the United States and abroad have created an uncertain environment for the medical device industries,” said Griffin and Aisen of MDI Consultants. “Several factors contribute to this, including inconsistent regulations, inconsistent level of inspection expertise, graft and corruption in a few of the regulatory agencies, and constant posturing of countries that believe that their system is the best and, as such, do not want to collaborate with other regulators. The end result for business is trying to comply with a burdensome and inconsistent regulatory regime while simultaneously meeting customer demands for new and improved technologies.”
It is indeed frustrating for medical device companies to keep up with regulatory changes year to year, when the lifetime of a medical device from conception to market can sometimes span decades. Brazil, for instance, once a key player in the emerging medtech markets (part of the BRIC bloc—Brazil, Russia, India, and China), has recently experienced an unprecedented economic burnout, leaving medical device hopefuls questioning whether their efforts there have now been rendered useless.
According to a recent CNN report, five years ago, Brazil’s economy was growing three times faster than the United States’. In 2011, its economic size surpassed Great Britain’s. Millions of Brazilians moved from poverty to the middle class, and the president at the time, Luiz Inácio Lula da Silva, had an 83 percent approval rating. But massive political scandal brought the economy down with it. The country suffered from the European debt crisis, as well as slowed economic growth in China.
Nonetheless, a TforG Healthcare Market review report for Brazil released in February reported that a growing middle class and aging population left room for healthcare industry growth. Although unemployment rates are dismal and rising, the report predicts an uptick in the economy to the tune of 3 to 5 percent per year. If timing is everything, the timing might be right for medtech companies seeking to jump in while others might be ignoring what seems to be an unpromising market.
References
- “FDA Approving New High-Risk Devices at Fastest Pace in Last Decade, Report Finds.” Regulatory Affairs Professionals Society. tinyurl.com/jpne5da
- “How long it has historically taken the FDA to clear 510(k) submissions.” Emergo Group. tinyurl.com/n9l3ede