"The Evolution of Medical Device Clinical Trials, Part 2"

Note: This is the second of a two-part series that explores regulatory and compliance specialist David R. Dills’ analysis of the state of medical device regulations, clinical investigation trends and medical devices’ unique regulatory challenges. Part 1 can be read here.

The conclusion of this blog series on the dynamic world of medical device clinical trials focuses on the contemporary clinical landscape’s six core areas of greatest significance:

• The vital importance of regulatory data consistency
• The criticality of robust clinical evidence
• Adapting to the transforming clinical investigations environment
• Modernized approaches to medical device clinical investigations
• The state of regulatory compliance
• Visualizing the future of medical device clinical trials

Regulatory Data Consistency: The Engine That Drives the Clinical Machine

The U.S. Food and Drug Administration’s (FDA) Human Subject Protection: Acceptance of Data from Clinical Studies for Medical Devices FAQ guidance was developed with the intent of promoting global uniformity in clinical trial data while assuring satisfactory protections for human subject participants. According to the final rule cited in the Federal Register, the agency ""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."" Spurred by troubling inconsistencies in data reported from studies conducted inside the U.S. versus those from other regions, the proposed rule was initially devised to update the standards for FDA acceptance of data from clinical studies conducted outside the U.S.

The amended requirements for FDA acceptance of clinical data collected outside the U.S. in support of medical device submissions go into effect Feb. 21, 2019. As of that effective date, acceptable data from device trials must be collected in compliance with the guidelines set forth in the ISO 14155:2011 standard (the primary, globally recognized regulatory pathway for taking a device through clinical trials, as discussed in the first part of this blog series). Since ISO 14155 compliance is already required in most jurisdictions, the final amended rules are not expected to be particularly disruptive to medical device manufacturers.

Consistency in medical device clinical trial data is primarily imperative because regulatory standards continue to evolve. Many standards are now extending far beyond those set forth in the Helsinki Declaration, the cornerstone document that defines ethical principles regarding human experimentation that was last amended by the World Medical Association (WMA) in 2013. The deliberate development of good clinical practice (GCP) recommendations continues to be championed by globally engaged agencies like the World Health Organization (WHO), the International Standards Organization (ISO), the International Conference on Harmonization (ICH) and others. As a vital response to these ongoing refinements to clinical practices, the FDA’s final rule on clinical data acceptance is expected to provide consistency in medical device clinical trial data, regardless of application or submission type.

The Necessity of Robust Clinical Evidence

Extensive clinical evidence is the most indispensable component of a medical device’s eventual marketing approval, practitioner adoption and safe use. Yet the paths for expediently collecting clinical data in support of medical device approvals are as diverse as the types of devices themselves. And, to complicate matters for device makers seeking to market products in the U.S., the amount of clinical data to be collected and the size of clinical studies to be conducted must be greater in the U.S. than in other regions if the FDA’s safety and effectiveness assurance requirements are to be satisfied.

Despite these complexities, there are benefits to collecting comprehensive data for devices that are unobtainable in other clinical investigation settings:

• So-called “gold standard” trials are often not practical or necessary for many medical devices, so the FDA commonly works with sponsors to tailor trial designs to the specific technology involved, the medical need being addressed, the feasibility of data collection, and the benefits/risks to affected patients.
• Many devices are developed to address unmet needs, which means that a greater degree of uncertainty is often permissible. (This is the concept at the core of the FDA’s Expedited Access Pathway (EAP) for “breakthrough” devices.)
• Existing useable data may already be available from other sources.

To improve the likelihood that data gathered in clinical trials is truly helpful in assessing patient needs, greater advancements are necessary in the area of patient input. So, as part of its increased focus on patient inclinations and input and on making more informed device-approval decisions, the FDA is collaborating with patient groups and other organizations to promote the evaluation of patient preferences regarding the benefits and acceptability of risks of a variety of devices.

Notwithstanding the FDA’s continued efforts to inspire designs that ensure trials are robust, reasonable and efficient, more data on devices’ benefit-risk profiles (compared with available alternatives) is still needed, as is a deeper understanding of devices based on more patient exposure in clinical practice. Compiling such sophisticated evidence can drastically delay patient access, so it’s essential that other stakeholders (i.e., practitioner communities and the wider industry) support such measures and provide additional evidence in the form of separate trials, registries or analyses of health record data.

The establishment of a global medical device evaluation system (through strategic investments, international collaboration or other catalytic measures) could help ensure that appropriate data collection continues throughout a medical device’s life cycle as part of a continually optimizing health care system. A globally recognized evaluation mechanism could empower patients and practitioners to be more informed about how to best use new technologies to support improved patient health and quality of life.  

Making Adaptations to a Dynamic Clinical Environment

Clinical trials continue to make the transition from aggregated processes that formerly were largely paper-based to much more complex and technologically sophisticated undertakings. As this evolution progresses, the regulatory landscape also adjusts to keep pace with the rapidly changing medical device development field. The ICH E6 (R2) GCP Guideline that became final in 2016, for instance, was devised to address the increasing scale and cost of medical device clinical trials and to take into consideration the advances that have been made in electronic data recording and reporting technologies.

Another example of regulatory agencies keeping abreast with the ever-progressing world of clinical trials is the FDA’s Early Feasibility Studies (EFS) program, which is intended to catalyze limited clinical investigations of devices that are in early development. The program was conceived to promote early feasibility studies of devices in the U.S. in order to support device innovation and increase patient access to potentially beneficial technologies. It provides a route for innovators, sponsors, clinicians and regulatory review teams to collaborate and presumably stimulate regulatory flexibility without jeopardizing adequate patient protection measures.

Typically, EFS studies:

• Enroll a small number of subjects
• Direct device modification
• Are used to evaluate design concepts in terms of their functionality and initial clinical safety

Indications from the FDA testify that medical device manufacturers are hungry for innovative programs like EFS. The agency claims the number of Investigational Device Exemptions (IDEs) submitted for EFS more than doubled in the first year following the finalization of the EFS guidance document in fiscal year 2017. This trend will have a considerable impact on smaller device manufacturers especially, since approximately half of EFS IDEs are submitted by small companies that depend on early clinical experience for securing financial resources.

Alternative Approaches to Device Trials

The mounting costs and time-consuming nature of clinical trials, among other pressing factors, are pushing many device companies to explore new approaches to clinical investigations, such as:

• Employing third-party contract research organizations (CROs) that offer deep knowledge and experience in conducting clinical investigations for devices. CROs often specialize in leveraging specific technology investments or unique methodologies, which makes them particularly appealing to device companies looking to revamp and/or streamline traditionally labor-intensive processes.
• Conducting clinical investigations outside the U.S. where expenses can be considerably reduced.

As the medical device industry flourishes on a global scale, clinical research is becoming increasingly essential to the assessment of the safety and effectiveness of devices in development or already on the worldwide market. This explosive growth necessitates new options for undertaking clinical trials. One such alternative approach is the FDA’s aforementioned EAP (or “Breakthrough Devices”) program, which recognizes that, for some new technologies geared toward addressing unmet medical needs, it may be appropriate to accept a greater degree of uncertainty in order to expedite a device’s availability to patients. Devices that embark on this alternative route to approval are required to rely heavily on postmarket data to provide the utmost certainty about their safety and effectiveness, and extensively evaluate potential risks that are not identified in premarket assessments.

The State of Compliance Moving Forward

The medical device industry has continued to experience a constructive global transformation since the FDA’s 2013 mandate that all device trials must be compliant with GCP rules similar to those for drugs/biologics. Given that such changes to the regulatory landscape have worldwide ramifications, it’s inevitable that medical device developers will increasingly be obligated to amplify their global approach.

Perhaps the greatest example of the medical device industry’s proliferation is the broader global adoption and integration of ISO 14155. The International Medical Device Regulators Forum (IMDRF) reports that regulators in an increasing number of major markets (like the EU, Japan, Brazil and Australia) are accepting data for medical device clinical investigations conducted in accordance with ISO 14155:2011 or equivalent requirements.

Many are hailing the FDA’s recognition of ISO 14155:2011 as the standard’s automatic confirmation as the definitive GCP for medical device trials conducted anywhere in the world. As ISO 14155 continues its march toward wider acceptance, however, it is critical to understand that there are nuanced differences between the standard and the GCP principles by which all medical device clinical investigations must abide for FDA approval. And, while ISO 14155:2011 more closely aligns with GCP principles than prior versions of the standard, there are important areas where FDA requirements based on GCP are more stringent than comparable requirements set forth in ISO 14155. Furthermore, in addition to the FDA’s GCP requirements, developers must also be mindful that individual national regulators may also impose additional requirements related to clinical trials beyond those found in ISO 14155. As a contingency measure to bridge any regulatory gaps, many countries have adopted GCP principles as laws and/or regulations.

Whether a device trial is conducted inside or outside the U.S., data from clinical trials will only be accepted by the FDA if the trials are conducted after getting Institutional Review Board (IRB) or International Electrotechnical Commission (IEC) approval. Also, the FDA must be able to verify via audit that each clinical trial includes informed consent from all participants prior to their involvement in a study.

The FDA encourages device developers to discuss their planned study designs with the agency using  its pre-submission process. This avenue provides device companies the opportunity to affirm their study design choices and identify specific concerns prior to commencing their trials.

The Future of the Medical Device Clinical Landscape

The point of convergence between technological innovation and potential patient benefits — as exemplified by the debut of programs like EFS — is emerging as the critical fulcrum of the regulatory approval process for medical devices. That the FDA attributes the remarkable increase in the number of IDE submissions to the EFS program is indicative that the industry — and the world as a whole — has a powerful appetite for the kinds of innovative medical devices that critical clinical research can yield. The medical device world is watching with enthusiastic anticipation to see if regulatory agencies will continue to foster the upsurge in regulatory flexibility and collaboration along with their deeper consideration of benefit-risk principles.