Institute of Medicine Report Medical Devices and the Public’s Health: The FDA 510(k) Clearance Process at 35 Years

Today, the Institute of Medicine (IOM) Committee on the Public Health Effectiveness of the FDA 510(k) Clearance Process released its long awaited, 245-page report, entitled, “Medical Devices and the Public’s Health The FDA 510(k) Clearance Process at 35 Years.”

The premarket notification, or the 510(k) clearance process, named after Section 510(k) of the authorizing legislation passed by Congress in 1976, is the primary pathway to market for Class II devices. More than 80% of 510(k)-cleared devices are categorized as Class II device types. Some Class I and Class III device types also are cleared through the 510(k) process.

The report and recommendations are focused on strengthening the science base needed to make better-informed regulatory decisions and on giving FDA the tools that it needs to identify and remove problematic devices from the market. The committee believes that taking the recommended steps will generate the information needed to design a robust regulatory framework for Class II devices. The new framework would increase the public’s confidence that safe and effective medical devices are being made available in a timely manner.

As described below, the IOM report on the 510(k) process contains broad recommendations that may have significant consequences and impacts on the medical device industry.  Specifically, IOM concluded that the 510(k) process “cannot be transformed into a premarket evaluation of safety and effectiveness as long as the standard for clearance is substantial equivalence to any previously cleared device” and that “the 510(k) clearance process is not intended to evaluate the safety and effectiveness of medical devices with some exceptions.”

Moreover, the report asserts that, FDA’s finite resources would be better invested in developing a new framework that uses both premarket clearance and improved postmarket surveillance of device performance to provide reasonable assurance of the safety and effectiveness of Class II devices throughout the duration of their use, the committee said.  The report also maintains that FDA should ensure that the new process allows devices to reach the market in as rapid and least burdensome a fashion as possible. 

“It’s not clear that the 510(k) process is serving the needs of either industry or patients, and simply modifying it again will not help,” said committee chair David Challoner, emeritus vice president for health affairs, University of Florida, Gainesville.  “The 510(k) process cannot achieve its stated goals — to promote innovation and make safe, effective devices available to patients in a timely manner — because they are fundamentally at odds with the statutes that govern how FDA must implement the process.  While current information is not adequate to immediately start designing a new framework, we believe the agency can get the necessary data and establish a new process within a reasonable time frame.”

As we noted yesterday, there is legal concern mounting already about the composition of the IOM committee as it pertains to the Federal Advisory Committee Act and the lack of fair balance representation.    

Without clear evidence the committee is recommending that the 510K process of approving substantially equivalent devices be scrapped in favor of adding additional studies and potentially delaying approval of competitive devices.

Background

In September 2009, the 510(k) Working Group and the Task Force on the Utilization of Science in Regulatory Decision Making were formed to address critical challenges facing the Centers for Devices and Radiological Health (CDRH),  and external constituencies.

Industry had raised concerns that the 510(k) program had become less predictable, consistent and transparent thereby stifling innovation and sending companies and jobs overseas, and that CDRH reviewers had become less responsive and more risk averse. Jeffrey Shuren, MD, JD, Director of CDRH noted that “an unpredictable environment discourages investment and stifles innovation, which, in turn, can spur companies to go overseas.”

Consumers, third-party payers, and some healthcare professional groups were concerned that, for some devices, the 510(k) program did not provide adequate assurances of safety and effectiveness nor did it provide sufficient information for healthcare providers and patients to make well-informed treatment or diagnostic decisions. 

Several high-profile mass-media reports and consumer-protection groups have profiled recognized or potential problems with medical devices cleared through the 510(k) clearance process. The medical-device industry and some patients have asserted that the process has become too burdensome and is delaying or stalling the entry of important new medical devices to the market.

CDRH employees expressed concerns that the current 510(k) program failed to adapt to the increasing complexity of devices, and that reviewers’ ability to make well-informed decisions was undermined by the poor quality of 510(k) submissions. In addition, an increasing workload was straining an already overburdened program.  

In August 2010, FDA’s CDRH released for public comment the preliminary reports from these committees.  At the time, CDRH proposed three key changes:

• A streamlined pathway for lower-risk denovo devices;
• A new subclass (Class IIb) for moderate-risk devices; and
• The creation of an internal CDRH Science Council

In addition to these changes, CDRH asked IOM to carry out a parallel, complementary assessment of the 501k changes they proposed in their report.  Subsequently, in January 2011, CDRH released its new actions for the 510(k) program, which included:

• Streamlining the review process for innovative, lower-risk products, called the “de novo” process;
• Publishing guidance for industry to clarify when clinical data should be submitted to  increase predictability and transparency;
• Developing a network of external experts who can use their knowledge and  experience to help the agency address important scientific issues regarding new  medical device technologies;
• Establishing a new Center Science Council of senior FDA experts within the  agency’s medical device center to assure more timely and consistent science based decision making; and
• Improving training for CDRH staff and industry

The FDA also said it would:

Establish a public database of important device information, such as medical  device labeling and summaries of the basis for the FDA’s decision to clear  specific devices; and

Require a brief description of scientific information regarding the safety and effectiveness known to the manufacturer for select higher-risk devices on a case by-case basis through device-specific guidance. 

At this time, FDA also released an implementation plan that outlined 25 specific actions and the timelines for completion or reaching a major milestone in 2011 to make the 510(k) program a blueprint for smarter medical device oversight; one that drives innovation and brings important technologies to the public.    

Consequently, FDA received comments on seven of the recommendations that stakeholders found problematic. As a result, FDA asked IOM to offer comments on the following recommendations:

• CDRH should consolidate the terms “indication for use” and “intended use” into a single term, “intended use”;
• CDRH should expand its statutory authority to consider off-label use when determining the intended use of a device;
• CDRH should issue guidance on when a device should no longer be available for use as a  predicate; 
• CDRH should issue a regulation on its rescission authority;
• CDRH should require manufacturers to keep one unit of a device available;
• CDRH should issue guidance to create a “Class IIb”; and 
• CDRH should seek greater authorities to require postmarket surveillance studies as a condition of clearance for certain devices.

Specifically, FDA stated to the IOM that the goals of the 510(k) clearance process are to “make available to consumers devices that are safe and effective” and to “promote innovation in the medical device industry.”  Accordingly,  FDA asked IOM to review the 510(k) clearance process and to answer two questions:

Does the current 510(k) clearance process optimally protect patients and promote innovation in support of public health?

If not, what legislative, regulatory, or administrative changes are recommended to optimally achieve the goals of the 510(k) clearance process?

FDA and Medical Device Regulation Background

In reviewing the legislative and regulatory history of the 510(k) program, the committee found that it was designed in 1976 to provide only a determination of the substantial equivalence of a new device to an already marketed (predicate) device; it was not designed to determine whether a new device provides a reasonable assurance of safety and effectiveness or whether it promotes innovation.

Prior to the Medical Device Amendments (MDA) of 1976, medical devices generally had not undergone premarket review by FDA. The MDA created three classes of device types on the basis of the risks posed and the ability of postmarket controls to manage them. Each device type includes a number of devices.

As originally contemplated, the high-risk category (Class III) would require FDA review and approval, through the premarket approval (PMA) process, before a device could be marketed. The moderate-risk and low-risk categories (Class II and Class I, respectively) would not require as rigorous a review. Rather, device manufacturers would be required to notify the FDA at least 90 days before they marketed such a device. This premarket-notification requirement was contained in Section 510(k) of the Federal Food, Drug, and Cosmetic Act and is commonly referred to as 510(k) notification or 510(k) clearance.

A device not on the market at the time of the enactment of the MDA (a “postamendment” device) would be required to demonstrate through a 510(k) notification that it was “substantially equivalent” to a “preamendment” device and, for Class II devices, complied with the applicable performance standard promulgated by the FDA.

Congress’s interpretation of substantial equivalence, as stated in the Safe Medical Device Amendments (SMDA), is that: the term “substantially equivalent” or “substantial equivalence” means, with respect to a device being compared to a predicate device, that the device has the same intended use as the predicate device and that [FDA] by order has found that the device –

Has the same technological characteristics as the predicate device, or

Has different technological characteristics and the information submitted that the device is substantially equivalent to the predicate device contains information, including clinical data if deemed necessary by [FDA], that demonstrates that the device is as safe and effective as a legally marketed device and (II) does not raise different questions of safety and efficacy than the predicate device.

The term “different technological characteristics” means, with respect to a device being compared to a predicate device, that there is a significant change in the materials, design, energy source, or other features of the device from those of the predicate device.

If the new device were substantially equivalent, it would be cleared for marketing subject to the same terms and conditions as that preamendment device (for example, conformance to a performance standard). Postamendment devices that were not substantially equivalent to any preamendment device would be automatically placed in Class III and would require either PMA or reclassification by the FDA to Class I or Class II to enter the market.

The SDMA of 1990 permitted substantial equivalence to be established to marketed postamendment, in addition to preamendment, “predicate” devices, except for devices approved by PMA.

The Food and Drug Administration Modernization Act (FDAMA) of 1997 eliminated the requirement for 510(k) clearance for most Class I and some Class II device types, narrowed the array of issues that the FDA may consider in a 510(k) review, and directed the FDA to limit, to the “least burdensome” level, the scientific evidence requested to determine substantial equivalence of devices that involved new technologies.

In 2002, in an effort to address insufficient resources of the 510(k) and PMA programs, Congress passed legislation to create a 5-year user-fee program—the Medical Device User Fee and Modernization Act (MDUFMA). The user-fee program was renewed in 2007 for another 5 years.

IOM’s Conclusions

In a letter to CDRH Director Dr. Shuren, Dr. Challoner, Chair of the IOM Committee, noted that because of time constraints, the IOM committee was unable to study fully the seven recommendations referred to it by FDA. 

Dr. Challoner did note however, that the committee was able to address many of the broader issues related to CDRH’s 510(k) and Science Report Recommendations. The committee evaluated components of the 510(k) process and other relevant factors, including:

• The legislative history of the 510(k) program.
• The 510(k) regulatory framework that resulted from legislation.
• How the 510(k) process fits into the larger medical-device regulatory framework. (The 510(k) clearance process is an integrated component of the larger medical-device regulatory framework. The committee evaluated the 510(k) program in the context of this larger framework.)
• How the 510(k) process is implemented by the FDA.
• Available postmarket information on the safety and effectiveness of 510(k)-cleared devices.
• Other factors that affect medical-device regulation (for example, the process of innovation and the environment in which medical devices are developed and commercialized).

On the basis of its review and evaluation of legislative, regulatory, and administrative components of the 510(k) clearance process and other related components of medical-device regulation, the committee came to two major conclusions.

Conclusion 7-1 The 510(k) clearance process is not intended to evaluate the safety and effectiveness of medical devices with some exceptions. The 510(k) process cannot be transformed into a premarket evaluation of safety and effectiveness as long as the standard for clearance is substantial equivalence to any previously cleared device.

By law, the 510(k) process uses substantial equivalence to any previously cleared device as the standard for clearance with some exceptions. In practice, the assessment of substantial equivalence generally does not require evidence of safety or effectiveness of a device. According to the FDA and the Supreme Court, when the FDA finds a device substantially equivalent to a predicate device, it has done no more than find that the new device is as safe and effective as the predicate.

Importantly, devices that were on the market before the enactment of the 1976 MDA—the origin of all predicate devices for the 510(k) process—have never been systematically assessed to determine their safety and effectiveness. Because the preamendment device to which equivalence was established was not itself reviewed for safety or effectiveness, the committee found that clearance of a 510(k) submission was not a determination that the cleared device was safe or effective.

The 1990 SMDA permitted the FDA to require evidence of safety and effectiveness, including clinical studies, when necessary to determine whether a difference in technologic characteristics between a new device and its predicate renders the new device less safe or effective than the predicate or raises different questions of safety and effectiveness from the predicate.

If, despite the change in technologic characteristics, the new device is as safe and effective as the predicate, it will be found substantially equivalent. Nearly all 510(k) submissions for devices that have new technologic characteristics receive a determination of substantial equivalence.

The committee found that available information on postmarket performance of devices does not provide sufficient information about potential harm or lack of effectiveness to be a useful source of data on the safety and effectiveness of marketed devices.

The committee did not believe, however, that there is a public-health crisis related to unsafe or ineffective medical devices. Although the safety and effectiveness of preamendment Class II devices have not been systematically reviewed, their continued use in clinical practice provides at least a level of confidence in their safety and effectiveness.

Conclusion 7-2 Information that would allow an understanding of the extent to which the 510(k) clearance process either facilitates or inhibits innovation does not exist.

The committee noted that it is not necessary for a Class II device to be demonstrated to be innovative to be cleared for marketing. The FDA should not be the arbitrator of what constitutes innovation, nor should it seek to channel device development and premarket review toward agency-determined public-health priorities.

Accordingly, the committed noted that FDA’s role in facilitating innovation in Class II medical devices through premarket review should be to create a regulatory framework that sets appropriate thresholds for bringing products to the market. Those thresholds should be stringent enough to satisfy the agency’s objective of ensuring that marketed medical devices will be safe and effective throughout their life cycles but realistic enough to permit timely entry of new devices that may offer improvements over already marketed devices. Rather than be charged with promoting innovation, the committee believes that the FDA should seek to facilitate it.

To assess how innovation is affected by medical-device regulation, the committee studied the legislative history and implementation of the 510(k) process. It is unclear—and the committee argues that it is indeterminable, given current data—whether legislative, regulatory, and administrative changes over the last 35 years have had a positive or negative effect on innovation.

The committee noted that while FDA has procedures for developing, adopting, and implementing guidance and standards, the agency however, is persistently hindered in fully developing those materials by a lack of or limitations on human, fiscal, and technologic resources and capabilities. IOM acknowledged that the lack of clear guidance affects the timeliness and consistency of 510(k) device submissions provided by industry and the ability of reviewers to evaluate them.

RECOMMENDATIONS

CDRH’s proposed recommendations 1–3 are related to FDA’s postmarket authorities for medical devices. As stated in its report, the IOM committee found that the FDA has a broad array of tools available to address safety concerns in the postmarket period but that the agency does not use these tools extensively. However, IOM asserted that FDA has not adequately explained the limitations of the tools and why it has not used them more widely.

 As a result, the IOM committee recommended in its report that the FDA identify the limitations of its current regulatory tools and seek to address the limitations.

The IOM committee supports the concept of allowing conditional clearance based on postmarket surveillance in appropriate cases and has suggested this option as a potential component of a modified de novo process.

CDRH’s proposed recommendations 4–7 are related to FDA’s authorities for the 510(k) program. The IOM committee’s report concludes that the 510(k) process generally is not intended to evaluate the safety and effectiveness of medical devices and, furthermore, cannot be transformed into a premarket evaluation of safety and effectiveness. The report’s recommendations are focused not on making improvements in the 510(k) process but rather on the steps needed to develop a more rational medical-device regulatory framework.

The IOM committee does not believe that the FDA should use its sparse resources to modify the 510(k) clearance process. Instead, it believes that the FDA’s resources would be put to better use in obtaining information needed to develop a new regulatory framework for Class II medical devices and addressing problems with other components of the medical-device regulatory framework.

The committee recognized that scarce resources in the FDA could affect its ability to implement the recommendations and, therefore, has directed the recommendations toward activities that are useful in both the short term and the long term to conserve scarce resources.

With regard specifically to CDRH’s proposed recommendation 5, the IOM committee’s report includes an extensive discussion of issues related to the lack of clarity in the phrases intended use and indications for use. It is not clear to the IOM committee how combining these regulatory phrases would lead to more consistency and transparency.

Designing a New Medical Device Regulatory Framework

Recommendation 7-1 FDA should obtain adequate information to inform the design of a new medical-device regulatory framework for Class II devices so that the current 510(k) process, in which the standard for clearance is substantial equivalence to previously cleared devices, can be replaced with an integrated premarket and postmarket regulatory framework that effectively provides a reasonable assurance of safety and effectiveness throughout the device life cycle. Once adequate information is available to design an appropriate medical-device regulatory framework, Congress should enact legislation to do so.

The committee believes that a move away from the 510(k) clearance process should occur as soon as reasonably possible but recognizes that it will take time to obtain the information needed to design the new framework.

The new regulatory framework must be based on sound science and be developed in harmony with other components of the FDA’s medical-device regulatory system. The committee does not believe that available information is adequate to inform the design of an appropriate framework.

On the basis of its findings, the committee identified several topics to which the FDA should give particular consideration as it develops a new framework. A number of existing and emerging technologies (for example, combination products, software, nanotechnology, and medical robotics) merit detailed thought as part of the development of the new framework.

The committee stated that the FDA should consider integrating some elements of the quality-system regulations, especially those related to design controls and product-release criteria, into the premarket review process of the new framework to demonstrate that devices will perform as represented by their manufacturers. The FDA should also consider, as part of the new framework, including a more extensive review of device labeling and a system of tracking of labeling changes.

The committee urged FDA to create a regulatory framework that closely matches the ideal regulatory framework outlined by the committee:

• The process should be based on sound science.
• The process should be clear, predictable, straightforward, and fair.
• The process should be self-sustaining and self-improving.
• The process should facilitate innovation that improves public health by making medical devices available in a timely manner and ensuring their safety and effectiveness throughout their lifecycle.
• The process should apply relevant and appropriate regulatory authorities and standards throughout the life cycle of devices to ensure safety and effectiveness.
• The process should be risk-based.

Postmarketing Surveillance

The committee found substantial weakness in postmarketing surveillance of medical devices. The inadequate postmarketing surveillance systems, both those in the FDA and those that are privately funded, and the resulting lack of useful, consistent, and reliable data make it impossible to draw confident conclusions about the performance of medical devices that are now on the market.

Recommendation 7-2 FDA should develop and implement a comprehensive strategy to collect, analyze, and act on medical-device postmarket performance information.

IOM recommended that FDA give priority to postmarketing surveillance as an invaluable investment in short-term and long-term oversight of medical-device safety and assessment of device effectiveness. They stated that Congress should support the capacity of the FDA’s postmarketing surveillance programs by providing stable and adequate funding.

In particular, the committee noted that FDA should develop a postmarketing surveillance strategy to meet the following objectives: providing performance information for use in the premarket review process, informing the development and use of postmarketing tools (that is, general and special controls2) to manage the risk-benefit ratio throughout the life cycle of devices better, and informing the design of a new regulatory framework.

Postmarket Regulatory Authorities

The FDA reports that there are “important limitations” on the use of postmarket authorities, but does not describe them. The committee identified the procedural requirements that the FDA must fulfill to exercise the authorities, but the requirements do not in themselves appear to explain the agency’s perception that there are limitations on its use of postmarket tools.

Recommendation 7-3 The Food and Drug Administration should review its postmarket regulatory authorities for medical devices to identify existing limitations on their use and to determine how the limitations can be addressed.

IOM stated that FDA should analyze barriers to efficient and effective use of the authorities and identify means of mitigating them. If it is required, Congress should pass legislation to remove unnecessary barriers to the FDA’s use of postmarket regulatory authorities.

A Modified De Novo Process

The de novo process is a mechanism by which the FDA can down-classify, to Class I or Class II, devices that have no predicates but are deemed to be of low to moderate risk. The process avoids having novel, low- to moderate-risk devices go through the PMA process. In the de novo process, a 510(k) submission for the device is sent to the FDA, which issues a determination of “not substantially equivalent” and indicates to the applicant that the device may be eligible for the de novo process. Special controls generally need to be developed for the device. The general and special controls must be sufficient to provide reasonable assurance of safety and effectiveness.

IOM stated that the de novo process offers a potential basis of a better regulatory model for premarket review of Class II devices. In its current state, however, the de novo process is time-consuming and difficult for both the FDA and manufacturers to navigate.

Recommendation 7-4 The Food and Drug Administration should investigate the viability of a modified de novo process as a mechanism for evaluating the safety and effectiveness of Class II devices.

A pilot program of a modified de novo process would allow the FDA to determine its feasibility as a replacement for the 510(k) clearance process. As part of a modified de novo process, IOM recommended that the FDA explore ways to expedite development of special controls, develop guidance, and adopt standards for devices. The agency also should consider expanded use of external expertise and preinvestigational device-exemption meetings with submitters and use of conditional clearances (such as postmarketing surveillance or use of registries) for devices on which there is little premarket performance information.

A Continuous Quality-Improvement Program

The committee assessed that the FDA lacks a continuous quality-assurance process for regulation of medical devices. As a result, the FDA cannot effectively address new issues as they arise.

Recommendation 7-5 The Food and Drug Administration should develop and implement a program of continuous quality-improvement to track regulatory decisions on medical devices, identify potential process improvements in the medical device regulatory framework, and address emerging issues that affect decision-making.

The committee found evidence that the inadequate information technology and management infrastructure in the FDA affects not only the 510(k) program but the agency’s other programs for regulating medical devices. For example, because data systems are inadequate, the FDA does not have the ability to trace the history of 510(k) decisions. Prior 510(k) clearances are legally binding on the FDA when making 510(k)-clearance decisions.

Thus, any unsafe or ineffective devices are embedded in the system and as both a legal and a practical matter may be used as predicates for new devices until the predicates are removed from the market. It may be difficult for the FDA to remove devices from the market because it has no systematic way to identify them. By developing a business model grounded in continuous quality improvement, the FDA will be better able to identify problems with devices and develop the information and capacity to address them in a data-driven, transparent manner.

Facilitating Innovation in the Medical Device Industry

The FDA’s role in facilitating innovation with respect to Class II devices is to create and enforce a regulatory framework for which the threshold to market provides reasonable assurance that medical devices are safe and effective throughout their life cycle while permitting timely entry of new devices that may offer improvements over already marketed devices. The committee did not find assessments of how much and in what way (that is, facilitating or inhibiting) innovation is influenced by the 510(k) clearance process.

Recommendation 7-6 FDA should commission an assessment to determine the effect of its regulatory process for Class II devices on facilitating or inhibiting innovation in the medical-device industry.

The recommended study should include various ways to measure innovation beyond “time to market” or the number of devices of a particular type on the market and instead focus on a broader understanding of the relationship among regulation, innovation, and patient health and safety throughout device life cycle.

Software

Manufacturers are increasingly using software in devices, software as devices, and software as a tool in producing devices. The committee found that current guidance on software validation is insufficient for preventing serious software-based device failures.

Recommendation 7-7 FDA should develop procedures that ensure the safety and effectiveness of software used in devices, software used as devices, and software used as a tool in producing devices.

The FDA should develop a better understanding of the roles of software in medical devices, analyze its potential effects on the safety and effectiveness of the devices, and insist on evidence-based procedures that ensure device safety and effectiveness. The committee believes that the FDA should review and update its guidance on software validation.

Preamendment 510(k)-Eligible Class III Devices

After 35 years, the FDA has not completed the task of calling for PMAs for or reclassifying preamendment Class III device types. Until the FDA completes that task, those devices are allowed to enter the market through the 510(k) clearance process. Congress in 1990 directed the FDA to complete this task in a timely manner. Twenty-six Class III device types remain eligible to enter the market through the 510(k) process.

The FDA has begun a five-step process to require PMAs or to down-classify those device types. As of April 2011, the FDA had assessed the risks and benefits associated with 21 device types (step 2 of the process) and had received and reviewed public comments on five device types (step 4 of the process). The agency has not issued final rules requiring PMAs or reclassifying the devices for any of the 26 device types. The committee recognizes the resource constraints that have prolonged the process, but it nevertheless urges the FDA to give high priority to completing the task.

Recommendation 7-8 FDA should promptly call for PMA applications for or reclassify Class III devices that remain eligible for 510(k) clearance.

This recommendation though not explained in the report will potentially add years to the approval of several important devices.

Discussion

Overall the recommendations are broad and in many places of the report vague.  It is disappointing that rather than answer the questions that the FDA asked to be answered the committee for the most part went down a road of strategic vs. tactical recommendations.   Not only did they not answer the questions they focused on the legislative history of the FDA and the 510K clearance.

What this report does is require that all class II devices that are substantially equivalent will now have to go through extensive studies and additional approval process.  It is not clear that there is evidence to make these recommendations.

Much of this as previously noted can be accounted for by the lack of inventor and industry representation on the committee.   You can clearly tell from reading the report the complete lack of understanding of current 510K approval process or have spent time filing a 510K.

The report does recognize the vast majority of device manufactures are small businesses with 50 or fewer employees and “Delays during any of those phases (regulatory and insurance reimbursement) extends the “burn rate” of capital (that is, the amount of funds spent in a given period) and can create financial difficulties for companies, particularly startup companies, which often have limited financial resources”. 

Throwing out the 510K process in favor of a more rigorous review process in the absence of evidence that there is an unacceptable risk posed by current class II devices has the potential to cause considerably more harm than good.  It was clear given this restraint that additional regulations especially in the pre-market arena will result in vastly fewer devices coming to market.  This result will help neither inventors nor patients.