The Evolution of Medical Device Clinical Trials: Their Background and a Look Toward the Future

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David R. Dills, Global Regulatory Affairs & Compliance Consultant White Paper

Demonstrating the effectiveness and safety of new medical products is a critical part of the medical product development process and requires significant resources to accomplish. The goal of every medical device company is to ensure that they are designing and implementing clinical trials for success while having comprehensive knowledge of coordinating, monitoring and managing a clinical trial within a framework of good clinical practices and regulatory requirements.

Medical devices play a critical role in the lives and health of millions of people worldwide. From everyday household items such as oral thermometers to complex implantables such as deep-brain stimulators, patients and the general public rely on regulators to ensure that legally marketed medical devices have been shown to be safe and effective. Regulators expect the data provided by device manufacturers to reflect the risk profile of the device.

A medical device is anything that is not either a drug or a biologic product. Medical devices usually work physically, while pharmaceutical products usually work chemically or biologically. Medical devices can be therapeutic, diagnostic or something else, whereas pharmaceutical products are usually therapeutic. Medical devices are invented, while drugs are usually discovered.

Medical Device Development and Approval The U.S. Food and Drug Administration (FDA) approval process for medical devices is different compared to drugs from pharmaceutical industries. Medical devices are submitted for approval to the FDA’s Center for Devices and Radiologic Health (CDRH) or Center for Biologics Evaluation and Research (CBER), while drugs from pharmaceutical companies are submitted for approval to the Center for Drug Evaluation and Research (CDER) or CBER at the FDA. Not all devices need to go through controlled clinical trials to gain regulatory approval. If a device needs a confirmatory study to support a premarket approval (PMA) application, this does not rely on randomized concurrent control but on historical controls showing evidence that the device is “safe and effective.”i This confirmatory study is usually enough to support a PMA application while pharmaceutical applications generally require two adequate, well-controlled confirmatory clinical trials.

When studying new drugs, a clinical trial is required. However, when studying medical devices, REQUIRMENTS FOR A CLINICAL TRIAL clinical trials may not be required, depending on the risk stratification Class I Class II Class III (or class) of the device. + Adhesive bandage + Knee prosthesis + Drug-eluting stent In the U.S., all Class III (and some Example + Surgical glove + Single-use scalpel + Insulin pen Class II) devices require a clinical trial. Source: FDA Needs a No Maybe Yes clinical trial?

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The development of a medical device follows a different route than that of a drug. While clinical trials on drugs focus on dose response study, medical device clinical trials give attention to prototype development. Drug development follows an extensive Phase I, II, III and IV clinical trialing process to test for safety, efficacy and toxicity, whereas medical devices have feasibility, pilot and pivotal study models. Some medical device research involves substantial bench and animal testing for reliability and biocompatibility (like in implants), but there are no studies for toxicity on devices like the Phase I or animal studies required for pharmaceutical research. Pilot and feasibility studies on medical devices are considered first-in-man studies.

For drug studies, post-marketing CLINICAL TRIAL CLASSIFICATION studies are typically considered Phase IV studies. For device studies, Device Studies Drug Studies the requirement for long-term data Pilot: Phase I: is generally satisfied with a post- Small study (10-30 patients with the condition) Small study (20-100 healthy volunteers or people approval study. Source: FDA to determine preliminary safety and performance with condition) to determine preliminary safety and dosage

Pivotal: Phase II: Larger study (150-300 patients with the condition) to Larger study (up to several hundred people with the determine efﬁcacy and adverse effects condition) to determine efﬁcacy and adverse effects

Post-approval: Phase III: Post-approval study to collect long-term data (sometimes known as pivotal study) Even larger study (up to thousands of people with the condition) to determine efﬁcacy and monitor adverse effects

Phase IV: Post-marketing study to collect long-term data

Device development is iterative, and designs may be refined or improved as device development progresses. While user feedback, adverse events or difficulties in deploying or delivering a device can all lead to changes to the device, second- or third-generation designs do not always require a new clinical trial. Bridging the new to the old design may require additional bench studies or small confirmatory post-market studies.

A medical device can be changed during clinical development and once it’s on the market a newer, improved version may already be in development. Thus, the life cycle of a medical device may only be as short as a couple of years. In contrast, drugs are usually on the market for many years. Medical devices are approved through the PMA application process and a single confirmatory study is often sufficient for approval. In contrast, drugs are approved through the New Drug Application (NDA) process and drug development is characterized by Phases I through IV clinical trials. There are numerous medical device companies registered with the FDA.

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The medical device manufacturing industry is becoming a major player in health-care delivery. Physicians treat many illnesses and conditions, such as cardiovascular and neurological diseases, with medical devices as often as with medicine. Medical device manufacturers can conduct clinical trials more easily in Europe where currently regulatory barriers to clinical testing have less constraints. Consequently, new innovative medical devices typically come to market in Europe first. Approval for marketing these devices in the U.S. follows in five to 10 years, then an additional five to 10 years for Japan, which has the longest regulatory pathway.

A medical device clinical trial can cost between $5 and $10 million USDii, and this varies for obvious reasons, in the U.S. or Western Europe and more in Japan. The cost of the same trial conducted in Eastern Europe will be considerably lower, and in India, China, or Korea, it may be one-tenth as expensive.iii Manufacturers are turning to Asian countries for their high-risk, first-in-human studies and even for their pivotal studies because these countries contain a huge available human population with limited alternatives for healthcare. Also, the regulatory barrier to starting a device clinical trial in India, China or Korea is sometimes easier but this can vary due to a multitude of factors.

Regulations and Good Clinical Practices Regulations for conducting medical device clinical trials around the world have varied widely. Complications that arise between trials conducted under different protocols make bringing a device to market difficult in a stricter country. Data may be considered questionable given different requirements. The time required to determine acceptability and perhaps repeat trials may delay the device’s approval, frustrating patients as well as manufacturers.

In addition, the safety of human subjects participating in the clinical trial – and ultimately patients – is in question in countries with lax regulations and resultant uncontrolled clinical settings. Less rigorous studies cannot ensure consistent performance quality, thus potentially jeopardizing the health the devices are meant to protect.

In 2011, the International Organization for Standardization (ISO) adopted and published a revised version of ISO14155, essentially a clinical practice roadmap for taking a medical device through the clinical trial life cycle. This amendment to the 2003 standard, known as ISO 14155:2011, provides guidance for conducting medical device clinical investigations, in which sponsors are responsible for implementing a risk management program, classification of adverse events and monitoring the ongoing safety evaluation of the clinical investigation for their medical devices.iv

Perhaps the most obvious change is the title of the standard itself: ISO 14155:2011 Clinical Investigation of Medical Devices for Human Subjects – Good Clinical Practice (GCP). The addition of GCP to the title indicates the alignment of medical device investigations to the International Conference on Harmonization Good Clinical Practices (ICH GCP) E6 guidelines.v

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For medical devices, frequent innovations in the design and use (for example, minor modifications that enhance safety, reliability, patient comfort, or ease of use) are common and often do not require prior regulatory approval. Bench and/or animal testing is often sufficient to validate the suitability of a design change.

In cases when a clinical trial is required (for example, for high-risk or some medium-risk devices), evidence can come from sources other than well-controlled clinical studies, when justified. Such sources may include, but are not limited to the following:

1. Partially controlled clinical studies 2. Clinical studies and objective trials without matched controls 3. Well-documented case histories conducted by qualified experts 4. Reports of significant human experience with a marketed device

The reason for these varied sources of evidence is that the design of medical- device clinical trials may present some special challenges that do not arise with drug trials. Some of the challenges are well known, including:

• Challenges in designing clinical trials for medical devices • Devices are primarily used by healthcare professionals: The clinical outcomes of a medical device’s safety and effectiveness are a function of the user’s skill paired with the device-patient interaction. Having training in the use of the medical device is a key part of its clinical performance. • Inability to blind the user/patient: Medical devices are often designed differently, and this can introduce bias into the assessment of the clinical performance if the clinical investigator is jointly responsible for treatment and assessment of performance. Thus, whenever possible, blinded evaluators are preferred to clinical investigators for the assessment of efficacy. • Limitation in comparative trial design (for example, an implanted device): Comparative clinical trials may be precluded due to ethical considerations. The use of historical controls in the trial or patients as their own controls (pre- and post-surgery) may be required to evaluate outcomes.

Often, the process for regulatory clearance or approval for medical devices is more flexible than it is for drug development.

Meeting Regulatory Expectations: Key Principles of Clinical Study Design The CDRH released an extensive new final guidance document on the design of pivotal clinical investigations meant to support the approval of medical devices. The 57-page guidance, Design Considerations for Pivotal Clinical Investigations for Medical Devices,vi was first released in draft form August 2011 and pertains to the stages of development in which a device is evaluated for safety and efficacy, otherwise known as the pivotal stage of development.

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In general, such studies are used to support PMAs, but a smaller subset may also be used to support premarket notification [510(k)s] and De Novo submissions as well.

As explained by the FDA, the guidance elaborates on various “principles” of study design that will meet the FDA’s expectations for premarket clinical data requirements, but regulators stressed it is not meant as a “comprehensive tutorial on the best clinical and statistical practices for investigational medical device studies.”vii

The guidance is divided into seven sections, with several containing extensive sub-sections:

• Regulatory Framework for Level of Evidence and Study Design • Types of Medical Devices • The Importance of Exploratory Studies in Pivotal Study Design • Some Principles for the Choice of Clinical Study Design • Clinical Outcome Studies • Diagnostic Clinical Performance Studies • Sustaining the Quality of Clinical Studies • The Investigational Plan or Protocol

Adaptive Design Back in 2015, a draft guidance from the FDA was issued to outline the appropriate uses of medical device clinical trial designs that allow for planned trial changes to be implemented based on accrued data while maintaining study validity and integrity.viii

Known as adaptive design, the method can minimize clinical trial sponsors’ resource requirements and increase chances of study success. By spelling out when adaptive designs are acceptable in clinical trials for devices requiring PMA or 510(k) premarket notification, the FDA seeks to better inform both device manufacturers and its own review staff on the benefits and proper implementation of adaptive designs.

The guidance provides several examples of how to properly incorporate adaptive designs into clinical trials, as well as advantages of utilizing such designs: efficiency and cost effectiveness, better understanding of device benefits and risks, and stronger transitions from pre-market analysis to post-market follow-up.

“Overall, adaptive designs may enable more timely device development decision- making and therefore, more efficient investment in resources in a clinical study,” states the FDA guidance.ix Meeting clinical study and data requirements can be one of the most costly and challenging issues for manufacturers registering their

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devices in the U.S. Through this new guidance, the FDA has demonstrated that adaptive clinical study designs may be one way to offset those challenges for some Class II and III devices undergoing premarket review.

Overcoming Patient Barriers in Medical Device Clinical Trials Back in October of 2017, FDA Patient Engagement Advisory Committee (PEAC) met for the first time to look at ways to increase patient engagement in clinical trials for medical devices. Owen Faris, clinical trials director at the CDRH, said the opportunity to engage with patients goes beyond using patient reported outcomes (PROs) and patient preference information (PPI) in regulatory decision-making.

According to Faris, patients should be engaged “at the very beginning when we’re thinking about what technologies need to be developed in the first place” and when designing preclinical and clinical studies.x

Throughout the meeting, participants and members of the PEAC brought up a number of challenges and barriers that patients face with clinical trials. One of the biggest challenges raised is that many patients are not all well-informed about how clinical trials work or how to get involved with them.

As a potential solution, PEAC members said that a framework or roadmap should be developed to demystify the clinical trial process for patients. The committee also said that information about clinical trials and informed consent documents should be written in plain language to make it easier for patients to understand.

Yet, as industry and FDA know, there is a wide array of clinical trial designs and data sources that may be used to support the safety and effectiveness of medical devices. Unlike for pharmaceuticals, which generally see double-blind, randomized Phase III trials assessing outcomes prior to approval, it has been written that there are practical limitations related to the device or disease condition that require alternative approaches for many devices. For example, the FDA has stated it may be infeasible to conduct a blinded trial of an implantable device because it would be unethical and impractical to implant a placebo device. And for some devices, alternative data sources, such as existing registries or modeling techniques, can allow regulators to have a good idea of the risks and benefits of the device without the need for conducting detailed trials.

For the majority of devices, the benefits and risks can be revealed through registries and evolve as clinical techniques are refined and the technologies are modified and improved. Such a continuous improvement cycle would be impossible if every device iteration required a full trial to test its safety and efficacy. This may also be attributable to the fact that FDA has in many cases accepted a somewhat greater degree of uncertainty regarding those benefits and risks early in a device’s life cycle.

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Consistency of Regulatory Data from Device Clinical Trials We can recall back in February 2013 that the medical device industry was not too pleased with a proposed regulation that would require all companies to make sure their clinical trials, no matter where in the world those trials are conducted, to adhere to U.S. clinical trials regulations. The FDA draft regulation, Human Subject Protection: Acceptance of Data from Clinical Studies for Medical Devices, would notably require sponsors to obtain approval from an independent ethics committee (also known as an Institutional Review Board or an Ethical Review Board), and obtain and document informed consent of study participants.xi

The proposed rule was intended to update the standards for FDA acceptance of data from clinical studies conducted outside the U.S. and to help ensure the protection of human subjects and the quality and integrity of data obtained from these studies. The goal, regulators explained, was to promote consistency in the trials while assuring that human subjects participating in the trials were given adequate protections.

FDA now accepts data from foreign-conducted clinical studies so long as they meet 21 CFR 812-14, which states that the obtained data must be scientifically valid and must have been collected per the ethical guidelines of the Declaration of Helsinki or local laws (whichever offers stronger protection to research subjects).xii

This data is most commonly used in support of an application that includes data from the U.S., but the FDA encourages sponsors to meet with it if the application will be “based solely on foreign clinical data.”xiii Those requirements are less stringent than required for clinical trials conducted within the U.S., which are held to various U.S.-specific regulations such as 21 CFR 56 (IRBs)xiv and 21 CFR 50 (informed consent).xv However, these requirements are just for PMAs, as FDA’s 510(k) and Investigational Device Exemption (IDE) regulations do not address FDA requirements for the acceptance of data from either inside or outside the U.S.

These inconsistencies were – and are – troubling to the FDA, which argues in the proposed regulation that it “believes that the requirements for FDA’s acceptance of data from clinical studies should be consistent regardless of the type of submission or application in which the data are submitted to FDA.”xvi

Why the need for consistency? First, standards continue to evolve far beyond those first elucidated by the Helsinki Declaration, including the development of GCP guidelines issued by the World Health Organization, the International Standards Organization, the Pan American Health Organization and the International Conference on Harmonization (ICH), among others.

The FDA amended requirements for the acceptance of clinical data collected outside the U.S. to support medical device submissions, effective February 21, 2019. The amended requirements apply to PMA, humanitarian device exemption (HDE), IDE, 510(k), product development protocols, and De Novo classification request submissions.

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As of the effective date, acceptable data must be collected in compliance with the GCP for medical device clinical trials outlined in the ISO Standard 14155:2011. ISO 14155 is the required standard for medical device trials in most of the developed world and is a recognized consensus standard with the FDA (Recognition # 2-205). Prior to the effective date, investigators are required to follow either the Declaration of Helsinki, or local regulations, depending on which one provides the most stringent human subjects protections. The changes would apply a single standard, particularly with regard to informed consent and review and approval by an independent ethics committee.

Since ISO 14155 compliance is already a requirement in most jurisdictions, the amended requirements should not create issues for most manufacturers. On 18 February 2018, the FDA generated a guidance document, Acceptance of Clinical Data to Support Medical Device Applications and Submissions – Frequently Asked Questions, addressing issues relating to the acceptance of medical device clinical data generated outside the U.S.

Many of these standards are adopted either in whole or in part by the FDA, which, as noted above, now wants to amend standards such as 21 CFR 814.15, 807 and 812 to require all clinical trials conducted for medical devices to meet GCP standards set by the FDA. The Agency believes that the proposed standard helps to ensure adequate human subject protection and the quality and integrity of data obtained from such studies, while also being sufficiently flexible to accommodate differences in how countries regulate the conduct of clinical research and obtain informed consent.

The change should also make sure data is of the same quality and integrity, regardless of its geographic source, FDA argued.xvii Some of the most critical elements of GCP emphasized by the FDA include provisions pertaining to the assurance that results are credible, accurate and fully monitored throughout the trial. Human subject protections will also be upgraded under the proposed rule, with FDA emphasizing a harmonized, “unifying approach, which may simplify such trials and decrease the regulatory burden on sponsors.”xviii

The FDA also said that under the rule, it would require that 510(k) and IDE applications adhere to the same standards as PMAs. This will help ensure the protection of human subjects and the quality and integrity of data obtained from these studies.xix

But if the FDA hoped that its comments would allay industry incredulity, comments submitted to FDA’s federal docket indicate that this attempt was unsuccessful. Medical device industry group AdvaMed said it was “very concerned” about the proposed rule, arguing that without international support, trials could run into significant problems.xx FDA’s approach, it said, seems based on the ICH model for pharmaceutical products. “Unfortunately, no such harmonized international medical device good clinical practice guideline exists for medical device and in vitro diagnostic clinical investigations,” it said.

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“Absent a similar common foundation for medical devices, FDA and industry alike may run into resistance from the OUS (outside the United States) regulatory and clinical community to implementation of the proposed rule,” it continued. Such a rule should be put on hold until an internationally-harmonized system is put into place, AdvaMed concluded.xxi

The final rule (effective February 21, 2019) updates the criteria for FDA acceptance of data from clinical investigations conducted outside the U.S. to help ensure the quality and integrity of data obtained from these investigations and the protection of human subjects.xxii As part of this final rule, FDA is also amending the IDE, 510(k), and HDE regulations to address the requirements for FDA acceptance of data from clinical investigations conducted inside the U.S. The final rule provides consistency in FDA requirements for acceptance of data from clinical investigations, whatever the application or submission type.

The FDA also published a guidance document, Acceptance of Clinical Data to Support Medical Device Applications and Submissions Frequently Asked Questions (Guidance), to clarify requirements outlined in the final rule.xxiii The bottom line is that the effective date for the rule is February 21, 2019, one year after its publication. The regulations will not be applied to clinical investigations outside the U.S. that begin prior to the effective date, meaning studies that enroll their first subjects before February 21, 2019. A subject is considered enrolled when the subject or subject’s authorized representative agrees to participate in the study by signing the informed consent form. Foreign investigations that enroll their first subjects prior to the rule’s effective date will be subject to the old requirements in 21 CFR § 814.15 regulating PMA applications. For these investigations, the FDA will accept the data if the data is valid and the investigators have conducted the studies in conformance with the Declaration of Helsinki or the laws and regulations of the country in which the research is conducted.

• Additional education of contract research organizations (CROs) and ex-U.S. clinical trial sites around GCP compliance will be necessary. • Clinical trial agreements will need to be modified to require representations concerning GCP compliance. • Additional costs of GCP compliance may affect strategic decisions about where to conduct future clinical trials (within versus outside the United States).

Making Adaptations in an Dynamic Clinical Landscape As a reminder of other recent updates, the ICH E6 (R2) GCP Guideline became final in November 2016.xxiv As noted in the guideline, since the original ICH E6 (R1) was released, clinical trials were performed in a largely paper-based process. E6 (R2) was developed to address the increased scale, complexity, and cost of clinical trials, and to include the advances that have been made in electronic data recording and reporting technologies, as well as the implementation of other approaches and, in fact, encourages the implementation of improved and more

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efficient approaches to clinical trial design, conduct, oversight, recording and reporting while continuing to ensure human subject protection and reliability of trial results.

Approximately 10 years ago, when medical device manufacturers wanted to gain early clinical experience with their new devices they often went overseas to conduct first-in-human or small clinical studies. Moving a device from bench to bedside for use in patients is a critical step along the development path. However, going overseas delayed access to potentially beneficial devices for American physicians and patients.

Today, CDRH has an Early Feasibility Studies Program (EFS) that provides a route for innovators, sponsors, FDA review teams, and clinicians to work together to facilitate the early clinical evaluation of medical devices in the United States under the IDE regulations.xxv

An EFS is a limited clinical study on a device early in its development, typically before the device design has been finalized, for a specific indication. It may be used to evaluate the device design concept with respect to initial clinical safety and device functionality. The EFS Program includes enhanced opportunities for collaboration, increased regulatory flexibility, and consideration of benefit-risk principles, while maintaining appropriate patient protection measures.

Since the release of the EFS guidance document in October 2013, and the FDA’s promotion of the EFS Program as part of the 2014-2015 Strategic Priorities, there have been an increase and earlier clinical studies on devices in the U.S. Specifically, the number of IDEs submitted for EFS has more than doubled with 26 submitted in the first year following the finalization of the EFS guidance document, compared to 57 submitted in fiscal year 2017.xxvi It’s worth noting that most of these studies have received timely approval by the FDA. Over the past two years, in fact, three-fourths of IDE submissions (which are required to conduct a clinical study on an investigational device) have either been approved outright by the FDA or approved with conditions within one 30-day review cycle.xxvii

There are plentiful examples proving how the EFS program is driving device innovation and enhancing early patient access to new technologies. One such case is Mitralign, Inc., a developer of a novel treatment for tricuspid regurgitation (TR), which occurs when the heart’s tricuspid valve doesn’t open and close correctly. Due to high-risk comorbidities, many TR patients aren’t open heart surgery candidates. However, Mitralign’s valve repair system provides minimally invasive transcatheter technology that may expand these patients’ treatment options. Mitralign received IDE approval in just 28 days, which allowed them to conduct a U.S.-based EFS that reduced the time, money and human resources needed to conduct the study.

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The positive and direct effect that EFS has had on medical device innovation will have an impact on all medical device developers but may be particularly crucial for small manufacturers. In fact, approximately half of EFS IDEs are submitted by device manufacturers, the majority of which are small companies that depend on early clinical experience for securing financial resources.xxviii

The Significance of Robust Clinical Evidence The most important factor for successful marketing approval, practitioner adoption, and safe use of higher-risk and innovative moderate-risk medical devices is robust clinical evidence. However, the most appropriate, least burdensome paths for gathering clinical data to support marketing approval for medical devices are as varied as the devices themselves. Because the U.S. regulatory standard for approval is reasonable assurance of safety and effectiveness whereas most other countries use a safety and performance standard, generally more clinical data must be collected, and larger clinical studies must be conducted to support U.S. marketing approval.

The FDA works with sponsors to develop a clinical trial design and statistical analysis approach that is best tailored to the technology, the medical need being addressed, the feasibility of data collection, and the benefits and risks to affected patients. In some cases, the FDA expects and is provided with clinical data from trials that are similar in design to a “gold standard” drug trial — large, blinded, randomized, controlled trials. For many devices, however, such designs are impractical or unnecessary. Often, the clinical data are confirmatory to extensive bench studies, studies in animals, and modeling studies that provide essential information on safety and effectiveness.

For other devices that are already available in other geographic locations or for other indications, there may be existing data from registries or studies outside the United States available to support approval. Advancements in the science of patient input are also needed to help ensure that clinical trials are designed to assess what matters most to patients and to facilitate patient enrollment in studies.

Consequently, the FDA has been working with patient groups and other groups to foster the evaluation of patient preferences for benefits and acceptability of risks of devices for particular diseases to inform device-approval decisions. In the future, FDA sees such data generation helping to inform the development of medical-device clinical trials and becoming a routine part of those trials.

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The FDA has taken a number of actions to expedite the safe initiation of clinical trials in the U.S. and to collaborate with trial sponsors, the professional- provider community, and patients to design better trials — ones that are robust, reasonable, and efficient. However, to make well-informed decisions, practitioners, patients, and payers often need additional data on the benefit–risk profile of the device as compared with available alternatives, as well as a deeper understanding of the device derived from greater patient exposure in clinical practice.

Because generating such evidence before marketing may inappropriately delay patient access to important technologies in some cases or may not be within FDA authority to require, it is critical that other stakeholders, such as the industry and the practitioner communities, support and provide additional evidence in the form of trials, registries or analyses of data from health records.

This challenge is not unique to the United States. Strategic investments and collaboration to establish a medical-device national evaluation system that are currently under way could improve the efficiency, timeliness, and comprehensiveness of postmarketing evidence generation. Such partnerships on a national and an international level are needed to ensure that appropriate data collection continues throughout the life cycle of a medical device as part of a learning health care system so that patients and practitioners are fully informed as to how best to use these technologies to support improved patient health and quality of life.

The FDA also recognizes that, for some technologies intended to address important unmet needs, it may be appropriate to accept a greater degree of uncertainty in order to expedite the availability of the device for patients, relying on postmarketing data to provide greater certainty about the safety or effectiveness of a device. This is the concept behind the FDA Expedited Access Pathway for “breakthrough” medical devices. For other devices that are already available in other geographic locations or for other indications, there may be existing data — from registries or studies outside the United States — available to support approval.

Advancements in the science of patient input are also needed to help ensure that clinical trials are designed to assess what matters most to patients and to facilitate patient enrollment in studies.

While clinical investigations of medical devices are essential, they can also be time-consuming. One study of the FDA’s review of innovative medical devices estimates that clinical trials range in duration from three months to seven years, with a median duration of three years.xxix Of course, the duration of clinical investigations of medical devices does not include time required for initial research and product development, or the time required for medical device review and approval by regulatory authorities. These timeframes can represent significant challenges for medical device manufacturers seeking to introduce new and innovative medical devices to the market.

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Another challenge facing medical device manufacturers is the cost of clinical investigations, which can range from $250,000 USD to as much as $10 million or more for a single product.xxx The cost factor can be especially daunting for small and mid-sized device manufacturers which make up the clear majority of medical device companies.

Keeping Up with the Changing Medical Device Regulatory Landscape Yes, ISO 14155 provides a detailed framework for the design, conduct and reporting of clinical investigations involving human subjects for the purposes of assessing the safety or performance of many types of medical devices (in-vitro diagnostic medical devices are excluded from the scope of the standard). However, it will behoove industry to stay informed and up-to-date with FDA trends.

Industry needs to pay attention to clinical trials and investigations.

On December 18, 2017, FDA announced the availability of a new draft guidance, titled “Investigational IVDs Used in Clinical Investigations of Therapeutic Products.”xxxi The draft guidance is intended to inform both product sponsors and IRBs regarding the application of the IDE regulation to investigational in vitro diagnostic devices (IVDs) used in therapeutic product clinical trials.

On May 17, 2016, FDA issued draft guidance encouraging clinical investigators to make their electronic data capture (EDC) systems interoperable with health care organizations’ electronic health records (EHRs).xxxii Although EHRs are generally under the control of health care organizations and institutions (not FDA-regulated entities such as sponsors), when records are used in clinical investigations, FDA has certain expectations about the source of data.

There are more proposed guidance documents and readers are encouraged to stay current with this dynamic and changing regulatory landscape for the medical device community.

Alternative Clinical Approaches The escalating costs of clinical investigations along with other factors have led many medical device manufacturers to explore alternative approaches. One approach is to conduct clinical investigations in countries outside of the U.S. where investigation expenses can be considerably less. Another option is the use of a third-party CRO that can offer in-depth knowledge and experience in conducting clinical investigations, and that can leverage investments in technology and other processes to transform the traditionally labor-intensive investigative process. Using a CRO is independent of where the investigation is conducted and can potentially lead to time savings, especially when this may be one of the first times the manufacturer has conducted a clinical investigation.

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The medical device industry is inevitably growing and becoming more important. Its clinical research is very essential in assessing the safety and effectiveness of numerous medical devices in the market or in the development process. It is also a very important element in pharmaceutical research, like devices used to deliver drugs or diagnostic imaging to monitor therapies. In addition to highlighting examples of high-risk devices and the trials conducted, FDA’s “breakthrough” or expedited access pathway, which recognizes that for some new technologies looking to address unmet medical needs, it may be appropriate to accept a greater degree of uncertainty in order to expedite the availability of the device for patients, relying on postmarketing data to provide greater certainty about the safety or effectiveness of a device.

Medical device regulations around the world generally require manufacturers of most types of medical devices to supply data as part of the regulatory review process that supports claims regarding the safety, performance and effectiveness of their devices. For new or novel devices that may not have a predicated device, this data is typically derived from clinical investigations, studies or trials conducted by the manufacturer or an appointed third-party CRO with specialized expertise in conducting such investigations.

However, the cost of a clinical investigation can run into the millions of dollars and often take a year or more to execute. Further, nuanced differences in regulatory requirements can render the data from a clinical investigation inadmissible or otherwise unacceptable by authorities in a given jurisdiction. These challenges require manufacturers to design and execute medical device clinical investigations that meet threshold requirements for safety and effectiveness while also addressing variations in how regulators define these requirements.

Because of the potential risks associated with their use, medical devices are typically subject to clinical investigations to establish their safety and effectiveness prior to receiving approval from regulators and being placed on the market. The scope of a clinical investigation required for a given medical device can depend on several factors, including the level of risk posed by the device and the specific regulatory requirements of a jurisdiction. Post-market clinical studies may also be required to assess device effectiveness and to evaluate potential risks not identified in the pre-market assessment.

The State of Regulatory Compliance As of February 2018, it has been nearly five years ago to the date that makes it mandatory for all clinical trials conducted with new medical devices to be compliant with GCP rules similar to those for drugs and biologics. Although the notification refers to non-U.S. clinical trials, the details of the rule make it clear that this rule applies to trials conducted in the U.S. as well. Data from clinical trials with devices will only be accepted by the FDA if the trial was conducted after getting IRB or IEC approval, included informed consent from each study participant prior to participation, and which the FDA can verify in an audit. Clinical trials are needed for most PMAs and a few 510k devices, and, in the U.S., are mostly conducted under an IDE and follow GCP.

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Many countries have adopted GCP principles as laws and/or regulations. The FDA’s regulations for the conduct of clinical trials, which have been in effect since the 1970s, address both GCP and human subject protection (HSP). The FDA also actively encourages medical device manufacturers to discuss their anticipated clinical investigation design with FDA representatives through the agency’s pre- submission process. Medical device manufacturers that contemplate seeking FDA approval for their products should consider the potential benefits of such a discussion to affirm their choice of study design and to identify any specific concerns in advance.

According to the International Medical Device Regulators Forum (IMDRF), regulators in a number of major medical device markets will either accept data from clinical investigations that have been conducted in accordance with ISO 14155:2011 or have adopted clinical investigation requirements that are the equivalent of those in ISO 14155:2011.xxxiii Some examples cited by the IMDRF affirming the acceptance by regulators in major markets of ISO 14155:2011 for medical device clinical investigations include the EU, Japan, Brazil and Australia, but industry does indeed need to “think” global with a changing regulatory landscape.

Broader acceptance by ISO 14155 in other countries can be expected as regulators adopt integrate ISO 14155:2011 into existing regulations. However, it is important to note that individual national regulators may also impose additional requirements related to clinical trials beyond those found in ISO 14155. In the U.S., the situation regarding the acceptance of data from clinical investigations based on ISO 14155:2011 requirements is a little more nuanced to a certain degree. Why? The FDA specifically requires that clinical investigations of medical devices comply with GCP principles. While ISO 14155:2011 more closely aligns with GCP principles than prior versions of the standard, there are still important areas where FDA requirements based on GCP are more stringent than comparable requirements in ISO 14155. Something to consider indeed.

FDA does not require that all medical device manufacturers file clinical findings along with regulatory submissions. Companies developing medical devices that are similar to other products in the U.S. market can use the pre-market notification 510(k) submission which requires bench and laboratory data, but not full-blown clinical trials. Despite not having to perform trials, some organizations still complete clinical trials in an effort to bolster their submission case and/or build stronger product profiles for consumers and payers.

The Bottom Line For most medical device companies, clinical trials are the largest single area of R&D operating expense. The need to develop an accurate study budget is therefore critical, since an insufficient study budget may result in the inability to cover all expenses and this may affect the credibility within the industry, the institution, and the Principal Investigator.

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Budgeting a clinical trial is therefore a challenging task. At the time of creating the budget, there are still a lot of unknown variables, making it more difficult to accurately estimate the final budget. Several study assessments may not be known, and although a draft study design is most often in place at the time of budget creation, it still remains difficult to make the “best estimate.” A second difficulty lies in the estimation of the amount of work for the investigational sites. A fair market value should be paid to the sites, depending on the assessments and procedures performed. It is necessary to walk a fine line – the budget needs to be fair, but not excessive.

Companies completing clinical trials pre-510(k) submission can earn more extensive product claims than those submitting without clinical trials. Clinical trials can also satisfy any questions that companies may anticipate from the FDA, expediting regulatory clearance. Though these trials can be time-consuming and expensive, some companies feel that the regulatory and commercial benefits justify the costs. Just to put things into perspective with Drug and Device Approval Paradigm (with some subtle variations), the message is clear: it’s a process.

For drug studies, post-marketing NEW DRUGS studies are typically considered

Phase IV studies. For device studies, • Synthesis and Puriﬁcation • Phase 1 the requirement for long-term data • Toxicology/Lab Testing • Phase 2 Fast Track Phase 4 MedWatch • Animal Testing • Phase 3 is generally satisfied with a post- approval study. Source: FDA IND NDA REVIEW DECISION

Pre-Clinical Clinical Review Post-Market

IDE PMA REVIEW DECISION

MOLECULAR • Device Development • FIH DISEASE and Bench Testing • Early Feasibility Expedited Access Post Approval Study • Biocompatibility • Feasibility 522 Study • Animal Testing • Pivotal MDR • Sterility and Manufacturing

CLASS III DEVICES

Conclusion Bringing new medical devices to market is about more than breakthrough technology or innovative design. It also requires the application of a rigorous clinical investigation process, as well as in-depth knowledge of the requirements of regulators regarding such studies. Adherence to GCP principles, including adequate HSP, is universally recognized as a critical requirement to the conduct of research involving human subjects.

Finally, for those readers who are interested, more than double the number of IDEs were submitted in 2017 compared to 2014, a sign that critical clinical research of innovative new medical devices is returning to the United States, according to the FDA. The agency credits this increase from 26 to 57 submissions to the success of its Early Feasibility Studies (EFS) Program.

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“Ten years ago, when medical device manufacturers wanted to gain early clinical experience with their new devices, they often went overseas to conduct first-in- human or small clinical studies,” according to the CDRH.xxxiv The EFS Program, which was finalized in 2013, promotes collaboration, regulatory flexibility, and consideration of benefit-risk principles. The EFS is a limited clinical investigation of a device early in development and typically: enrolls a small number of subjects; is used to evaluate the device design concept with respect to initial clinical safety and device functionality; and may guide device modifications.

References (i) FDA Premarket Approval website. Viewed on May 25, 2018 at: https://www. fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/ premarketsubmissions/premarketapprovalpma/ (ii) “Good Clinical Practice for Medical Device Trials,” p.1. Viewed on May 25, 2018 at: https://standardslearn.org/documents/Good_Clinical_Practice_for_Medical_ Device_Trials_rev_1.pdf (iii) Ibid (iv) ISO 14155:2011(en) – Clinical investigation of medical devices for human subjects – Good clinical practice. Viewed on May 25, 2018 at: https://www.iso.org/ obp/ui/#iso:std:iso:14155:ed-2:v1:en (v) FDA Guidance for Industry “E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1),” March 2018. Viewed on May 25, 2018 at: https://www. fda.gov/downloads/Drugs/Guidances/UCM464506.pdf (vi) FDA Guidance for Industry, Clinical Investigators, Institutional Review Boards and Food and Drug Administration Staff “Design Considerations for Pivotal Clinical Investigations for Medical Devices,” Nov. 7, 2013. Viewed on May 25, 2018 at: https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/ guidancedocuments/ucm373766.pdf (vii) Ibid, p. 4 (viii) FDA Guidance for Industry and Food and Drug Administration Staff “Adaptive Designs for Medical Device Clinical Studies,” July 27, 2016. Viewed on May 25, 2018 at: https://www.fda.gov/downloads/medicaldevices/ deviceregulationandguidance/guidancedocuments/ucm446729.pdf (ix) Ibid, p. 10. (x) Michael Mezher, “Patient Engagement in Device Trials: FDA Meeting Discusses Challenges and Opportunities,” RAPS Regulatory Focus, October 16, 2017. Viewed on May 25, 2018 at: https://www.raps.org/news-articles/news-articles/2017/10/ patient-engagement-in-device-trials-fda-meeting-discusses-challenges-and- opportunities (xi) Federal Register “Human Subject Protection; Acceptance of Data from Clinical Investigations for Medical Devices,” February 25, 2013. Viewed May 25, 2018 at: https://www.federalregister.gov/documents/2013/02/25/2013-04201/human- subject-protection-acceptance-of-data-from-clinical-studies-for-medical-devices

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(xii) FDA Guidance for Industry and Food and Drug Administration Staff “Acceptance of Clinical Data to Support Medical Device Applications and Submissions – Frequently Asked Questions,” February 26, 2018. Viewed May 25, 2018 at: https://www.fda.gov/downloads/MedicalDevices/ DeviceRegulationandGuidance/GuidanceDocuments/UCM597273.pdf (xiii) Ibid, p. 4. (xiv) CFR – Code of Federal Regulations Title 21, Part 56— Institutional Review Boards. Viewed on May 25, 2018 at: https:// www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch. cfm?CFRPart=56&showFR=1&subpartNode=21:1.0.1.1.21.3 (xv) CFR – Code of Federal Regulations Title 21, Subpart B—Informed Consent of Human Subjects. Viewed on May 25, 2018 at: https:// www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch. cfm?Part=50&showFR=1&subpartNode=21:1.0.1.1.21.3 (xvi) Federal Register “Human Subject Protection; Acceptance of Data from Clinical Investigations for Medical Devices,” February 21, 2013. Viewed May 25, 2018 at: https://www.federalregister.gov/documents/2018/02/21/2018-03244/ human-subject-protection-acceptance-of-data-from-clinical-investigations-for- medical-devices (xvii) Alexander Gaffney, RAC, “Patient Engagement in Device Trials: FDA Meeting Discusses Challenges and Opportunities,” RAPS Regulatory Focus, February 26, 2013. Viewed on May 25, 2018 at: https://www.raps.org/regulatory- focus%E2%84%A2/news-articles/2013/2/fda-proposal-would-require-all-device- trials,-regardless-of-location,-to-adhere-to-fda-regulations?feed=Regulatory- Focus (xviii) Ibid. (xvix) FDA In Brief press release, “FDA updates regulations to better define when studies run outside U.S. can support U.S. regulatory device submissions; and to improve data quality, integrity, and ensure patient safety,” February 20, 2018. Viewed on May 25, 2018 at: https://www.fda.gov/NewsEvents/Newsroom/ FDAInBrief/ucm597341.htm (xx) AdvaMed letter Re: Docket No. FDA-2015-D-0975, July 1, 2015, p. 6. Viewed on May 29, 2018 at: https://www.advamed.org/sites/default/files/ resource/942_7_1_2015_advamed_comments_re_fda_2015_d_0975_ acceptance_of_ous_medical_device_clinical_data.pdf (xxi) Ibid, p.7 (xxii) Federal Register, Vol. 83, No. 35, February 21, 2018, p. 7366. Viewed on May 29, 2018 at: https://www.gpo.gov/fdsys/pkg/FR-2018-02-21/pdf/2018-03244.pdf (xxiii) FDA Guidance for Industry and Food and Drug Administration Staff “Acceptance of Clinical Data to Support Medical Device Applications and Submissions – Frequently Asked Questions,” February 26, 2018. Viewed May 25, 2018 at: https://www.fda.gov/downloads/MedicalDevices/ DeviceRegulationandGuidance/GuidanceDocuments/UCM597273.pdf

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(xxiv) ICH Harmonised Guideline “Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2), June 11, 2015. Viewed on May 29, 2018 at: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/ Efficacy/E6/E6_R2__Addendum_Step2.pdf (xxv) FDA Early Feasibility Studies (EFS) Program website. Viewed on May 25, 2018 at: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/ Guidelines/Efficacy/E6/E6_R2__Addendum_Step2.pdf (xxvi) Maureen L. Dreher, Ph.D., Andrew Farb, M.D., and Owen Faris, PhD., “Bringing Early Feasibility Studies for Medical Devices Back to the United States,” FDA Voice blog, December 12, 2017. Viewed on May 29, 2018 at: https://blogs.fda.gov/ fdavoice/index.php/tag/early-feasibility-studies-efs/ (xxvii) Ibid. (xxviii) Ibid. (xxix) Joshua P. Rising and Ben Moscovitch, “Characteristics of Pivotal Trials and FDA Review of Innovative Devices,” PLoS One, February 4, 2015. Viewed on May 29, 2018 at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317185/ (xxx) UL LLC White Paper “Medical Device Clinical Investigations and ISO 14155,” 2017. Viewed on May 29, 2018 at: https://library.ul.com/wp-content/uploads/ sites/40/2017/09/10484_White-Paper-Web_090517-1-1.pdf (xxxi) FDA Guidance for Industry, and Food and Drug Administration Staff, Sponsors, and Institutional Review Boards, “Investigational IVDs Used in Clinical Investigations of Therapeutic Products,” December 18, 2017. Viewed May 29, 2018 at: https://www.fda.gov/downloads/MedicalDevices/ DeviceRegulationandGuidance/GuidanceDocuments/UCM589083.pdf (xxxii) FDA Draft Guidance for Industry, “Use of Electronic Health Record Data in Clinical Investigations,” May 2016. Viewed May 29, 2018 at: https://www.fda. gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM501068.pdf (xxxiii) ISO 14155:2011 Standard “Clinical investigation of medical devices for human subjects -- Good clinical practice,” February 2011. Viewed May 29, 2018 at: https://www.iso.org/standard/45557.html (xxxiv) Maureen L. Dreher, Ph.D., Andrew Farb, M.D., and Owen Faris, PhD., “Bringing Early Feasibility Studies for Medical Devices Back to the United States,” FDA Voice blog, December 12, 2017. Viewed on May 29, 2018 at: https://blogs.fda. gov/fdavoice/index.php/tag/early-feasibility-studies-efs/

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